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Archive for the ‘Myelofibrosis’ Category


Erythropoietin

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 Erythropoietin test

The erythropoietin test measures the amount of a hormone called erythropoietin (EPO) in blood.

The hormone tells stem cells in the bone marrow to make more red blood cells. EPO is made by cells in the kidney. These cells release more EPO when blood oxygen levels are low.

https://www.nlm.nih.gov/medlineplus/ency/article/003683.htm

The Story of Erythropoietin

Millions of patients worldwide have benefited from research on erythropoietin spanning many decades. In the last 15 years, epoetin alfa (Epo) has become one of the most widely used drugs created through recombinant DNA technology, in which a nearly identical form of a substance that naturally occurs in the body – in this case, erythropoietin – is created by replicating human DNA in a laboratory. Epo is used to treat anemia, a shortage of red blood cells. Since red blood cells carry oxygen to the tissues and organs, anemia causes symptoms such as weakness, fatigue, and shortness of breath. Epo treats this condition by imitating the action of the hormone erythropoietin, stimulating the body to produce more red blood cells. Patients who may benefit from Epo therapy include those with chronic kidney disease, those who are anemic from AIDS or from a wide variety of hematologic disorders (including multiple myeloma and myelodysplastic syndromes), and some cancer patients who are anemic from receiving chemotherapy. In selected patients, Epo may be used to reduce the need for blood transfusions in surgery.

A century ago, two French investigators reported that small amounts of plasma from anemic rabbits injected into normal animals caused an increase in red blood cell production (erythropoiesis) within a few hours. They referred to this activity as hemopoietine. Over time, as investigators became more convinced that this red-blood-cell stimulating activity was caused by a single protein in the blood plasma, they gave it a variety of names – erythropoietic-stimulating activity, erythropoietic-stimulating factor, and, ultimately, “erythropoietin.”

It wasn’t until the 1950s and ’60s that several American investigators again took up the concept that a hormone regulated red cell production. Refining the work of the French scientists, the American investigators conclusively showed that a hormone stimulated red cell production, that the kidneys were the primary source of erythropoietin, and that low oxygen was the main driver of erythropoietin production. Soon, researchers found that patients with anemia responded by increasing their levels of erythropoietin to stimulate increased red blood cell production. Patients who required an increase in red blood cells in order to make up for low oxygen levels in the blood (such as patients with lung disease or patients living at high altitudes) also had elevated erythropoietin levels.

At the same time, other technologies were being developed that set the stage for a remarkable breakthrough involving a combination of medical and molecular engineering. In the early 1960s came the development of hemodialysis, a method of removing waste products from the blood when the kidneys are unable to perform this function, to sustain the lives of patients with end-stage kidney disease. As a result of this treatment advance, these patients were able to survive the underlying disease, but their damaged kidneys could no longer make erythropoietin, leaving them severely anemic and in desperate need of Epo therapy.

In 1983, scientists discovered a method for mass producing a synthetic version of the hormone. Experiments were conducted to test the safety and effectiveness of the new drug, Epo, for treating anemia in patients with kidney failure. The results of these early clinical trials were dramatic. Patients who had been dependent on frequent blood transfusions were able to increase their red blood cell levels to near-normal within just a few weeks of starting therapy. Patients’ appetites returned, and they resumed their active lives. It was the convergence of two technologies – long-term dialysis and molecular biology – that set the stage for anemia management in this group of patients. Since then, millions of patients worldwide have benefited from Epo therapy.

This article was published in December 2008 as part of the special ASH anniversary brochure,50 Years in Hematology: Research That Revolutionized Patient Care.

http://www.hematology.org/About/History/50-Years/1532.aspx

Erythropoietin Stimulating Agents

https://my.clevelandclinic.org/health/diseases_conditions/hic_Anemia/hic_erythropoietin-stimulating_agents

What is erythropoietin?

Red blood cells are produced in the bone marrow (the spongy tissue inside the bone). In order to make red blood cells, the body maintains an adequate supply of erythropoietin (EPO), a hormone that is produced by the kidney.

EPO helps make red blood cells. Having more red blood cells raises your hemoglobin levels. Hemoglobin is the protein in red blood cells that helps blood carry oxygen throughout the body.

Anemia is a disorder that occurs when there is not enough hemoglobin in a person’s blood. There are several different causes of anemia. For instance, anemia can be caused by the body’s inability to produce enough EPO to make red blood cells. If this is the case, the person may have to have a blood transfusion to treat this type of anemia. If you have anemia, your physician can determine the cause.

What is recombinant erythropoietin?

In cases where transfusions are not an option—for example, when the patient cannot have, or refuses, a transfusion—it may be necessary to give the patient recombinant erythropoietin. Recombinant erythropoietin is a man-made version of natural erythropoietin. It is produced by cloning the gene for erythropoietin.

Recombinant erythropoietin drugs are known as erythropoietin-stimulating agents (ESAs). These drugs are given by injection (shot) and work by stimulating the production of more red blood cells. These cells are then released from the bone marrow into the bloodstream.

There are two ESAs on the U.S. market: epoetin alfa (Procrit,® Epogen®), and darbepoietin alfa (Aranesp®).

Who receives ESAs?

ESAs are usually given to patients who have chronic (long-lasting) kidney disease or end-stage renal (kidney) disease. These patients usually have lower hemoglobin levels because they can’t produce enough erythropoietin.

ESAs are also prescribed for patients who have cancer. These patients often have anemia, which can be caused by chemotherapy.

What are the side effects of ESAs?

The side effects that occur most often with ESA use include:

  • High blood pressure
  • Swelling
  • Fever
  • Dizziness
  • Nausea
  • Pain at the site of the injection.

What should the patient consider before using ESAs?

There are several safety issues with ESAs:

  • ESAs increase the risk of venous thromboembolism (blood clots in the veins). A blood clot can break away from one location and travel to the lung (pulmonary embolism), where it can block circulation. Symptoms of blood clots include chest pain, shortness of breath, pain in the legs, and sudden numbness or weakness in the face, arm, or leg.
  • ESAs can cause hemoglobin to rise too high, which puts the patient at higher risk for heart attack, stroke, heart failure, and death.
  • In patients who have cancer, ESAs may cause the tumor to grow. If ESAs are used for these patients, they are usually stopped after the patient’s chemotherapy is finished.
  • The health care provider will keep an eye on the patient’s blood cell counts to make sure they do not put him or her at a higher risk. The dosing may change, depending on the patient’s needs.

Patients who have the following conditions need to consult with their health care provider if an ESA is being considered as part of the treatment plan:

  • Heart disease
  • High blood pressure
  • Porphyria (a group of diseases that are caused by enzyme deficiencies)
  • Seizures
  • An allergy to epoetin alfa or any other part of this medicine
  • Uncontrolled high blood pressure

In addition, women who are pregnant, planning to become pregnant, or breastfeeding should consult with their health care provider before taking an ESA.

Other issues to consider:

  • Transfusions may improve symptoms of anemia right away. ESAs may take from weeks to months to provide noticeable relief of the symptoms of anemia.
  • If a patient has several transfusions, he or she can develop an “iron overload,” or high iron levels. This is a serious medical problem.
  • Iron supplements are often needed for patients who are on ESAs.
  • Keep your health care provider informed about any change in your condition.
  • Check your blood pressure and heart rate as recommended by your health care provider.
  • Remain informed about the results from any blood work that is done.
  • The body may develop antibodies to an ESA. If this happens, the antibodies will block or lessen the body’s ability to make red blood cells. This could result in an anemia. It is important that the patient keep the health care provider informed of any unusual tiredness, lack of energy, dizziness, or fainting.

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Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle


Metabolic Genomics and Pharmaceutics, Vol. 1 of BioMed Series D available on Amazon Kindle

Reporter: Stephen S Williams, PhD

 

Leaders in Pharmaceutical Business Intelligence would like to announce the First volume of their BioMedical E-Book Series D:

Metabolic Genomics & Pharmaceutics, Vol. I

SACHS FLYER 2014 Metabolomics SeriesDindividualred-page2

which is now available on Amazon Kindle at

http://www.amazon.com/dp/B012BB0ZF0.

This e-Book is a comprehensive review of recent Original Research on  METABOLOMICS and related opportunities for Targeted Therapy written by Experts, Authors, Writers. This is the first volume of the Series D: e-Books on BioMedicine – Metabolomics, Immunology, Infectious Diseases.  It is written for comprehension at the third year medical student level, or as a reference for licensing board exams, but it is also written for the education of a first time baccalaureate degree reader in the biological sciences.  Hopefully, it can be read with great interest by the undergraduate student who is undecided in the choice of a career. The results of Original Research are gaining value added for the e-Reader by the Methodology of Curation. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012.  All new articles on this subject, will continue to be incorporated, as published with periodical updates.

We invite e-Readers to write an Article Reviews on Amazon for this e-Book on Amazon.

All forthcoming BioMed e-Book Titles can be viewed at:

https://pharmaceuticalintelligence.com/biomed-e-books/

Leaders in Pharmaceutical Business Intelligence, launched in April 2012 an Open Access Online Scientific Journal is a scientific, medical and business multi expert authoring environment in several domains of  life sciences, pharmaceutical, healthcare & medicine industries. The venture operates as an online scientific intellectual exchange at their website http://pharmaceuticalintelligence.com and for curation and reporting on frontiers in biomedical, biological sciences, healthcare economics, pharmacology, pharmaceuticals & medicine. In addition the venture publishes a Medical E-book Series available on Amazon’s Kindle platform.

Analyzing and sharing the vast and rapidly expanding volume of scientific knowledge has never been so crucial to innovation in the medical field. WE are addressing need of overcoming this scientific information overload by:

  • delivering curation and summary interpretations of latest findings and innovations on an open-access, Web 2.0 platform with future goals of providing primarily concept-driven search in the near future
  • providing a social platform for scientists and clinicians to enter into discussion using social media
  • compiling recent discoveries and issues in yearly-updated Medical E-book Series on Amazon’s mobile Kindle platform

This curation offers better organization and visibility to the critical information useful for the next innovations in academic, clinical, and industrial research by providing these hybrid networks.

Table of Contents for Metabolic Genomics & Pharmaceutics, Vol. I

Chapter 1: Metabolic Pathways

Chapter 2: Lipid Metabolism

Chapter 3: Cell Signaling

Chapter 4: Protein Synthesis and Degradation

Chapter 5: Sub-cellular Structure

Chapter 6: Proteomics

Chapter 7: Metabolomics

Chapter 8:  Impairments in Pathological States: Endocrine Disorders; Stress

                   Hypermetabolism and Cancer

Chapter 9: Genomic Expression in Health and Disease 

 

Summary 

Epilogue

 

 

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Treatment for Chronic Leukemias [2.4.4B]

Larry H. Bernstein, MD, FCAP, Author, Curator, Editor

https://pharmaceuticalintelligence.com/2015/8/11/larryhbern/Treatment-for-Chronic-Leukemias-[2.4.4B]

2.4.4B1 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

  1. Targeted therapy
  2. Chemotherapy
  3. Biologic therapy
  4. High-dose chemotherapy with stem cell transplant
  5. Donor lymphocyte infusion (DLI)
  6. Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Six types of standard treatment are used:

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.

Surgery

Splenectomy

What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.

Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

2.4.4.B2 Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

  1. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
  2. Leukemia may affect red blood cells, white blood cells, and platelets.
  3. Older age can affect the risk of developing chronic lymphocytic leukemia.
  4. Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
  5. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
  6. Certain factors affect treatment options and prognosis (chance of recovery).
  7. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

  1. Red blood cells that carry oxygen and other substances to all tissues of the body.
  2. White blood cells that fight infection and disease.
  3. Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  1. B lymphocytes that make antibodies to help fight infection.
  2. T lymphocytes that help B lymphocytes make antibodies to fight infection.
  3. Natural killer cells that attack cancer cells and viruses.
Blood cell development. CDR526538-750

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

  • Adult Acute Lymphoblastic Leukemia Treatment.
  • Childhood Acute Lymphoblastic Leukemia Treatment.
  • Adult Acute Myeloid Leukemia Treatment.
  • Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
  • Chronic Myelogenous Leukemia Treatment.
  • Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

  • Being middle-aged or older, male, or white.
  • A family history of CLL or cancer of the lymph system.
  • Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:

  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Feeling very tired.
  • Pain or fullness below the ribs.
  • Fever and infection.
  • Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:

The number of red blood cells and platelets.

The number and type of white blood cells.

The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.

The portion of the blood sample made up of red blood cells.

Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

  • Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab1
  • In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)1

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

  • In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)1

Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.

If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.

Initial treatment

Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

  • FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
  • Bendamustine (sometimes with rituximab)
  • FR: fludarabine and rituximab
  • CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
  • CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
  • Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
  • PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
  • Alemtuzumab (Campath)
  • Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.

If the leukemia responds, stem cell transplant may be an option for some patients.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.

Treating complications of CLL

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

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Treatments other than Chemotherapy for Leukemias and Lymphomas

Author, Curator, Editor: Larry H. Bernstein, MD, FCAP

2.5.1 Radiation Therapy 

http://www.lls.org/treatment/types-of-treatment/radiation-therapy

Radiation therapy, also called radiotherapy or irradiation, can be used to treat leukemia, lymphoma, myeloma and myelodysplastic syndromes. The type of radiation used for radiotherapy (ionizing radiation) is the same that’s used for diagnostic x-rays. Radiotherapy, however, is given in higher doses.

Radiotherapy works by damaging the genetic material (DNA) within cells, which prevents them from growing and reproducing. Although the radiotherapy is directed at cancer cells, it can also damage nearby healthy cells. However, current methods of radiotherapy have been improved upon, minimizing “scatter” to nearby tissues. Therefore its benefit (destroying the cancer cells) outweighs its risk (harming healthy cells).

When radiotherapy is used for blood cancer treatment, it’s usually part of a treatment plan that includes drug therapy. Radiotherapy can also be used to relieve pain or discomfort caused by an enlarged liver, lymph node(s) or spleen.

Radiotherapy, either alone or with chemotherapy, is sometimes given as conditioning treatment to prepare a patient for a blood or marrow stem cell transplant. The most common types used to treat blood cancer are external beam radiation (see below) and radioimmunotherapy.
External Beam Radiation

External beam radiation is the type of radiotherapy used most often for people with blood cancers. A focused radiation beam is delivered outside the body by a machine called a linear accelerator, or linac for short. The linear accelerator moves around the body to deliver radiation from various angles. Linear accelerators make it possible to decrease or avoid skin reactions and deliver targeted radiation to lessen “scatter” of radiation to nearby tissues.

The dose (total amount) of radiation used during treatment depends on various factors regarding the patient, disease and reason for treatment, and is established by a radiation oncologist. You may receive radiotherapy during a series of visits, spread over several weeks (from two to 10 weeks, on average). This approach, called dose fractionation, lessens side effects. External beam radiation does not make you radioactive.

2.5.2  Bone marrow (BM) transplantation

http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm

There are three kinds of bone marrow transplants:

Autologous bone marrow transplant: The term auto means self. Stem cells are removed from you before you receive high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer (cryopreservation). After high-dose chemotherapy or radiation treatments, your stems cells are put back in your body to make (regenerate) normal blood cells. This is called a rescue transplant.

Allogeneic bone marrow transplant: The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor’s genes must at least partly match your genes. Special blood tests are done to see if a donor is a good match for you. A brother or sister is most likely to be a good match. Sometimes parents, children, and other relatives are good matches. Donors who are not related to you may be found through national bone marrow registries.

Umbilical cord blood transplant: This is a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for matching. But blood counts take much longer to recover.

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways:

Ablative (myeloablative) treatment: High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains, and allows new stem cells to grow in the bone marrow.

Reduced intensity treatment, also called a mini transplant: Patients receive lower doses of chemotherapy and radiation before a transplant. This allows older patients, and those with other health problems to have a transplant.

A stem cell transplant is usually done after chemotherapy and radiation is complete. The stem cells are delivered into your bloodstream usually through a tube called a central venous catheter. The process is similar to getting a blood transfusion. The stem cells travel through the blood into the bone marrow. Most times, no surgery is needed.

Donor stem cells can be collected in two ways:

  • Bone marrow harvest. This minor surgery is done under general anesthesia. This means the donor will be asleep and pain-free during the procedure. The bone marrow is removed from the back of both hip bones. The amount of marrow removed depends on the weight of the person who is receiving it.
  • Leukapheresis. First, the donor is given 5 days of shots to help stem cells move from the bone marrow into the blood. During leukapheresis, blood is removed from the donor through an IV line in a vein. The part of white blood cells that contains stem cells is then separated in a machine and removed to be later given to the recipient. The red blood cells are returned to the donor.

Why the Procedure is Performed

A bone marrow transplant replaces bone marrow that either is not working properly or has been destroyed (ablated) by chemotherapy or radiation. Doctors believe that for many cancers, the donor’s white blood cells can attach to any remaining cancer cells, similar to when white cells attach to bacteria or viruses when fighting an infection.

Your doctor may recommend a bone marrow transplant if you have:

Certain cancers, such as leukemia, lymphoma, and multiple myeloma

A disease that affects the production of bone marrow cells, such as aplastic anemia, congenital neutropenia, severe immunodeficiency syndromes, sickle cell anemia, thalassemia

Had chemotherapy that destroyed your bone

2.5.3 Autologous stem cell transplantation

Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

O.W Press,  F Appelbaum,  P.J Martin, et al.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(95)92225-3/abstract

25 patients with relapsed B-cell lymphomas were evaluated with trace-labelled doses (2·5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumor sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12·765-29·045 GBq) followed by autologous hemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

Autologous (Self) Transplants

http://www.leukaemia.org.au/treatments/stem-cell-transplants/autologous-self-transplants

An autologous transplant (or rescue) is a type of transplant that uses the person’s own stem cells. These cells are collected in advance and returned at a later stage. They are used to replace stem cells that have been damaged by high doses of chemotherapy, used to treat the person’s underlying disease.

In most cases, stem cells are collected directly from the bloodstream. While stem cells normally live in your marrow, a combination of chemotherapy and a growth factor (a drug that stimulates stem cells) called Granulocyte Colony Stimulating Factor (G-CSF) is used to expand the number of stem cells in the marrow and cause them to spill out into the circulating blood. From here they can be collected from a vein by passing the blood through a special machine called a cell separator, in a process similar to dialysis.

Most of the side effects of an autologous transplant are caused by the conditioning therapy used. Although they can be very unpleasant at times it is important to remember that most of them are temporary and reversible.

Procedure of Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient’s own stem cells are used) or allogeneic (the stem cells come from a donor).

Hematopoietic Stem Cell Transplantation

Author: Ajay Perumbeti, MD, FAAP; Chief Editor: Emmanuel C Besa, MD
http://emedicine.medscape.com/article/208954-overview

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of autologous or allogeneic stem cells to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.

The image below illustrates an algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy.

An algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy: If a matched sibling donor is not available, then a MUD is selected; if a MUD is not available, then choices include a mismatched unrelated donor, umbilical cord donor(s), and a haploidentical donor.

Supportive Therapies

2.5.4  Blood transfusions – risks and complications of a blood transfusion

  • Allogeneic transfusion reaction (acute or delayed hemolytic reaction)
  • Allergic reaction
  • Viruses Infectious Diseases

The risk of catching a virus from a blood transfusion is very low.

HIV. Your risk of getting HIV from a blood transfusion is lower than your risk of getting killed by lightning. Only about 1 in 2 million donations might carry HIV and transmit HIV if given to a patient.

Hepatitis B and C. The risk of having a donation that carries hepatitis B is about 1 in 205,000. The risk for hepatitis C is 1 in 2 million. If you receive blood during a transfusion that contains hepatitis, you’ll likely develop the virus.

Variant Creutzfeldt-Jakob disease (vCJD). This disease is the human version of Mad Cow Disease. It’s a very rare, yet fatal brain disorder. There is a possible risk of getting vCJD from a blood transfusion, although the risk is very low. Because of this, people who may have been exposed to vCJD aren’t eligible blood donors.

  • Fever
  • Iron Overload
  • Lung Injury
  • Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a condition in which white blood cells in the new blood attack your tissues.

2.5.5 Erythropoietin

Erythropoietin, (/ɨˌrɪθrɵˈpɔɪ.ɨtɨn/UK /ɛˌrɪθr.pˈtɪn/) also known as EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain’s response to neuronal injury.[1] EPO is also involved in the wound healing process.[2]

Exogenous erythropoietin is produced by recombinant DNA technology in cell culture. Several different pharmaceutical agents are available with a variety ofglycosylation patterns, and are collectively called erythropoiesis-stimulating agents (ESA). The specific details for labelled use vary between the package inserts, but ESAs have been used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Boxed warnings include a risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence.[3]

2.5.6  G-CSF (granulocyte-colony stimulating factor)

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

There are different types, including

  • Lenograstim (Granocyte)
  • Filgrastim (Neupogen, Zarzio, Nivestim, Ratiograstim)
  • Long acting (pegylated) filgrastim (pegfilgrastim, Neulasta) and lipegfilgrastim (Longquex)

Pegylated G-CSF stays in the body for longer so you have treatment less often than with the other types of G-CSF.

2.5.7  Plasma Exchange (plasmapheresis)

http://emedicine.medscape.com/article/1895577-overview

Plasmapheresis is a term used to refer to a broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.[1, 2] The filtering of plasma from whole blood can be accomplished via centrifugation or semipermeable membranes.[3] Centrifugation takes advantage of the different specific gravities inherent to various blood products such as red cells, white cells, platelets, and plasma.[4] Membrane plasma separation uses differences in particle size to filter plasma from the cellular components of blood.[3]

Traditionally, in the United States, most plasmapheresis takes place using automated centrifuge-based technology.[5] In certain instances, in particular in patients already undergoing hemodialysis, plasmapheresis can be carried out using semipermeable membranes to filter plasma.[4]

In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and red blood cells along with replacement colloid such as donor plasma or albumin is returned to the patient. In membrane plasma filtration, secondary membrane plasma fractionation can selectively remove undesired macromolecules, which then allows for return of the processed plasma to the patient instead of donor plasma or albumin. Examples of secondary membrane plasma fractionation include cascade filtration,[6] thermofiltration, cryofiltration,[7] and low-density lipoprotein pheresis.

The Apheresis Applications Committee of the American Society for Apheresis periodically evaluates potential indications for apheresis and categorizes them from I to IV based on the available medical literature. The following are some of the indications, and their categorization, from the society’s 2010 guidelines.[2]

  • The only Category I indication for hemopoietic malignancy is Hyperviscosity in monoclonal gammopathies

2.5.8  Platelet Transfusions

Indications for platelet transfusion in children with acute leukemia

Scott Murphy, Samuel Litwin, Leonard M. Herring, Penelope Koch, et al.
Am J Hematol Jun 1982; 12(4): 347–356
http://onlinelibrary.wiley.com/doi/10.1002/ajh.2830120406/abstract;jsessionid=A6001D9D865EA1EBC667EF98382EF20C.f03t01
http://dx.doi.org:/10.1002/ajh.2830120406

In an attempt to determine the indications for platelet transfusion in thrombocytopenic patients, we randomized 56 children with acute leukemia to one of two regimens of platelet transfusion. The prophylactic group received platelets when the platelet count fell below 20,000 per mm3 irrespective of clinical events. The therapeutic group was transfused only when significant bleeding occurred and not for thrombocytopenia alone. The time to first bleeding episode was significantly longer and the number of bleeding episodes were significantly reduced in the prophylactic group. The survival curves of the two groups could not be distinguished from each other. Prior to the last month of life, the total number of days on which bleeding was present was significantly reduced by prophylactic therapy. However, in the terminal phase (last month of life), the duration of bleeding episodes was significantly longer in the prophylactic group. This may have been due to a higher incidence of immunologic refractoriness to platelet transfusion. Because of this terminal bleeding, comparison of the two groups for total number of days on which bleeding was present did not show a significant difference over the entire study period.

Clinical and Laboratory Aspects of Platelet Transfusion Therapy
Yuan S, Goldfinger D
http://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-transfusion-therapy

INTRODUCTION — Hemostasis depends on an adequate number of functional platelets, together with an intact coagulation (clotting factor) system. This topic covers the logistics of platelet use and the indications for platelet transfusion in adults. The approach to the bleeding patient, refractoriness to platelet transfusion, and platelet transfusion in neonates are discussed elsewhere.

Pooled Platelets – A single unit of platelets can be isolated from every unit of donated blood, by centrifuging the blood within the closed collection system to separate the platelets from the red blood cells (RBC). The number of platelets per unit varies according to the platelet count of the donor; a yield of 7 x 1010 platelets is typical [1]. Since this number is inadequate to raise the platelet count in an adult recipient, four to six units are pooled to allow transfusion of 3 to 4 x 1011 platelets per transfusion [2]. These are called whole blood-derived or random donor pooled platelets.

Advantages of pooled platelets include lower cost and ease of collection and processing (a separate donation procedure and pheresis equipment are not required). The major disadvantage is recipient exposure to multiple donors in a single transfusion and logistic issues related to bacterial testing.

Apheresis (single donor) Platelets – Platelets can also be collected from volunteer donors in the blood bank, in a one- to two-hour pheresis procedure. Platelets and some white blood cells are removed, and red blood cells and plasma are returned to the donor. A typical apheresis platelet unit provides the equivalent of six or more units of platelets from whole blood (ie, 3 to 6 x 1011 platelets) [2]. In larger donors with high platelet counts, up to three units can be collected in one session. These are called apheresis or single donor platelets.

Advantages of single donor platelets are exposure of the recipient to a single donor rather than multiple donors, and the ability to match donor and recipient characteristics such as HLA type, cytomegalovirus (CMV) status, and blood type for certain recipients.

Both pooled and apheresis platelets contain some white blood cells (WBC) that were collected along with the platelets. These WBC can cause febrile non-hemolytic transfusion reactions (FNHTR), alloimmunization, and transfusion-associated graft-versus-host disease (ta-GVHD) in some patients.

Platelet products also contain plasma, which can be implicated in adverse reactions including transfusion-related acute lung injury (TRALI) and anaphylaxis. (See ‘Complications of platelet transfusion’ .)

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Hematological Malignancy Diagnostics

Author and Curator: Larry H. Bernstein, MD, FCAP

 

2.4.3 Diagnostics

2.4.3.1 Computer-aided diagnostics

Back-to-Front Design

Robert Didner
Bell Laboratories

Decision-making in the clinical setting
Didner, R  Mar 1999  Amer Clin Lab

Mr. Didner is an Independent Consultant in Systems Analysis, Information Architecture (Informatics) Operations Research, and Human Factors Engineering (Cognitive Psychology),  Decision Information Designs, 29 Skyline Dr., Morristown, NJ07960, U.S.A.; tel.: 973-455-0489; fax/e-mail: bdidner@hotmail.com

A common problem in the medical profession is the level of effort dedicated to administration and paperwork necessitated by various agencies, which contributes to the high cost of medical care. Costs would be reduced and accuracy improved if the clinical data could be captured directly at the point they are generated in a form suitable for transmission to insurers or machine transformable into other formats. Such a capability could also be used to improve the form and the structure of information presented to physicians and support a more comprehensive database linking clinical protocols to outcomes, with the prospect of improving clinical outcomes. Although the problem centers on the physician’s process of determining the diagnosis and treatment of patients and the timely and accurate recording of that process in the medical system, it substantially involves the pathologist and laboratorian, who interact significantly throughout the in-formation-gathering process. Each of the currently predominant ways of collecting information from diagnostic protocols has drawbacks. Using blank paper to collect free-form notes from the physician is not amenable to computerization; such free-form data are also poorly formulated, formatted, and organized for the clinical decision-making they support. The alternative of preprinted forms listing the possible tests, results, and other in-formation gathered during the diagnostic process facilitates the desired computerization, but the fixed sequence of tests and questions they present impede the physician from using an optimal decision-making sequence. This follows because:

  • People tend to make decisions and consider information in a step-by-step manner in which intermediate decisions are intermixed with data acquisition steps.
  • The sequence in which components of decisions are made may alter the decision outcome.
  • People tend to consider information in the sequence it is requested or displayed.
  • Since there is a separate optimum sequence of tests and questions for each cluster of history and presenting symptoms, there is no one sequence of tests and questions that can be optimal for all presenting clusters.
  • As additional data and test results are acquired, the optimal sequence of further testing and data acquisition changes, depending on the already acquired information.

Therefore, promoting an arbitrary sequence of information requests with preprinted forms may detract from outcomes by contributing to a non-optimal decision-making sequence. Unlike the decisions resulting from theoretical or normative processes, decisions made by humans are path dependent; that is, the out-come of a decision process may be different if the same components are considered in a different sequence.

Proposed solution

This paper proposes a general approach to gathering data at their source in computer-based form so as to improve the expected outcomes. Such a means must be interactive and dynamic, so that at any point in the clinical process the patient’s presenting symptoms, history, and the data already collected are used to determine the next data or tests requested. That de-termination must derive from a decision-making strategy designed to produce outcomes with the greatest value and supported by appropriate data collection and display techniques. The strategy must be based on the knowledge of the possible outcomes at any given stage of testing and information gathering, coupled with a metric, or hierarchy of values for assessing the relative desirability of the possible outcomes.

A value hierarchy

  • The numbered list below illustrates a value hierarchy. In any particular instance, the higher-numbered values should only be considered once the lower- numbered values have been satisfied. Thus, a diagnostic sequence that is very time or cost efficient should only be considered if it does not increase the likelihood (relative to some other diagnostic sequence) that a life-threatening disorder may be missed, or that one of the diagnostic procedures may cause discomfort.
  • Minimize the likelihood that a treatable, life-threatening disorder is not treated.
  • Minimize the likelihood that a treatable, discomfort-causing disorder is not treated.
  • Minimize the likelihood that a risky procedure(treatment or diagnostic procedure) is inappropriately administered.
  • Minimize the likelihood that a discomfort-causing procedure is inappropriately administered.
  • Minimize the likelihood that a costly procedure is inappropriately administered.
  • Minimize the time of diagnosing and treating thepatient.8.Minimize the cost of diagnosing and treating the patient.

The above hierarchy is relative, not absolute; for many patients, a little bit of testing discomfort may be worth a lot of time. There are also some factors and graduations intentionally left out for expository simplicity (e.g., acute versus chronic disorders).This value hierarchy is based on a hypothetical patient. Clearly, the hierarchy of a health insurance carrier might be different, as might that of another patient (e.g., a geriatric patient). If the approach outlined herein were to be followed, a value hierarchy agreed to by a majority of stakeholders should be adopted.

Efficiency

Once the higher values are satisfied, the time and cost of diagnosis and treatment should be minimized. One way to do so would be to optimize the sequence in which tests are performed, so as to minimize the number, cost, and time of tests that need to be per-formed to reach a definitive decision regarding treatment. Such an optimum sequence could be constructed using Claude Shannon’s information theory.

According to this theory, the best next question to ask under any given situation (assuming the question has two possible outcomes) is that question that divides the possible outcomes into two equally likely sets. In the real world, all tests or questions are not equally valuable, costly, or time consuming; therefore, value(risk factors), cost, and time should be used as weighting factors to optimize the test sequence, but this is a complicating detail at this point.

A value scale

For dynamic computation of outcome values, the hierarchy could be converted into a weighted value scale so differing outcomes at more than one level of the hierarchy could be readily compared. An example of such a weighted value scale is Quality Adjusted Life Years (QALY).

Although QALY does not incorporate all of the factors in this example, it is a good conceptual starting place.

The display, request, decision-making relationship

For each clinical determination, the pertinent information should be gathered, organized, formatted, and formulated in a way that facilitates the accuracy, reliability, and efficiency with which that determination is made. A physician treating a patient with high cholesterol and blood pressure (BP), for example, may need to know whether or not the patient’s cholesterol and BP respond to weight changes to determine an appropriate treatment (e.g., weight control versus medication). This requires searching records for BP, certain blood chemicals (e.g., HDLs, LDLs, triglycerides, etc.), and weight from several

sources, then attempting to track them against each other over time. Manually reorganizing this clinical information each time it is used is extremely inefficient. More important, the current organization and formatting defies principles of human factors for optimally displaying information to enhance human information-processing characteristics, particularly for decision support.

While a discussion of human factors and cognitive psychology principles is beyond the scope of this paper, following are a few of the system design principles of concern:

  • Minimize the load on short-term memory.
  • Provide information pertinent to a given decision or component of a decision in a compact, contiguous space.
  • Take advantage of basic human perceptual and pat-tern recognition facilities.
  • Design the form of an information display to com-plement the decision-making task it supports.

F i g u re 1 shows fictitious, quasi-random data from a hypothetical patient with moderately elevated cholesterol. This one-page display pulls together all the pertinent data from six years of blood tests and related clinical measurements. At a glance, the physician’s innate pattern recognition, color, and shape perception facilities recognize the patient’s steadily increasing weight, cholesterol, BP, and triglycerides as well as the declining high-density lipoproteins. It would have taken considerably more time and effort to grasp this information from the raw data collection and blood test reports as they are currently presented in independent, tabular time slices.

Design the formulation of an information display to complement the decision-making task.

The physician may wish to know only the relationship between weight and cardiac risk factors rather than whether these measures are increasing or decreasing, or are within acceptable or marginal ranges. If so, Table 1 shows the correlations between weight and the other factors in a much more direct and simple way using the same data as in Figure 1. One can readily see the same conclusions about relations that were drawn from Figure 1.This type of abstract, symbolic display of derived information also makes it easier to spot relationships when the individual variables are bouncing up and down, unlike the more or less steady rise of most values in Figure 1. This increase in precision of relationship information is gained at the expense of other types of information (e.g., trends). To display information in an optimum form then, the system designer must know what the information demands of the task are at the point in the task when the display is to be used.

Present the sequence of information display clusters to complement an optimum decision-making strategy.

Just as a fixed sequence of gathering clinical, diagnostic information may lead to a far from optimum outcome, there exists an optimum sequence of testing, considering information, and gathering data that will lead to an optimum outcome (as defined by the value hierarchy) with a minimum of time and expense. The task of the information system designer, then, is to provide or request the right information, in the best form, at each stage of the procedure. For ex-ample, Figure 1 is suitable for the diagnostic phase since it shows the current state of the risk factors and their trends. Table 1, on the other hand, might be more appropriate in determining treatment, where there may be a choice of first trying a strict dietary treatment, or going straight to a combination of diet plus medication. The fact that Figure 1 and Table 1 have somewhat redundant information is not a problem, since they are intended to optimally provide information for different decision-making tasks. The critical need, at this point, is for a model of how to determine what information should be requested, what tests to order, what information to request and display, and in what form at each step of the decision-making process. Commitment to a collaborative relationship between physicians and laboratorians and other information providers would be an essential requirement for such an undertaking. The ideal diagnostic data-collection instrument is a flexible, computer-based device, such as a notebook computer or Personal Digital Assistant (PDA) sized device.

Barriers to interactive, computer-driven data collection at the source

As with any major change, it may be difficult to induce many physicians to change their behavior by interacting directly with a computer instead of with paper and pen. Unlike office workers, who have had to make this transition over the past three decades, most physicians’ livelihoods will not depend on converting to computer interaction. Therefore, the transition must be made attractive and the changes less onerous. Some suggestions follow:

  1. Make the data collection a natural part of the clinical process.
  2. Ensure that the user interface is extremely friendly, easy to learn, and easy to use.
  3. Use a small, portable device.
  4. Use the same device for collection and display of existing information (e.g., test results and his-tory).
  5. Minimize the need for free-form written data entry (use check boxes, forms, etc.).
  6. Allow the entry of notes in pen-based free-form (with the option of automated conversion of numeric data to machine-manipulable form).
  7. Give the physicians a more direct benefit for collecting data, not just a means of helping a clerk at an HMO second-guess the physician’s judgment.
  8. Improve administrative efficiency in the office.
  9. Make the data collection complement the clinical decision-making process.
  10. Improve information displays, leading to better outcomes.
  11. Make better use of the physician’s time and mental effort.

Conclusion

The medical profession is facing a crisis of information. Gathering information is costing a typical practice more and more while fees are being restricted by third parties, and the process of gathering this in-formation may be detrimental to current outcomes. Gathered properly, in machine-manipulable form, these data could be reformatted so as to greatly improve their value immediately in the clinical setting by leading to decisions with better outcomes and, in the long run, by contributing to a clinical data warehouse that could greatly improve medical knowledge. The challenge is to create a mechanism for data collection that facilitates, hastens, and improves the outcomes of clinical activity while minimizing the inconvenience and resistance to change on the part of clinical practitioners. This paper is intended to provide a high-level overview of how this may be accomplished, and start a dialogue along these lines.

References

  1. Tversky A. Elimination by aspects: a theory of choice. Psych Rev 1972; 79:281–99.
  2. Didner RS. Back-to-front design: a guns and butter approach. Ergonomics 1982; 25(6):2564–5.
  3. Shannon CE. A mathematical theory of communication. Bell System Technical J 1948; 27:379–423 (July), 623–56 (Oct).
  4. Feeny DH, Torrance GW. Incorporating utility-based quality-of-life assessment measures in clinical trials: two examples. Med Care 1989; 27:S190–204.
  5. Smith S, Mosier J. Guidelines for designing user interface soft-ware. ESD-TR-86-278, Aug 1986.
  6. Miller GA. The magical number seven plus or minus two. Psych Rev 1956; 65(2):81–97.
  7. Sternberg S. High-speed scanning in human memory. Science 1966; 153: 652–4.

Table 1

Correlation of weight with other cardiac risk factors

Cholesterol 0.759384
HDL 0.53908
LDL 0.177297
BP-syst. 0.424728
BP-dia. 0.516167
Triglycerides 0.637817

Figure 1  Hypothetical patient data.

(not shown)

Realtime Clinical Expert Support

https://pharmaceuticalintelligence.com/2015/05/10/realtime-clinical-expert-support/

Regression: A richly textured method for comparison and classification of predictor variables

https://pharmaceuticalintelligence.com/2012/08/14/regression-a-richly-textured-method-for-comparison-and-classification-of-predictor-variables/

Converting Hematology Based Data into an Inferential Interpretation

Larry H. Bernstein, Gil David, James Rucinski and Ronald R. Coifman
In Hematology – Science and Practice
Lawrie CH, Ch 22. Pp541-552.
InTech Feb 2012, ISBN 978-953-51-0174-1
https://www.researchgate.net/profile/Larry_Bernstein/publication/221927033_Converting_Hematology_Based_Data_into_an_Inferential_Interpretation/links/0fcfd507f28c14c8a2000000.pdf

A model for Thalassemia Screening using Hematology Measurements

https://www.researchgate.net/profile/Larry_Bernstein/publication/258848064_A_model_for_Thalassemia_Screening_using_Hematology_Measurements/links/0c9605293c3048060b000000.pdf

2.4.3.2 A model for automated screening of thalassemia in hematology (math study).

Kneifati-Hayek J, Fleischman W, Bernstein LH, Riccioli A, Bellevue R.
Lab Hematol. 2007; 13(4):119-23. http://dx.doi.org:/10.1532/LH96.07003.

The results of 398 patient screens were collected. Data from the set were divided into training and validation subsets. The Mentzer ratio was determined through a receiver operating characteristic (ROC) curve on the first subset, and screened for thalassemia using the second subset. HgbA2 levels were used to confirm beta-thalassemia.

RESULTS: We determined the correct decision point of the Mentzer index to be a ratio of 20. Physicians can screen patients using this index before further evaluation for beta-thalassemia (P < .05).

CONCLUSION: The proposed method can be implemented by hospitals and laboratories to flag positive matches for further definitive evaluation, and will enable beta-thalassemia screening of a much larger population at little to no additional cost.

Measurement of granulocyte maturation may improve the early diagnosis of the septic state.

2.4.3.3 Bernstein LH, Rucinski J. Clin Chem Lab Med. 2011 Sep 21;49(12):2089-95.
http://dx.doi.org:/10.1515/CCLM.2011.688.

2.4.3.4 The automated malnutrition assessment.

David G, Bernstein LH, Coifman RR. Nutrition. 2013 Jan; 29(1):113-21.
http://dx.doi.org:/10.1016/j.nut.2012.04.017

2.4.3.5 Molecular Diagnostics

Genomic Analysis of Hematological Malignancies

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy that occurs in children. Although more than 90% of children with ALL now survive to adulthood, those with the rarest and high-risk forms of the disease continue to have poor prognoses. Through the Pediatric Cancer Genome Project (PCGP), investigators in the Hematological Malignancies Program are identifying the genetic aberrations that cause these aggressive forms of leukemias. Here we present two studies on the genetic bases of early T-cell precursor ALL and acute megakaryoblastic leukemia.

  • Early T-Cell Precursor ALL Is Characterized by Activating Mutations
  • The CBFA2T3-GLIS2Fusion Gene Defines an Aggressive Subtype of Acute Megakaryoblastic Leukemia in Children

Early T-cell precursor ALL (ETP-ALL), which comprises 15% of all pediatric T-cell leukemias, is an aggressive disease that is typically resistant to contemporary therapies. Children with ETP-ALL have a high rate of relapse and an extremely poor prognosis (i.e., 5-year survival is approximately 20%). The genetic basis of ETP-ALL has remained elusive. Although ETP-ALL is associated with a high burden of DNA copy number aberrations, none are consistently found or suggest a unifying genetic alteration that drives this disease.

Through the efforts of the PCGP, Jinghui Zhang, PhD (Computational Biology), James R. Downing, MD (Pathology), Charles G. Mullighan, MBBS(Hons), MSc, MD (Pathology), and colleagues analyzed the whole-genome sequences of leukemic cells and matched normal DNA from 12 pediatric patients with ETP-ALL. The identified genetic mutations were confirmed in a validation cohort of 52 ETP-ALL specimens and 42 non-ETP T-lineage ALLs (T-ALL).

In the journal Nature, the investigators reported that each ETP-ALL sample carried an average of 1140 sequence mutations and 12 structural variations. Of the structural variations, 51% were breakpoints in genes with well-established roles in hematopoiesis or leukemogenesis (e.g., MLH2,SUZ12, and RUNX1). Eighty-four percent of the structural variations either caused loss of function of the gene in question or resulted in the formation of a fusion gene such as ETV6-INO80D. The ETV6 gene, which encodes a protein that is essential for hematopoiesis, is frequently mutated in leukemia. Among the DNA samples sequenced in this study, ETV6 was altered in 33% of ETP-ALL but only 10% of T-ALL cases.

Next-generation sequencing in hematologic malignancies: what will be the dividends?

Jason D. MerkerAnton Valouev, and Jason Gotlib
Ther Adv Hematol. 2012 Dec; 3(6): 333–339.
http://dx.doi.org:/10.1177/2040620712458948

The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.

Leveraging cancer genome information in hematologic malignancies.

Rampal R1Levine RL.
J Clin Oncol. 2013 May 20; 31(15):1885-92.
http://dx.doi.org:/10.1200/JCO.2013.48.7447

The use of candidate gene and genome-wide discovery studies in the last several years has led to an expansion of our knowledge of the spectrum of recurrent, somatic disease alleles, which contribute to the pathogenesis of hematologic malignancies. Notably, these studies have also begun to fundamentally change our ability to develop informative prognostic schema that inform outcome and therapeutic response, yielding substantive insights into mechanisms of hematopoietic transformation in different tissue compartments. Although these studies have already had important biologic and translational impact, significant challenges remain in systematically applying these findings to clinical decision making and in implementing new technologies for genetic analysis into clinical practice to inform real-time decision making. Here, we review recent major genetic advances in myeloid and lymphoid malignancies, the impact of these findings on prognostic models, our understanding of disease initiation and evolution, and the implication of genomic discoveries on clinical decision making. Finally, we discuss general concepts in genetic modeling and the current state-of-the-art technology used in genetic investigation.

p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

E Wattel, C Preudhomme, B Hecquet, M Vanrumbeke, et AL.
Blood, (Nov 1), 1994; 84(9): pp 3148-3157
http://www.bloodjournal.org/content/bloodjournal/84/9/3148.full.pdf

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < lo-‘). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P C lo-’). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil andlor CHOP andlor fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < IO-’). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

Genomic approaches to hematologic malignancies

Benjamin L. Ebert and Todd R. Golub
Blood. 2004; 104:923-932
https://www.broadinstitute.org/mpr/publications/projects/genomics/Review%20Genomics%20of%20Heme%20Malig,%20Blood%202004.pdf

In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research.

2.4.3.6 Flow cytometry

Introduction to Flow Cytometry: Blood Cell Identification

Dana L. Van Laeys
https://www.labce.com/flow_cytometry.aspx

No other laboratory method provides as rapid and detailed analysis of cellular populations as flow cytometry, making it a valuable tool for diagnosis and management of several hematologic and immunologic diseases. Understanding this relevant methodology is important for any medical laboratory scientist.

Whether you have no previous experience with flow cytometry or just need a refresher, this course will help you to understand the basic principles, with the help of video tutorials and interactive case studies.

Basic principles include:

  1. Immunophenotypic features of various types of hematologic cells
  2. Labeling cellular elements with fluorochromes
  3. Blood cell identification, specifically B and T lymphocyte identification and analysis
  4. Cell sorting to isolate select cell population for further analysis
  5. Analyzing and interpreting result reports and printouts

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Hematologic Malignancies , Table of Contents

Writer and Curator:  Larry H. Bernstein, MD, FCAP

Hematologic Malignancies 

Not excluding lymphomas [solid tumors]

The following series of articles are discussions of current identifications, classification, and treatments of leukemias, myelodysplastic syndromes and myelomas.

2.4 Hematological Malignancies

2.4.1 Ontogenesis of blood elements

Erythropoiesis

White blood cell series: myelopoiesis

Thrombocytogenesis

2.4.2 Classification of hematopoietic cancers

Primary Classification

Acute leukemias

Myelodysplastic syndromes

Acute myeloid leukemia

Acute lymphoblastic leukemia

Myeloproliferative Disorders

Chronic myeloproliferative disorders

Chronic myelogenous leukemia and related disorders

Myelofibrosis, including chronic idiopathic

Polycythemia, including polycythemia rubra vera

Thrombocytosis, including essential thrombocythemia

Chronic lymphoid leukemia and other lymphoid leukemias

Lymphomas

Non-Hodgkin Lymphoma

Hodgkin lymphoma

Lymphoproliferative disorders associated with immunodeficiency

Plasma Cell dyscrasias

Mast cell disease and Histiocytic neoplasms

Secondary Classification

Nuance – PathologyOutlines

2.4.3 Diagnostics

Computer-aided diagnostics

Back-to-Front Design

Realtime Clinical Expert Support

Regression: A richly textured method for comparison and classification of predictor variables

Converting Hematology Based Data into an Inferential Interpretation

A model for Thalassemia Screening using Hematology Measurements

Measurement of granulocyte maturation may improve the early diagnosis of the septic state.

The automated malnutrition assessment.

Molecular Diagnostics

Genomic Analysis of Hematological Malignancies

Next-generation sequencing in hematologic malignancies: what will be the dividends?

Leveraging cancer genome information in hematologic malignancies.

p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

Genomic approaches to hematologic malignancies

2.4.4 Treatment of hematopoietic cancers

2.4.4.1 Treatments for leukemia by type

2.4.4..2 Acute lymphocytic leukemias

2.4..4.3 Treatment of Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Leukemias Treatment & Management

Treatments and drugs

2.4.5 Acute Myeloid Leukemia

New treatment approaches in acute myeloid leukemia: review of recent clinical studies

Novel approaches to the treatment of acute myeloid leukemia.

Current treatment of acute myeloid leukemia

Adult Acute Myeloid Leukemia Treatment (PDQ®)

2.4.6 Treatment for CML

Chronic Myelogenous Leukemia Treatment (PDQ®)

What`s new in chronic myeloid leukemia research and treatment?

4.2.7 Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Treatment (PDQ®)

Results from the Phase 3 Resonate™ Trial

Typical treatment of chronic lymphocytic leukemia

4.2.8 Lymphoma treatment

4.2.8.1 Overview

4.2.8.2 Chemotherapy

………………………………..

Chapter 6

Total body irradiation (TBI)

Bone marrow (BM) transplantation

Autologous stem cell transplantation

Hematopoietic stem cell transplantation

Supportive Therapies

Blood transfusions

Erythropoietin

G-CSF (granulocyte-colony stimulating factor)

Plasma exchange (plasmapheresis)

Platelet transfusions

Steroids

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Allogeneic Stem Cell Transplantation

Writer and Curator: Larry H. Bernstein, MD, FCAP

This article has the following structure:

9.3.1  Cell based immunotherapy

9.3.2  Photodynamic therapy (PDT)

9.3.3  Small molecules targeted therapy drugs; Tyrosine kinase inhibitors; imatinib (Gleevec/Glivec) and gefitinib (Iressa).

9.3.4 Graft versus Host Disease

9.3.5 Aspergillus Complicating Allogeneic Transplantation

Introduction

9.3.1 Allogeneic Stem Cell Treatment

http://www.lls.org/treatment/types-of-treatment/stem-cell-transplantation/allogeneic-stem-cell-transplantation

Allogeneic stem cell transplantation involves transferring the stem cells from a healthy person (the donor) to your body after high-intensity chemotherapy or radiation.

Allogeneic stem cell transplantation is used to cure some patients who:

  • Are at high risk of relapse
  • Don’t respond fully to treatment
  • Relapse after prior successful treatment

Allogeneic stem cell transplantation can be a high-risk procedure. The high-conditioning regimens are meant to severely or completely impair your ability to make stem cells and you will likely experience side effects during the days you receive high-dose conditioning radiation or chemotherapy. The goals of high-conditioning therapy are to:

treat the remaining cancer cells intensively, thereby making a cancer recurrence less likely
inactivate the immune system to reduce the chance of stem cell graft rejection
enable donor cells to travel to the marrow (engraftment), produce blood cells and bring about graft versus tumor effect

Possible Adverse Effects

The immune system and the blood system are closely linked and can’t be separated from each other. Because of this, allogeneic transplantation means that not only the donor’s blood system but also his or her immune system is transferred. As a result, these adverse effects are possible:

  • Immune rejection of the donated stem cells by the recipient (host-versus-graft effect)
  • Immune reaction by the donor cells against the recipient’s tissues (graft-versus-host disease [GVHD])

The immune reaction, or GVHD, is treated by administering drugs to the patient after the transplant that reduce the ability of the donated immune cells to attack and injure the patient’s tissues. See Graft Versus Host Disease.

Allogeneic stem cell transplants for patients who are older or have overall poor health are relatively uncommon. This is because the pre-transplant conditioning therapy is generally not well tolerated by such patients, especially those with poorly functioning internal organs. However, reduced intensity allogeneic stem cell transplants may be an appropriate treatment for some older or sicker patients.

T-Lymphocyte Depletion

One goal of allogeneic stem cell transplant is to cause the T lymphocytes in the donor’s blood or marrow to take hold (engraft) and grow in the patient’s marrow. Sometimes the T lymphocytes attack the cancer cells. When this happens, it’s called graft versus tumor (GVT) effect (also called graft versus cancer effect). The attack makes it less likely that the disease will return. This effect is more common in myeloid leukemias than it is in other blood cancers.

Unfortunately, T lymphocytes are the same cells that cause graft versus host disease (GVHD). Because of this serious and sometimes life-threatening side effect, doctors in certain cases want to decrease the number of T lymphocytes to be infused with the stem cells. This procedure, called T-lymphocyte depletion, is currently being studied by researchers. The technique involves treating the stem cells collected for transplant with agents that reduce the number of T lymphocytes.

The aim of T-lymphocyte depletion is to lessen GVHD’s incidence and severity. However, it can also cause increased rates of graft rejection, a decreased GVT effect and a slower immune recovery. Doctors must be careful about the number of T lymphocytes removed when using this technique.

Stem Cell Selection

Stem cell selection is another technique being studied in clinical trials that can reduce the number of T lymphocytes that a patient receives. Because of specific features on the outer coat of stem cells, doctors can selectively remove stem cells from a cell mixture. This technique produces a large number of stem cells and fewer other cells, including T lymphocytes.

9.3.2 Defining Characteristics of  Stem Cells

http://stemcells.nih.gov/info/basics/pages/basics1.aspx

Stem cells have the remarkable potential to develop into many different cell types in the body during early life and growth. In addition, in many tissues they serve as a sort of internal repair system, dividing essentially without limit to replenish other cells as long as the person or animal is still alive. When a stem cell divides, each new cell has the potential either to remain a stem cell or become another type of cell with a more specialized function, such as a muscle cell, a red blood cell, or a brain cell.

Stem cells are distinguished from other cell types by two important characteristics. First, they are unspecialized cells capable of renewing themselves through cell division, sometimes after long periods of inactivity. Second, under certain physiologic or experimental conditions, they can be induced to become tissue- or organ-specific cells with special functions. In some organs, such as the gut and bone marrow, stem cells regularly divide to repair and replace worn out or damaged tissues. In other organs, however, such as the pancreas and the heart, stem cells only divide under special conditions.

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic “somatic” or “adult” stem cells. The functions and characteristics of these cells will be explained in this document. Scientists discovered ways to derive embryonic stem cells from early mouse embryos more than 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures.

When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be “reprogrammed” genetically to assume a stem cell-like state. This new type of stem cell is called induced pluripotent stem cells (iPSCs).

Stem cells differ from other kinds of cells in the body. All stem cells—regardless of their source—have three general properties: they are capable of dividing and renewing themselves for long periods; they are unspecialized; and they can give rise to specialized cell types.

Stem cells are capable of dividing and renewing themselves for long periods. Unlike muscle cells, blood cells, or nerve cells—which do not normally replicate themselves—stem cells may replicate many times, or proliferate. A starting population of stem cells that proliferates for many months in the laboratory can yield millions of cells. If the resulting cells continue to be unspecialized, like the parent stem cells, the cells are said to be capable of long-term self-renewal.

Scientists are trying to understand two fundamental properties of stem cells that relate to their long-term self-renewal:

  1. Why can embryonic stem cells proliferate for a year or more in the laboratory without differentiating, but most adult stem cells cannot; and
  2. What are the factors in living organisms that normally regulate stem cell proliferation and self-renewal?

Discovering the answers to these questions may make it possible to understand how cell proliferation is regulated during normal embryonic development or during the abnormal cell division that leads to cancer.

Stem cells are unspecialized. One of the fundamental properties of a stem cell is that it does not have any tissue-specific structures that allow it to perform specialized functions. For example, a stem cell cannot work with its neighbors to pump blood through the body (like a heart muscle cell), and it cannot carry oxygen molecules through the bloodstream (like a red blood cell). However, unspecialized stem cells can give rise to specialized cells, including heart muscle cells, blood cells, or nerve cells.

Stem cells can give rise to specialized cells. When unspecialized stem cells give rise to specialized cells, the process is called differentiation. While differentiating, the cell usually goes through several stages, becoming more specialized at each step. Scientists are just beginning to understand the signals inside and outside cells that trigger each step of the differentiation process. The internal signals are controlled by a cell’s genes, which are interspersed across long strands of DNA and carry coded instructions for all cellular structures and functions. The external signals for cell differentiation include chemicals secreted by other cells, physical contact with neighboring cells, and certain molecules in the microenvironment. The interaction of signals during differentiation causes the cell’s DNA to acquire epigenetic marks that restrict DNA expression in the cell and can be passed on through cell division.

Adult stem cells typically generate the cell types of the tissue in which they reside. For example, a blood-forming adult stem cell in the bone marrow normally gives rise to the many types of blood cells. It is generally accepted that a blood-forming cell in the bone marrow—which is called a hematopoietic stem cell—cannot give rise to the cells of a very different tissue, such as nerve cells in the brain.

Through years of experimentation, scientists have established some basic protocols or “recipes” for the directed differentiation of embryonic stem cells into some specific cell types (Figure 1). (For additional examples of directed differentiation of embryonic stem cells, refer to the NIH stem cell report available at

http://stemcells.nih.gov/info/scireport/pages/2006report.aspx.)

stem cell differentiation figure1_sm

stem cell differentiation figure1_sm

http://stemcells.nih.gov/StaticResources/images/figure1_sm.jpg

9.3.3 Types of Stem Cell Transplants for Treating Cancer

http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/bonemarrowandperipheralbloodstemcelltransplant/stem-cell-transplant-types-of-transplant

In a typical stem cell transplant for cancer very high doses of chemo are used, often along with radiation therapy, to try to destroy all the cancer cells. This treatment also kills the stem cells in the bone marrow. Soon after treatment, stem cells are given to replace those that were destroyed. These stem cells are given into a vein, much like a blood transfusion. Over time they settle in the bone marrow and begin to grow and make healthy blood cells. This process is called engraftment.

There are 3 basic types of transplants. They are named based on who gives the stem cells.

  • Autologous (aw-tahl-uh-gus)—the cells come from you
  • Allogeneic (al-o-jen-NEE-ick or al-o-jen-NAY-ick)—the cells come from a matched related or unrelated donor
  • Syngeneic (sin-jen-NEE-ick or sin-jen-NAY-ick)—the cells come from your identical twin or triplet
hematopoietic stem cell transplant

hematopoietic stem cell transplant

Autologous stem cell transplants

These stem cells come from you alone. In this type of transplant, your stem cells are taken before you get cancer treatment that destroys them. Your stem cells are removed, or harvested, from either your bone marrow or your blood and then frozen. To find out more about that process, please see the section “What’s it like to donate stem cells?” After you get high doses of chemo and/or radiation the stem cells are thawed and given back to you.

One advantage of autologous stem cell transplant is that you are getting your own cells back. When you donate your own stem cells you don’t have to worry about the graft attacking your body (graft-versus-host disease) or about getting a new infection from another person. But there can still be graft failure, and autologous transplants can’t produce the “graft-versus-cancer” effect.

This kind of transplant is mainly used to treat certain leukemias, lymphomas, and multiple myeloma. It’s sometimes used for other cancers, like testicular cancer and neuroblastoma, and certain cancers in children.

Getting rid of cancer cells in autologous transplants

A possible disadvantage of an autologous transplant is that cancer cells may be picked up along with the stem cells and then put back into your body later. Another disadvantage is that your immune system is still the same as before when your stem cells engraft. The cancer cells were able to grow despite your immune cells before, and may be able to do so again. The need to remove cancer cells from transplants or transplant patients and the best way to do it is being researched.

Doing 2 autologous transplants in a row is known as a tandem transplant or a double autologous transplant. In this type of transplant, the patient gets 2 courses of high-dose chemo, each followed by a transplant of their own stem cells. All of the stem cells needed are collected before the first high-dose chemo treatment, and half of them are used for each transplant. Most often both courses of chemo are given within 6 months, with the second one given after the patient recovers from the first one.

Allogeneic stem cell transplants

In the most common type of allogeneic transplant, the stem cells come from a donor whose tissue type closely matches the patient’s. (This is discussed later under “HLA matching” in the section called “ Donor matching for allogeneic transplant.”) The best donor is a close family member, usually a brother or sister. If you do not have a good match in your family, a donor might be found in the general public through a national registry. This is sometimes called a MUD (matched unrelated donortransplant. Transplants with a MUD are usually riskier than those with a relative who is a good match.

Blood taken from the placenta and umbilical cord of newborns is a newer source of stem cells for allogeneic transplant. Called cord blood, this small volume of blood has a high number of stem cells that tend to multiply quickly. But the number of stem cells in a unit of cord blood is often too low for large adults, so this source of stem cells is limited to small adults and children. Doctors are now looking at different ways to use cord blood for transplant in larger adults, such as using cord blood from 2 donors.

Pros of allogeneic stem cell transplant: The donor stem cells make their own immune cells, which could help destroy any cancer cells that remain after high-dose treatment. This is called the graft-versus-cancer effect. Other advantages are that the donor can often be asked to donate more stem cells or even white blood cells if needed, and stem cells from healthy donors are free of cancer cells.

Cons to allogeneic stem cell transplants: The transplant, also known as the graft, might not take — that is, the donor cells could die or be destroyed by the patient’s body before settling in the bone marrow. Another risk is that the immune cells from the donor may not just attack the cancer cells – they could attack healthy cells in the patient’s body. This is called graft-versus-host disease (described in the section called “Problems that may come up shortly after transplant”). There is also a very small risk of certain infections from the donor cells, even though donors are tested before they donate. A higher risk comes from infections you have had, and which your immune system has under control. These infections often surface after allogeneic transplant because your immune system is held in check (suppressed) by medicines called immunosuppressive drugs. These infections can cause serious problems and even death.

Allogeneic transplant is most often used to treat certain types of leukemia, lymphomas, multiple myeloma,myelodysplastic syndrome, and other bone marrow disorders such as aplastic anemia.

Mini transplants (non-myeloablative transplants)

For some people, age or certain health conditions make it more risky to wipe out all of their bone marrow before a transplant. For those people, doctors can use a type of allogeneic transplant that’s sometimes called a mini-transplant. Compared with a standard allogeneic transplant, this one uses less chemo and/or radiation to get the patient ready for the transplant. Your doctor might refer to it as a non-myeloablative transplant or mention reduced-intensity conditioning (RIC). The idea here is to kill some of the cancer cells along with some of the bone marrow, and suppress the immune system just enough to allow donor stem cells to settle in the bone marrow.

Unlike the standard allogeneic transplant, cells from both the donor and the patient exist together in the patient’s body for some time after a mini-transplant. But slowly, over the course of months, the donor cells take over the bone marrow and replace the patient’s own bone marrow cells. These new cells can then develop an immune response to the cancer and help kill off the patient’s cancer cells — the graft-versus-cancer effect.

Syngeneic stem cell transplants – for those with an identical sibling

This is a special kind of allogeneic transplant that can only be used when the recipient has an identical sibling (twin or triplet) who can donate — someone who will have the same tissue type. An advantage of syngeneic stem cell transplant is that graft-versus-host disease will not be a problem. There are no cancer cells in the transplant, either, as there would be in an autologous transplant.

A disadvantage is that because the new immune system is so much like the recipient’s immune system, there is no graft-versus-cancer effect, either. Every effort must be made to destroy all the cancer cells before the transplant is done to help keep the cancer from relapsing (coming back).

9.3.4 Graft versus Host Disease

http://bethematch.org/For-Patients-and-Families/Life-after-transplant/Graft-versus-host-disease–GVHD-/

Graft-versus-host disease(GVHD) occurs because of differences between the cells of your body and the donated cells and is a common side effect of an allogeneic bone marrow transplant.

An allogeneic transplant uses blood cells from a family member, unrelated donor or cord blood unit. GVHD can affect many different parts of the body including the skin, eyes, mouth, stomach, and intestines.

There are two types of GVHD:

  • Acute GVHD: Develops in the first 100 days or so after transplant but can occur later. This primarily affects the skin, stomach, intestines, and liver.
  • Chronic GVHD: Usually develops 3-6 months after transplant, but signs can appear earlier or later. If you have had or currently have acute GVHD, you are more likely to have chronic GVHD.

The severity of acute and chronic GVHD can range from mild to life-threatening.

Doctors often see mild GVHD as a good thing after an allogeneic transplant when the transplant was done for a blood cancer. It is a sign that the donor’s immune system is working to destroy any remaining cancer cells. Patients who experience some GVHD have a lower risk of the cancer returning after transplant than patients who do not develop GVHD. If the transplant was to treat a disease other than cancer disease, like aplastic anemia, then the doctor may want to treat even mild GVHD.

Graft-versus-Host Disease

JLM FerraraJE LevineP Reddy, and E Holler
Lancet. 2009 May 2; 373(9674): 1550–1561.
http://dx.doi.org:/10.1016/S0140-6736(09)60237-3

The number of allogeneic hematopoietic cell transplantations (HCT) continues to increase with more than 25,000 allogeneic transplantations performed annually. The graft-versus-leukemia / tumor (GVL) effect during allogeneic HCT effectively eradicates many hematological malignancies.1 The development of novel strategies that use donor leukocyte infusions, non-myeloablative conditioning and umbilical cord blood (UCB) transplantation have helped expand the indications for allogeneic HCT over the last several years, especially among older patients.2 Improvements in infectious prophylaxis, immunosuppressive medications, supportive care and DNA-based tissue typing have also contributed to improved outcomes after allogeneic HCT.1 Yet the major complication of allogeneic HCT, graft-versus-host disease (GVHD), remains lethal and limits the use of this important therapy.2 Given current trends, the number of transplants from unrelated donors is expected to double within the next five years, significantly increasing the population of patients with GVHD. In this seminar we review advances made in identifying the genetic risk factors and pathophysiology of this major HCT complication, as well as its prevention, diagnosis and treatment.

Etiology and Clinical Features

Fifty years ago Billingham formulated three requirements for the development of GVHD: the graft must contain immunologically competent cells; the recipient must express tissue antigens that are not present in the transplant donor; and the recipient must be incapable of mounting an effective response to eliminate the transplanted cells.3 We know now that the immunologically competent cells are T cells, and that GVHD can develop in various clinical settings when tissues containing T cells (blood products, bone marrow, and solid organs) are transferred from one person to another who is not able to eliminate those cells.45 Patients, whose immune systems are suppressed, and who receive white blood cells from another individual, are at particularly high risk for GVHD.

GVHD occurs when donor T cells respond to genetically defined proteins on host cells. The most important proteins are Human Leukocyte Antigens (HLA)267, which are highly polymorphic and are encoded by the major histocompatibility complex (MHC). Class I HLA (A, B, and C) proteins are expressed on almost all nucleated cells of the body at varying densities. Class II proteins (DR, DQ, and DP) are primarily expressed on hematopoietic cells (B cells, dendritic cells, monocytes), but their expression can be induced on many other cell types following inflammation or injury. High-resolution DNA typing of HLA genes with polymerase chain reaction (PCR)-based techniques have now largely replaced earlier methods. The incidence of acute GVHD is directly related to the degree of mismatch between HLA proteins89 and thus ideally, donors and recipients are matched at HLA-A, -B, -C, and -DRB1, (“8/8 matches”), but mismatches may be tolerated for UCB grafts (see below).1012

Non-HLA Genetics

Despite HLA identity between a patient and donor, approximately 40% of patients receiving HLA-identical grafts develop acute GVHD due to genetic differences that lie outside the HLA loci, or “minor” histocompatibility antigens (HA). Some minor HAs, such as HY and HA-3, are expressed on all tissues and are targets for both GVHD and GVL.13 Other minor HAs, such as HA-1 and HA-2, are expressed most abundantly on hematopoietic cells (including leukemic cells) and may therefore induce a greater GVL effect with less GVHD.1314

Polymorphisms in both donors and recipients for cytokines that are involved in the classical `cytokine storm’ of GVHD (discussed below) have been implicated as risk factors for GVHD.15 Tumor Necrosis Factor (TNF)-α, Interleukin 10 (IL-10), Interferon-γ (IFNγ) variants have correlated with GVHD in some, but not all, studies.1618 Genetic polymorphisms of proteins involved in innate immunity, such as nucleotide oligomerization domain 2 and Keratin 18 receptors, have also been associated with GVHD.1922 Future strategies to identify the best possible transplant donor will probably incorporate both HLA and non-HLA genetic factors.

Clinical Features of Acute GVHD

Based on an early Seattle experience, acute GVHD was defined to occur prior to day 100, whereas chronic GVHD occurred after that time.2325 This definition is far from satisfactory, and a recent National Institutes of Health classification includes late-onset acute GVHD (after day 100) and an overlap syndrome with features of both acute and chronic GVHD.26 Late-onset acute GVHD and the overlap syndrome occur with greater frequency after reduced-intensity conditioning (RIC), an increasingly widespread technique (see below). As shown in Table 1, the clinical manifestations of acute GVHD occur in the skin, gastrointestinal tract and liver.27 In a comprehensive review, Martin et al found that at the onset of acute GVHD, 81% of patients had skin involvement, 54% had GI involvement, and 50% had liver involvement.23 Recent data suggest that lungs might also be targets of experimental GVHD.28

Acute GVHD Symptoms

Table 1

Pathophysiology of Acute GVHD

Two important principles are important to consider regarding the pathophysiology of acute GVHD. First, acute GVHD reflects exaggerated but normal inflammatory mechanisms mediated by donor lymphocytes infused into the recipient where they function appropriately, given the foreign environment they encounter. Second, the recipient tissues that stimulate donor lymphocytes have usually been damaged by underlying disease, prior infections, and the transplant conditioning regimen.29 As a result, these tissues produce molecules (sometimes referred to as “danger” signals) that promote the activation and proliferation of donor immune cells.4245 Mouse models havebeen central to our identification and understanding of the pathophysiologic mechanisms of GVHD, and canine models have been critical to the development of clinically useful strategies for GVHD prophylaxis and treatment and to the development of donor leukocyte infusions.364647 Based largely on these experimental models, the development of acute GVHD can be conceptualized in three sequential steps or phases: (1) activation of the APCs; (2) donor T cell activation, proliferation, differentiation and migration; and (3) target tissue destruction (Figure 3).

Figure 3

GVHD Pathophysiology

In Phase I, the recipient conditioning regimen damages host tissues and causes release of inflammatory cytokines such as TNFα, IL-1 and IL-6. Increased levels of these cytokines leads to activation of host antigen presenting cells (APCs). In Phase II, host APCs activate mature donor cells. The subsequent proliferation and differentiation of these activated T cells produces additional effectors that mediate the tissue damage, including Cytotoxic T Lymphocytes, Natural Killer (NK) cells, TNFα and IL-1. Lipopolysaccharide (LPS) that has leaked through the damaged intestinal mucosa triggers additional TNFα production. TNFα can damage tissue directly by inducing necrosis and apoptosis in the skin and GI tract through either TNF receptors or the Fas pathway. TNFα plays a direct role in intestinal GVHD damage which further amplifies damage in the skin, liver and lung in a “cytokine storm.”

GVHD pathophysiology nihms-115970-f0003

GVHD pathophysiology nihms-115970-f0003

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735047/bin/nihms-115970-f0003.jpg

Phase I: Activation of Antigen Presenting Cells (APCs)

The first step involves the activation of APCs by the underlying disease and the HCT conditioning regimen. Damaged host tissues respond by producing “danger” signals, including proinflammatory cytokines (e.g., TNF-α), chemokines, and increased expression of adhesion molecules, MHC antigens and costimulatory molecules on host APCs.424850 A recent report demonstrated that at one week after HCT, increased levels of TNF-α receptor I, a surrogate marker for TNF-α, strongly correlated with the later development of GVHD.51 Damage to the GI tract from the conditioning is particularly important because it allows for systemic translocation of additional inflammatory stimuli such as microbial products including lipopolysaccaride (LPS) or other pathogen-associated molecular patterns that further enhance the activation of host APCs.49 The secondary lymphoid tissue in the GI tract is likely the initial site of interaction between activated APCs and donor T cells.52 These observations have led an important clinical strategy to reduce acute GVHD by reducing the intensity of the conditioning regimen. Experimental GVHD can also be reduced by manipulating distinct subsets of APCs.53,54 In addition, non-hematopoietic stem cells, such as mesenchymal stem cells or stromal cells, can reduce allogeneic T cell responses, although the mechanism for such inhibition remains unclear.2

The concept that enhanced activation of host APCs increases the risk for acute GVHD unifies a number of seemingly disparate clinical associations with that risk, such as advanced stages of malignancy, more intense transplant conditioning regimens and histories of viral infections. APCs detect infections by recognizing conserved molecular patterns that are unique to microbes, called pathogen-associated molecular patterns (PAMPs). Among the classes of receptors that recognize such patterns, the Toll-like receptors (TLR) are the best characterized.55 For example, TLR4 recognizes LPS55 and mice with mutant TLR4 receptors that do not respond to LPS cause less GVHD when used as donors.56 Other TLRs that recognize viral DNA or RNA also activate APCs and may enhance GVHD, providing a potential mechanistic basis for increased GVHD associated with viral infections such as cytomegalovirus (CMV).57

Phase II: Donor T Cell Activation

The core of the GVH reaction is Step 2, where donor T cells proliferate and differentiate in response to host APCs. The “danger” signals generated in Phase I augment this activation at least in part by increasing the expression of costimulatory molecules.58 Blockade of co-stimulatory pathways to prevent GVHD is successful in animal models, but this approach has not yet been tested in large clinical trials.2

In mouse models, where genetic differences between donor and recipient strains can be tightly controlled, CD4+ cells induce acute GVHD to MHC class II differences, and CD8+ cells induce acute GVHD to MHC class I differences.5961 In the majority of HLA-identical HCTs, both CD4+ and CD8+ subsets respond to minor histocompatibility antigens and can cause GVHD in HLA-identical HCT.

Regulatory T cells can suppress the proliferation of conventional T cells and prevent GVHD in animal models when added to donor grafts containing conventional T cells.62 In mice, the Foxp3 protein functions as a master switch in the development of regulatory T cells, which normally constitute 5% of the CD4+ T cell population.62 Regulatory T cells secrete anti-inflammatory cytokines IL-10 and Transforming Growth Factor(TGF)-β and can also act through contact-dependent inhibition of APCs.62 It is likely that the use of regulatory T cells in clinical acute GVHD will require improved techniques to identify and expand them.

Natural Killer T cell (NKT) 1.1+ subsets of both the host and donors that have been shown to modulate acute GVHD.63 Host NKT cells have been shown to suppress acute GVHD in an IL-4 dependent manner.64 A recent clinical trial of total lymphoid irradiation used as conditioning significantly reduced GVHD and enhanced host NKT cell function.65 By contrast, donor NKT cells can reduce GVHD and enhance perforin mediated GVL in an experimental model.66

Activation of immune cells results in rapid intracellular biochemical cascades that induce transcription of genes for many proteins including cytokines and their receptors. Th1 cytokines (IFN-γ, IL-2 and TNF-α) are produced in large amounts during acute GVHD. IL-2 production by donor T cells remains the principal target of many current clinical therapeutic and prophylactic approaches to GVHD, such as cyclosporine, tacrolimus and monoclonal antibodies (mAbs) directed against IL-2 and its receptor.9 But emerging data indicate an important role for IL-2 in the generation and maintenance of CD4+ CD25+ T regs, suggesting that prolonged interference with IL-2 may have an unintended consequence of preventing the development of long term tolerance after allogeneic HCT.67 IFN-γ has multiple functions and can either amplify or reduce GVHD.68,69 IFN-γ may amplify GVHD by increasing the expression of molecules such as chemokines receptors, MHC proteins, and adhesion molecules; it also increases the sensitivity of monocytes and macrophages to stimuli such as LPS and accelerates intracellular cascades in response to these stimuli.70Early polarization of donor T cells so that they secrete less IFN-γ and more IL-4 can also attenuate experimental acute GVHD.71 IFN-γ may amplify GVHD by directly damaging epithelium in the GI tract and skin and inducing immnosuppression through the induction of nitric oxide.72 By contrast, IFN-γ may suppress GVHD by hastening the apoptosis of activated donor T cells.6973. This complexity means the manipulation of IFN-γ may have diverse effects in vivo, making it a challenging target with respect to therapeutic intervention. IL-10 plays a key role in suppression of immune responses, and clinical data suggest it may regulate acute GVHD.17 TGF-β, another suppressive cytokine can suppress acute GVHD but exacerbate chronic GVHD.74 Thus the timing and duration of the secretion of any given cytokine may determine the specific effects of that cytokine on GVHD severity.

Phase III: Cellular and Inflammatory Effector Phase

The effector phase of this process is a complex cascade of both cellular mediators such as cytotoxic T lymphocytes(CTLs) and NK cells and soluble inflammatory mediators such as TNF-α, IFN-γ, IL-1 and nitric oxide.229 These soluble and cellular mediators synergize to amplify local tissue injury and further promote inflammation and target tissue destruction.

Cellular Effectors

The cellular effectors of acute GVHD are primarily CTLs and NK cells.49 CTLs that preferentially use the Fas/FasL pathway of target lysis and appear to predominate in GVHD liver damage (hepatocytes express large amounts of Fas) whereas GVHD CTLs that use the perforin /granzyme pathways are more important in the GI tract and skin.275 Chemokines direct the migration of donor T cells from lymphoid tissues to the target organs where they cause damage. Macrophage inflammatory protein-1alpha (MIP-1α) and other chemokines such as CCL2-5, CXCL2, CXCL9-11, CCL17 and CCL27 are over-expressed and enhance the homing of cellular effectors to target organs during experimental GVHD.76Expression of integrins, such as α4β7 and its ligand MadCAM-1, are also important for homing of donor T cells to Peyer’s patches during intestinal GVHD.527778

Prevention of GVHD

Based on the evidence from animal models regarding the central role of T cells in initiating GVHD, numerous clinical studies evaluating T cell depletion (TCD) as prophylaxis for GVHD were performed in the 1980’s and 1990’s. There were three principal TCD strategies: (1) negative selection of T cells ex vivo, (2) positive selection of CD34+ stem cells ex vivo; and (3) anti-T cell antibodies in vivo.83Most strategies showed a significant limitation in both acute and chronic GVHD.8488 Unfortunately, the lower incidence of severe GVHD was offset by high rates of graft failure, relapse of malignancy, infections, and Epstein-Barr virus-associated lymphoproliferative disorders. Negative selection purging strategies using various anti-T cell antibodies achieved similar long-term results regardless of the breadth of antibody specificity.8993 One large registry study demonstrated that purging strategies using antibodies with broad specificities produced inferior leukemia-free survival than standard immunosuppression in patients receiving unrelated donor transplants.94 Several studies have investigated partial T cell depletion, either by eliminating specific T cell subsets (e.g., CD8+) or by titrating the dose of T cells present in the inoculum.9597 None of these approaches, however, has convincingly demonstrated an optimal strategy that improves long-term survival.

Alemtuzumab is a monoclonal antibody that binds CD52, a protein expressed on a broad spectrum of leukocytes including lymphocytes, monocytes, and dendritic cells. Its use in GVHD prophylaxis in a Phase II trial decreased the incidence of acute and chronic GVHD following reduced intensity transplant.98 In two prospective studies, patients who received alemtuzumab rather than methotrexate showed significantly lower rates of acute and chronic GVHD,99 but experienced more infectious complications and higher rates of relapse, so that there was no overall survival benefit. Alemtuzumab may also contribute to graft failure when used with minimal intensity conditioning regimens.100

An alternative strategy to TCD attempted to induce anergy in donor T cells by ex vivo antibody blockade of co-stimulatory pathways prior to transplantation. A small study using this approach in haploidentical HCT recipients was quite encouraging, but has not yet been replicated.101 Thus the focus of most prevention strategies remains pharmacological manipulation of T cells after transplant.

Administration of anti-T cell antibodies in vivo as GVHD prophylaxis has also been extensively tested. The best studied drugs are anti-thymocyte globulin (ATG) or antilymphocyte globulin (ALG) preparations. These sera, which have high titers of polyclonal antibodies, are made by immunizing animals (horses or rabbits) to thymocytes or lymphocytes, respectively. A complicating factor in determining the role of these polyclonal sera in transplantation is the observation that even different brands of the same class of sera exert different biologic effects.102 However, the side effects of ATG/ALG infusions are common across different preparations and include fever, chills, headache, thrombocytopenia (from cross-reactivity to platelets), and, infrequently, anaphylaxis. In retrospective studies, rabbit ATG reduced the incidence of GVHD in related donor HSCT recipients without appearing to improve survival.103104 In recipients of unrelated donor HSCT, addition of ALG to standard GVHD prophylaxis effectively prevented severe GVHD, but did not result in improved survival because of increased infections.105 In a long term follow-up study, however, pretransplant ATG provided significant protection against extensive chronic GVHD and chronic lung dysfunction.106

The primary pharmacologic strategy to prevent GVHD is the inhibition of the cytoplasmic enzyme, calcineurin, that is critical for in the activation of T cells. The calcineurin inhibitors, cyclosporine and tacrolimus, have similar mechanisms of action, clinical effectiveness and toxicity profiles, including hypomagnesemia, hyperkalemia, hypertension, and nephrotoxicity.9107 Serious side effects include transplant-associated thrombotic microangiopathy (TAM) and neurotoxicity that can lead to premature discontinuation. Although clinically similar to thrombotic thrombocytopenic purpura, TAM does not reliably respond to therapeutic plasmapheresis, carries a high mortality rate, and removal of the offending agent does not always result in improvement.108 Posterior reversible encephalopathy syndrome includes mental status changes, seizures, neurological deficits and characteristic magnetic resonance imaging findings; this syndrome has been seen in 1-2% of HCT recipients receiving and calcineurin inhibitors.109 Side effects of these drugs decrease as the dose is tapered, usually two to four months after HCT.

Calcineurin inhibitors are often administered in combination with other immunosuppressants, such as methotrexate, which is given at low doses in the early post-transplant period.9107 The toxicities of methotrexate (neutropenia and mucositis) have led some investigators to replace it with mycophenolate mofetil (MMF). In one prospective randomized trial, patients who received MMF as part of GVHD prophylaxis experienced significantly less severe mucositis and more rapid neutrophil engraftment than those who received methotrexate.110 The incidence and severity of acute GVHD was similar between the two groups, but the study closed early due to superiority of the MMF arm with respect to reduced mucositis and the speed of hematopoietic engraftment. A desire for faster neutrophil engraftment has led to the use of MMF in UCB blood transplants where graft failure is a major concern.111 MMF is also often used after RIC regimens for similar reasons.112113

Sirolimus is an immunosuppressant that is structurally similar to tacrolimus but does not inhibit calcineurin. In a small Phase II trial, it showed excellent efficacy in combination with tacrolimus;114 the drug damages endothelial cells, however, and it may enhance TAM that is associated with calcineurin inhibitors.115 The combination of tacrolimus and sirolimus is currently being compared in a large randomized multi-center trial.

RIC regimens attempt to suppress the host immune system sufficiently so that donor T cells can engraft and then ablate the lympho-hematopoietic compartment of the recipient. The term “non-myeloablative” is therefore somewhat misleading. RIC regimens produce less tissue damage and lower levels of the inflammatory cytokines that are important in the initiation of GVHD pathophysiology; this effect may explain the reduced incidence of severe GVHD following RIC compared to the full intensity conditioning used in historical controls.98116 The onset of acute GVHD may be delayed after RIC until after day 100, however, and it may present simultaneously with elements of chronic GVHD (“overlap syndrome”).116120

Treatment of Acute GVHD

GVHD generally first develops in the second month after HCT, during continued treatment with calcineurin-based prophylaxis.23121 Steroids, with their potent antilymphocyte and anti-inflammatory activity, are the gold standard for treatment of GVHD. Many centers treat mild GVHD of the skin (Grade I) with topical steroids alone, but for more severe skin GVHD and any degree of visceral GVHD involvement, high-dose systemic steroids are usually initiated. Steroid therapy results in complete remission in less than half of the patients,122 and more severe GVHD is less likely to respond to treatment.123124 In a prospective randomized study, the addition of ATG to steroids as primary therapy did not increase the response rate.124 In a retrospective study, the use of ATG in patients who showed early signs of steroid-resistance was beneficial,122 but not all studies show such benefit and ATG is not standardly used because of increased infection risks.106125126.

An increasingly common treatment for GVHD is extracorporeal photopheresis (ECP). During ECP, the patient’s white blood cells are collected by apheresis, incubated with the DNA-intercalating agent, 8-methoxypsoralen, exposed to ultraviolet light (UVA), and returned to the patient. ECP is known to induce cellular apoptosis, which has strong anti-inflammatory effects in a number of systems, including prevention of rejection of solid organ grafts.127 Animal studies show that ECP reverses acute GVHD by increasing the number of regulatory T cells.128 A Phase II clinical study of steroid-dependent or steroid refractory GVHD showed resolution of GVHD in a large majority of patients, with 50% long-term survival in this very high risk group.129 Randomized multi-center studies of this approach are needed to determine its place in the management of acute GVHD.

Another interesting strategy to treat GVHD is the blockade of the inflammatory cytokine TNF-α. TNF-α can activate APCs, recruit effector cells and cause direct tissue damage.130 In animal models, TNF-α plays a central role in GVHD of the GI tract, which is central to the “cytokine storm” and plasma levels of TNFR I (a surrogate marker for TNF-α) rise in patients before the clinical manifestations of GVHD appear. 51 A recent Phase II trial of etanercept, a solubilized TNFR II, showed significant efficacy when added to systemic steroids as primary therapy for acute GVHD. Seventy percent of patients had complete resolution of all GVHD symptoms within one month, with 80% complete responses in the GI tract and the skin. The authors also showed that plasma levels of TNFR I were a significant biomarker for clinical GVHD.131

Treatment of Chronic GVHD

In contrast to acute GVHD, the pathophysiology of chronic GVHD remains poorly understood, and it is treated with a variety of immunosuppressive agents. The response of chronic GVHD to treatment is unpredictable, and mixed responses in different organs can occur in the same patient. Confounding variables such as infection and co-morbidities also make responses hard to measure. The use of corticosteroids (with or without a calcineurin inhibitor) is the standard of care, but a randomized trial of more than 300 patients with chronic GVHD found no difference between cyclosporine plus prednisone versus prednisone alone.132 Chronic immunosuppressants, especially those containing steroids, are highly toxic and result in infectious deaths. Many second line therapies have been studied, but none has achieved widespread acceptance. As mentioned above, ECP shows some promise, with significant response rates in high-risk patients. The best responses were observed in skin, liver, oral mucosa, eye, and lung.133 This observation is particularly relevant because lung GVHD has the potential to be a particularly devastating complication necessitating lung transplant as the only therapeutic option.134135

Essential Supportive Care in GVHD Patients

Meticulous supportive care is critical for patients with both acute and chronic GVHD because of the extended duration of immunosuppressive treatments and because the multiple medications required may have synergistic toxicities. Such care includes extensive infectious prophylaxis, early interventions in cases of suspected infections, and prophylaxis against non-infectious side effects of medications (See Table 3). These complications often require rapid responses to prevent serious or irreversible damage, and are best handled in close collaboration between the primary physician and the transplant specialist.

Table 3

Recommendations for Supportive Care

All patients should receive at least fluconazole as prophylaxis against fungal infections. Invasive molds, especially aspergillus, are common in patients with prolonged steroid use.136 Prophylaxis with voriconazole or posaconazole should be considered for these patients. Usual sites of infection are the lungs, sinuses, brain, skin,137 and serial galactomannan assays may aid in the early detection.138 Candida can cause lesions in the lung and spleen, which may need screening with ultrasonography. Pneumocystis is another opportunistic infection that should receive cotrimoxazol (bactrim) prophylaxis.139

Viral infections are frequent in these patients with GVHD. Cytomegalovirus causes interstitial pneumonia and gastritis. Patients who are at risk should have their blood monitored several times monthly. Techniques that directly detect virus should be performed, such as CMV PCR or pp65 antigen, and evidence of increased viral load should prompt preemptive treatment with ganciclovir or foscarnet prior to clinical manifestations of disease. Shingles is not uncommon and acyclovir prophylaxis may be beneficial.140 Patients and caregivers should receive vaccinations against influenza, and treatment with neuraminidase inhibitors is recommended in the event of influenza infection.141142

Patients with GVHD often have IgG2 and IgG4 subclass deficiencies despite normal lgG levels, making them susceptible to infections with encapsulated organisms. Treatment of severe hypogammaglobulinemia with intravenous immunoglobulin is standard in many centers,143 but the level that triggers replacement varies considerably among transplant specialists. There is little supporting evidence for the routine use of intravenous immunoglobulin as prophylaxis144 but patients should receive routine prophylaxis (penicillin or its equivalent) due to the increased risk of streptococcal sepsis.145 Pneumococcal conjugate and hemophilus influenza vaccine may provide additional protection and are also recommended for all patients, including those with chronic GVHD.139146147 The sites of any indwelling catheters should be assessed regularly and early treatment of a suspected infection initiated. Early signs or symptoms of septic shock such as shaking chills or low blood pressure requires prompt evaluation with chest X-ray and/or CT scan, blood culture and broad spectrum antibiotics because shock may progress rapidly in these patients.

9.3.5 Aspergillus Complicating Allogeneic Transplantation

Aspergillus infections in allogeneic stem cell transplant recipients: have we made any progress?

E Jantunen, V-J Anttila and T Ruutu
BMT 2002; 30(12):925-929
http://www.nature.com/bmt/journal/v30/n12/full/1703738a.html
http://dx.doi.org:/10.1038/sj.bmt.1703738

Invasive aspergillosis (IA) is common in allogeneic SCT recipients, with an incidence of 4-10%. The majority of these infections are diagnosed several months after SCT and they are frequently associated with GVHD. The diagnosis is difficult and often delayed. Established IA is notoriously difficult to treat with a death rate of 80-90%. This review summarises recent data on this problem to assess whether there has been any progress. Effective prophylactic measures are still lacking. Severe immunosuppression is the main obstacle to the success of therapy. Recent and ongoing developments in diagnostic measures and new antifungal agents may improve treatment results to some extent, but Aspergillus infections still remain a formidable problem in allogeneic transplantation. Further studies in this field will focus on the role of various cytokines and combinations of antifungal agents.

Summary

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Hematologic Malignancies [2.4.3]

Writer and Curator:  Larry H. Bernstein, MD, FCAP

Updated on 4/14/2016

Hematologic Malignancies 

Not excluding lymphomas [solid tumors]

The following series of articles are discussions of current identifications, classification, and treatments of leukemias, myelodysplastic syndromes and myelomas.

6.2 Hematological Malignancies

6.2.1 Ontogenesis of blood elements

6.2.1.1 Erythropoiesis

6.2.1.2 White blood cell series: myelopoiesis

6.2.1.3 Thrombocytogenesis

6.2.2 Classification of hematopoietic cancers

6.2.2.1 Primary Classification

6.2.2.1.1 Acute leukemias

6.2.2.1.1 Myelodysplastic syndromes

6.2.2.1.2 Acute myeloid leukemia

6.2.2.1.3 Acute lymphoblastic leukemia

6.2.2.2 Myeloproliferative Disorders

6.2.2.2.1 Chronic myeloproliferative disorders

6.2.2.2.2 Chronic myelogenous leukemia and related disorders

6.2.2.2.3 Myelofibrosis, including chronic idiopathic

6.2.2.2.4 Polycythemia, including polycythemia rubra vera

6.2.2.2.5 Thrombocytosis, including essential thrombocythemia

6.2.2.3 Chronic lymphoid leukemia and other lymphoid leukemias

6.2.2.4 Lymphomas

6.2.2.4.1 Non-Hodgkin Lymphoma

6.2.2.4.2 Hodgkin lymphoma

6.2.2.5 Lymphoproliferative disorders associated with immunodeficiency

6.2.2.6 Plasma Cell dyscrasias

6.2.2.7 Mast cell disease and Histiocytic neoplasms

6.2.3 Secondary Classification

6.2.3.1 Nuance – PathologyOutlines

6.2.3.1..1-8

6.2.4 Diagnostics

6.2.4.1 Computer-aided diagnostics

6.2.4.1.1 Back-to-Front Design

6.2.4.1.2 Realtime Clinical Expert Support

6.2.4.1.3 Regression: A richly textured method for comparison and classification of predictor variables

6.2.4.1.4 Converting Hematology Based Data into an Inferential Interpretation

6.2.4.1.5 A model for Thalassemia Screening using Hematology Measurements

6.2.4.1.6 Measurement of granulocyte maturation may improve the early diagnosis of the septic state.

6.2.4.1.7 The automated malnutrition assessment.

6.2.4.2 Molecular Diagnostics

6.2.4.2.1 Genomic Analysis of Hematological Malignancies

6.2.4.2.2 Next-generation sequencing in hematologic malignancies: what will be the dividends?

6.2.4.2.3 Leveraging cancer genome information in hematologic malignancies.

6.2.4.2.4 p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

6.2.4.2.5 Genomic approaches to hematologic malignancies

6.2.5  Treatment of hematopoietic cancers

6.2.5.1 Treatments for leukemia by type

6.2.5.1.1 Acute lymphocytic leukemias

6.2.5.1.2 Treatment of Acute Lymphoblastic Leukemia

6.2.5.1.3 Acute Lymphoblastic Leukemia

6.2.5.1.4 Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

6.2.5.1.5 Leukemias Treatment & Management

6.2.5.1.6 Treatments and drugs

6.2.5.2 Acute Myeloid Leukemia

6.2.5.2.1 New treatment approaches in acute myeloid leukemia: review of recent clinical studies

6.2.5.2.2 Novel approaches to the treatment of acute myeloid leukemia.

6.2.5.2.3 Current treatment of acute myeloid leukemia

6.2.5.2.4 Adult Acute Myeloid Leukemia Treatment (PDQ®)

6.2.5.3 Treatment for CML

6.2.5.3.1 Chronic Myelogenous Leukemia Treatment (PDQ®)

6.2.5.3.2 What`s new in chronic myeloid leukemia research and treatment?

6.2.5.4 Chronic Lymphocytic Leukemia

6.2.5.4.1 Chronic Lymphocytic Leukemia Treatment (PDQ®)

6.2.5.4.2 Results from the Phase 3 Resonate™ Trial

6.2.5.4.3 Typical treatment of chronic lymphocytic leukemia

6.2.5.5 Lymphoma treatment

6.2.5.5.1 Overview

6.2.5.5.2 Chemotherapy

6.2.6 Primary treatments

6.2.6.1 Total body irradiation (TBI)

6.2.6.2 Bone marrow (BM) transplantation

6.2.6.2.1 Autologous stem cell transplantation

6.2.6.2.2  Hematopoietic stem cell transplantation

6.2.7 Supportive Therapies

6.2.7.1  Blood transfusions

6.2.7.2  Erythropoietin

6.2.7.3  G-CSF (granulocyte-colony stimulating factor)

6.2.7.4  Plasma exchange (plasmapheresis)

6.2.7.5  Platelet transfusions

6.2.7.6  Steroids

6.2.1 Ontogenesis of the blood elements: hematopoiesis

http://www.britannica.com/EBchecked/topic/69747/blood-cell-formation

Blood cells are divided into three groups: the red blood cells (erythrocytes), the white blood cells (leukocytes), and the blood platelets (thrombocytes). The white blood cells are subdivided into three broad groups: granulocytes, lymphocytes, and monocytes.

Blood cells do not originate in the bloodstream itself but in specific blood-forming organs, notably the marrow of certain bones. In the human adult, the bone marrow produces all of the red blood cells, 60–70 percent of the white cells (i.e., the granulocytes), and all of the platelets. The lymphatic tissues, particularly the thymus, the spleen, and the lymph nodes, produce the lymphocytes (comprising 20–30 percent of the white cells). The reticuloendothelial tissues of the spleen, liver, lymph nodes, and other organs produce the monocytes (4–8 percent of the white cells). The platelets, which are small cellular fragments rather than complete cells, are formed from bits of the cytoplasm of the giant cells (megakaryocytes) of the bone marrow.

In the human embryo, the first site of blood formation is the yolk sac. Later in embryonic life, the liver becomes the most important red blood cell-forming organ, but it is soon succeeded by the bone marrow, which in adult life is the only source of both red blood cells and the granulocytes. Both the red and white blood cells arise through a series of complex, gradual, and successive transformations from primitive stem cells, which have the ability to form any of the precursors of a blood cell. Precursor cells are stem cells that have developed to the stage where they are committed to forming a particular kind of new blood cell.

In a normal adult the red cells of about half a liter (almost one pint) of blood are produced by the bone marrow every week. Almost 1 percent of the body’s red cells are generated each day, and the balance between red cell production and the removal of aging red cells from the circulation is precisely maintained.

Cells-in-the-Bone-Marrow-1024x747

Cells-in-the-Bone-Marrow-1024×747

http://interactive-biology.com/wp-content/uploads/2012/07/Cells-in-the-Bone-Marrow-1024×747.png

6.2.1.1 Erythropoiesis

http://www.interactive-biology.com/3969/erythropoiesis-formation-of-red-blood-cells/

Erythropoiesis – Formation of Red Blood Cells

Because of the inability of erythrocytes (red blood cells) to divide to replenish their own numbers, the old ruptured cells must be replaced by totally new cells. They meet their demise because they don’t have the usual specialized intracellular machinery, which controls cell growth and repair, leading to a short life span of 120 days.

This short life span necessitates the process erythropoiesis, which is the formation of red blood cells. All blood cells are formed in the bone marrow. This is the erythrocyte factory, which is soft, highly cellar tissue that fills the internal cavities of bones.

Erythrocyte differentiation takes place in 8 stages. It is the pathway through which an erythrocyte matures from a hemocytoblast into a full-blown erythrocyte. The first seven all take place within the bone marrow. After stage 7 the cell is then released into the bloodstream as a reticulocyte, where it then matures 1-2 days later into an erythrocyte. The stages are as follows:

  1. Hemocytoblast, which is a pluripotent hematopoietic stem cell
  2. Common myeloid progenitor, a multipotent stem cell
  3. Unipotent stem cell
  4. Pronormoblast
  5. Basophilic normoblast also called an erythroblast.
  6. Polychromatophilic normoblast
  7. Orthochromatic normoblast
  8. Reticulocyte

These characteristics can be seen during the course of erythrocyte maturation:

  • The size of the cell decreases
  • The cytoplasm volume increases
  • Initially there is a nucleus and as the cell matures the size of the nucleus decreases until it vanishes with the condensation of the chromatin material.

Low oxygen tension stimulates the kidneys to secrete the hormone erythropoietin into the blood, and this hormone stimulates the bone marrow to produce erythrocytes.

Rarely, a malignancy or cancer of erythropoiesis occurs. It is referred to as erythroleukemia. This most likely arises from a common myeloid precursor, and it may occur associated with a myelodysplastic syndrome.

Summary of erythrocyte maturation

6.2.1.2 White blood cell series: myelopoiesis

http://www.nlm.nih.gov/medlineplus/ency/presentations/100151_3.htm

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/15220.jpg

There are various types of white blood cells (WBCs) that normally appear in the blood: neutrophils (polymorphonuclear leukocytes; PMNs), band cells (slightly immature neutrophils), T-type lymphocytes (T cells), B-type lymphocytes (B cells), monocytes, eosinophils, and basophils. T and B-type lymphocytes are indistinguishable from each other in a normal slide preparation. Any infection or acute stress will result in an increased production of WBCs. This usually entails increased numbers of cells and an increase in the percentage of immature cells (mainly band cells) in the blood. This change is referred to as a “shift to the left” People who have had a splenectomy have a persistent mild elevation of WBCs. Drugs that may increase WBC counts include epinephrine, allopurinol, aspirin, chloroform, heparin, quinine, corticosteroids, and triamterene. Drugs that may decrease WBC counts include antibiotics, anticonvulsants, antihistamine, antithyroid drugs, arsenicals, barbiturates, chemotherapeutic agents, diuretics and sulfonamides.   (Updated by: David C. Dugdale, III, MD)

https://www.med-ed.virginia.edu/courses/path/innes/nh/wcbmaturation.cfm

Note that the mature forms of the myeloid series (neutrophils, eosinophils, basophils), all have lobed (segmented) nuclei. The degree of lobation increases as the cells mature.

The earliest recognizable myeloid cell is the myeloblast (10-20m dia) with a large round to oval nucleus. There is fine diffuse immature chromatin (without clumping) and a prominant nucleolus.

The cytoplasm is basophilic without granules. Although one may see a small golgi area adjacent to the nucleus, granules are not usually visible by light microscopy. One should not see blast cells in the peripheral blood.

myeloblast x100b

myeloblast x100b

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20myeloblast%20x100b.jpeg

The promyelocyte (10-20m) is slightly larger than a blast. Its nucleus, although similar to a myeloblast shows slight chromatin condensation and less prominent nucleoli. The cytoplasm contains striking azurophilic granules or primary granules. These granules contain myeloperoxidase, acid phosphatase, and esterase enzymes. Normally no promyelocytes are seen in the peripheral blood.

At the point in development when secondary granules can be recognized, the cell becomes a myelocyte.

promyelocyte x100

promyelocyte x100

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20promyelocyte%20×100%20a.jpeg

Myelocytes (10-18m) are not normally found in the peripheral blood. Nucleoli may not be seen in the late myelocyte. Primary azurophilic granules are still present, but secondary granules predominate. Secondary granules (neut, eos, or baso) first appear adjacent to the nucleus. In neutrophils this is the “dawn” of neutrophilia.

Metamyelocytes (10-18m) have kidney shaped indented nuclei and dense chromatin along the nuclear membrane. The cytoplasm is faintly pink, and they have secondary granules (neutro, eos, or baso). Zero to one percent of the peripheral blood white cells may be metamyelocytes (juveniles).

metamyelocyte x100

metamyelocyte x100

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20metamyelocyte%20×100.jpeg

Bands, slightly smaller than juveniles, are marked by a U-shaped or deeply indented nucleus.

band neutrophilx100a

band neutrophilx100a

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20band%20x100a.jpeg

Segmented (segs) or polymorphonuclear (PMN) leukocytes (average 14 m dia) are distinguished by definite lobation with thin thread-like filaments of chromatin joining the 2-5 lobes. 45-75% of the peripheral blood white cells are segmented neutrophils.

https://www.med-ed.virginia.edu/courses/path/innes/images/nhjpeg/nh%20neutrophil%20×100%20d.jpeg

6.2.1.3 Thrombocytogenesis

The incredible journey: From megakaryocyte development to platelet formation

Kellie R. Machlus1,2 and Joseph E. Italiano Jr
JCB 2013; 201(6): 785-796
http://dx.doi.org:/10.1083/jcb.201304054

Large progenitor cells in the bone marrow called megakaryocytes (MKs) are the source of platelets. MKs release platelets through a series of fascinating cell biological events. During maturation, they become polyploid and accumulate massive amounts of protein and membrane. Then, in a cytoskeletal-driven process, they extend long branching processes, designated proplatelets, into sinusoidal blood vessels where they undergo fission to release platelets.

megakaryocyte production of platelets

megakaryocyte production of platelets

http://dm5migu4zj3pb.cloudfront.net/manuscripts/26000/26891/medium/JCI0526891.f4.jpg

platelets and the immune continuum nri2956-f3

platelets and the immune continuum nri2956-f3

http://www.nature.com/nri/journal/v11/n4/images/nri2956-f3.jpg

6.2.2 Classification of hematological malignancies
Practical Diagnosis of Hematologic Disoreders. 4th edition. Vol 2.
Kjeldsberg CR, Ed.  ASCP Press.  2006. Chicago, IL.

6.2.2.1 Primary Classification

6.2.2.1.1 Acute leukemias

6.2.2.1.1 Myelodysplastic syndromes

6.2.2.1.2 Acute myeloid leukemia

6.2.2.1.3 Acute lymphoblastic leukemia

6.2.2.2 Myeloproliferative Disorders

6.2.2.2.1 Chronic myeloproliferative disorders

6.2.2.2.2 Chronic myelogenous leukemia and related disorders

6.2.2.2.3 Myelofibrosis, including chronic idiopathic

6.2.2.2.4 Polycythemia, including polycythemia rubra vera

6.2.2.2.5 Thrombocytosis, including essential thrombocythemia

6.2.2.3 Chronic lymphoid leukemia and other lymphoid leukemias

6.2.2.4 Lymphomas

6.2.2.4.1 Non-Hodgkin Lymphoma

6.2.2.4.2 Hodgkin lymphoma

6.2.2.5 Lymphoproliferative disorders associated with immunodeficiency

6.2.2.6 Plasma Cell dyscrasias

6.2.2.7 Mast cell disease and Histiocytic neoplasms

6.2.3 Secondary Classification

6.2.3.1 Nuance – PathologyOutlines
Nat Pernick, Ed.

http://www.pathologyoutlines.com/leukemia.html

This site is up-to-date and revised periodically. It is the best site for pathology information.

6.2.4 Diagnostics

6.2.4.1 Computer-aided diagnostics

6.2.4.1.1 Back-to-Front Design

Robert Didner
Bell Laboratories

Decision-making in the clinical setting
Didner, R  Mar 1999  Amer Clin Lab

Mr. Didner is an Independent Consultant in Systems Analysis, Information Architecture (Informatics) Operations Research, and Human Factors Engineering (Cognitive Psychology),  Decision Information Designs, 29 Skyline Dr., Morristown, NJ07960, U.S.A.; tel.: 973-455-0489; fax/e-mail: bdidner@hotmail.com

A common problem in the medical profession is the level of effort dedicated to administration and paperwork necessitated by various agencies, which contributes to the high cost of medical care. Costs would be reduced and accuracy improved if the clinical data could be captured directly at the point they are generated in a form suitable for transmission to insurers or machine transformable into other formats. Such a capability could also be used to improve the form and the structure of information presented to physicians and support a more comprehensive database linking clinical protocols to outcomes, with the prospect of improving clinical outcomes. Although the problem centers on the physician’s process of determining the diagnosis and treatment of patients and the timely and accurate recording of that process in the medical system, it substantially involves the pathologist and laboratorian, who interact significantly throughout the in-formation-gathering process. Each of the currently predominant ways of collecting information from diagnostic protocols has drawbacks. Using blank paper to collect free-form notes from the physician is not amenable to computerization; such free-form data are also poorly formulated, formatted, and organized for the clinical decision-making they support. The alternative of preprinted forms listing the possible tests, results, and other in-formation gathered during the diagnostic process facilitates the desired computerization, but the fixed sequence of tests and questions they present impede the physician from using an optimal decision-making sequence. This follows because:

  • People tend to make decisions and consider information in a step-by-step manner in which intermediate decisions are intermixed with data acquisition steps.
  • The sequence in which components of decisions are made may alter the decision outcome.
  • People tend to consider information in the sequence it is requested or displayed.
  • Since there is a separate optimum sequence of tests and questions for each cluster of history and presenting symptoms, there is no one sequence of tests and questions that can be optimal for all presenting clusters.
  • As additional data and test results are acquired, the optimal sequence of further testing and data acquisition changes, depending on the already acquired information.

Therefore, promoting an arbitrary sequence of information requests with preprinted forms may detract from outcomes by contributing to a non-optimal decision-making sequence. Unlike the decisions resulting from theoretical or normative processes, decisions made by humans are path dependent; that is, the out-come of a decision process may be different if the same components are considered in a different sequence.

Proposed solution

This paper proposes a general approach to gathering data at their source in computer-based form so as to improve the expected outcomes. Such a means must be interactive and dynamic, so that at any point in the clinical process the patient’s presenting symptoms, history, and the data already collected are used to determine the next data or tests requested. That de-termination must derive from a decision-making strategy designed to produce outcomes with the greatest value and supported by appropriate data collection and display techniques. The strategy must be based on the knowledge of the possible outcomes at any given stage of testing and information gathering, coupled with a metric, or hierarchy of values for assessing the relative desirability of the possible outcomes.

A value hierarchy

  • The numbered list below illustrates a value hierarchy. In any particular instance, the higher-numbered values should only be considered once the lower- numbered values have been satisfied. Thus, a diagnostic sequence that is very time or cost efficient should only be considered if it does not increase the likelihood (relative to some other diagnostic sequence) that a life-threatening disorder may be missed, or that one of the diagnostic procedures may cause discomfort.
  • Minimize the likelihood that a treatable, life-threatening disorder is not treated.
  • Minimize the likelihood that a treatable, discomfort-causing disorder is not treated.
  • Minimize the likelihood that a risky procedure(treatment or diagnostic procedure) is inappropriately administered.
  • Minimize the likelihood that a discomfort-causing procedure is inappropriately administered.
  • Minimize the likelihood that a costly procedure is inappropriately administered.
  • Minimize the time of diagnosing and treating thepatient.8.Minimize the cost of diagnosing and treating the patient.

The above hierarchy is relative, not absolute; for many patients, a little bit of testing discomfort may be worth a lot of time. There are also some factors and graduations intentionally left out for expository simplicity (e.g., acute versus chronic disorders).This value hierarchy is based on a hypothetical patient. Clearly, the hierarchy of a health insurance carrier might be different, as might that of another patient (e.g., a geriatric patient). If the approach outlined herein were to be followed, a value hierarchy agreed to by a majority of stakeholders should be adopted.

Efficiency

Once the higher values are satisfied, the time and cost of diagnosis and treatment should be minimized. One way to do so would be to optimize the sequence in which tests are performed, so as to minimize the number, cost, and time of tests that need to be per-formed to reach a definitive decision regarding treatment. Such an optimum sequence could be constructed using Claude Shannon’s information theory.

According to this theory, the best next question to ask under any given situation (assuming the question has two possible outcomes) is that question that divides the possible outcomes into two equally likely sets. In the real world, all tests or questions are not equally valuable, costly, or time consuming; therefore, value(risk factors), cost, and time should be used as weighting factors to optimize the test sequence, but this is a complicating detail at this point.

A value scale

For dynamic computation of outcome values, the hierarchy could be converted into a weighted value scale so differing outcomes at more than one level of the hierarchy could be readily compared. An example of such a weighted value scale is Quality Adjusted Life Years (QALY).

Although QALY does not incorporate all of the factors in this example, it is a good conceptual starting place.

The display, request, decision-making relationship

For each clinical determination, the pertinent information should be gathered, organized, formatted, and formulated in a way that facilitates the accuracy, reliability, and efficiency with which that determination is made. A physician treating a patient with high cholesterol and blood pressure (BP), for example, may need to know whether or not the patient’s cholesterol and BP respond to weight changes to determine an appropriate treatment (e.g., weight control versus medication). This requires searching records for BP, certain blood chemicals (e.g., HDLs, LDLs, triglycerides, etc.), and weight from several

sources, then attempting to track them against each other over time. Manually reorganizing this clinical information each time it is used is extremely inefficient. More important, the current organization and formatting defies principles of human factors for optimally displaying information to enhance human information-processing characteristics, particularly for decision support.

While a discussion of human factors and cognitive psychology principles is beyond the scope of this paper, following are a few of the system design principles of concern:

  • Minimize the load on short-term memory.
  • Provide information pertinent to a given decision or component of a decision in a compact, contiguous space.
  • Take advantage of basic human perceptual and pat-tern recognition facilities.
  • Design the form of an information display to com-plement the decision-making task it supports.

F i g u re 1 shows fictitious, quasi-random data from a hypothetical patient with moderately elevated cholesterol. This one-page display pulls together all the pertinent data from six years of blood tests and related clinical measurements. At a glance, the physician’s innate pattern recognition, color, and shape perception facilities recognize the patient’s steadily increasing weight, cholesterol, BP, and triglycerides as well as the declining high-density lipoproteins. It would have taken considerably more time and effort to grasp this information from the raw data collection and blood test reports as they are currently presented in independent, tabular time slices.

Design the formulation of an information display to complement the decision-making task.

The physician may wish to know only the relationship between weight and cardiac risk factors rather than whether these measures are increasing or decreasing, or are within acceptable or marginal ranges. If so, Table 1 shows the correlations between weight and the other factors in a much more direct and simple way using the same data as in Figure 1. One can readily see the same conclusions about relations that were drawn from Figure 1.This type of abstract, symbolic display of derived information also makes it easier to spot relationships when the individual variables are bouncing up and down, unlike the more or less steady rise of most values in Figure 1. This increase in precision of relationship information is gained at the expense of other types of information (e.g., trends). To display information in an optimum form then, the system designer must know what the information demands of the task are at the point in the task when the display is to be used.

Present the sequence of information display clusters to complement an optimum decision-making strategy.

Just as a fixed sequence of gathering clinical, diagnostic information may lead to a far from optimum outcome, there exists an optimum sequence of testing, considering information, and gathering data that will lead to an optimum outcome (as defined by the value hierarchy) with a minimum of time and expense. The task of the information system designer, then, is to provide or request the right information, in the best form, at each stage of the procedure. For ex-ample, Figure 1 is suitable for the diagnostic phase since it shows the current state of the risk factors and their trends. Table 1, on the other hand, might be more appropriate in determining treatment, where there may be a choice of first trying a strict dietary treatment, or going straight to a combination of diet plus medication. The fact that Figure 1 and Table 1 have somewhat redundant information is not a problem, since they are intended to optimally provide information for different decision-making tasks. The critical need, at this point, is for a model of how to determine what information should be requested, what tests to order, what information to request and display, and in what form at each step of the decision-making process. Commitment to a collaborative relationship between physicians and laboratorians and other information providers would be an essential requirement for such an undertaking. The ideal diagnostic data-collection instrument is a flexible, computer-based device, such as a notebook computer or Personal Digital Assistant (PDA) sized device.

Barriers to interactive, computer-driven data collection at the source

As with any major change, it may be difficult to induce many physicians to change their behavior by interacting directly with a computer instead of with paper and pen. Unlike office workers, who have had to make this transition over the past three decades, most physicians’ livelihoods will not depend on converting to computer interaction. Therefore, the transition must be made attractive and the changes less onerous. Some suggestions follow:

  1. Make the data collection a natural part of the clinical process.
  2. Ensure that the user interface is extremely friendly, easy to learn, and easy to use.
  3. Use a small, portable device.
  4. Use the same device for collection and display of existing information (e.g., test results and his-tory).
  5. Minimize the need for free-form written data entry (use check boxes, forms, etc.).
  6. Allow the entry of notes in pen-based free-form (with the option of automated conversion of numeric data to machine-manipulable form).
  7. Give the physicians a more direct benefit for collecting data, not just a means of helping a clerk at an HMO second-guess the physician’s judgment.
  8. Improve administrative efficiency in the office.
  9. Make the data collection complement the clinical decision-making process.
  10. Improve information displays, leading to better outcomes.
  11. Make better use of the physician’s time and mental effort.

Conclusion

The medical profession is facing a crisis of information. Gathering information is costing a typical practice more and more while fees are being restricted by third parties, and the process of gathering this in-formation may be detrimental to current outcomes. Gathered properly, in machine-manipulable form, these data could be reformatted so as to greatly improve their value immediately in the clinical setting by leading to decisions with better outcomes and, in the long run, by contributing to a clinical data warehouse that could greatly improve medical knowledge. The challenge is to create a mechanism for data collection that facilitates, hastens, and improves the outcomes of clinical activity while minimizing the inconvenience and resistance to change on the part of clinical practitioners. This paper is intended to provide a high-level overview of how this may be accomplished, and start a dialogue along these lines.

References

  1. Tversky A. Elimination by aspects: a theory of choice. Psych Rev 1972; 79:281–99.
  2. Didner RS. Back-to-front design: a guns and butter approach. Ergonomics 1982; 25(6):2564–5.
  3. Shannon CE. A mathematical theory of communication. Bell System Technical J 1948; 27:379–423 (July), 623–56 (Oct).
  4. Feeny DH, Torrance GW. Incorporating utility-based quality-of-life assessment measures in clinical trials: two examples. Med Care 1989; 27:S190–204.
  5. Smith S, Mosier J. Guidelines for designing user interface soft-ware. ESD-TR-86-278, Aug 1986.
  6. Miller GA. The magical number seven plus or minus two. Psych Rev 1956; 65(2):81–97.
  7. Sternberg S. High-speed scanning in human memory. Science 1966; 153: 652–4.

Table 1

Correlation of weight with other cardiac risk factors

Cholesterol 0.759384
HDL 0.53908
LDL 0.177297
BP-syst. 0.424728
BP-dia. 0.516167
Triglycerides 0.637817

Figure 1  Hypothetical patient data.

(not shown)

6.2.4.1.2 Realtime Clinical Expert Support

https://pharmaceuticalintelligence.com/2015/05/10/realtime-clinical-expert-support/

6.2.4.1.3 Regression: A richly textured method for comparison and classification of predictor variables

https://pharmaceuticalintelligence.com/2012/08/14/regression-a-richly-textured-method-for-comparison-and-classification-of-predictor-variables/

6.2.4.1.4 Converting Hematology Based Data into an Inferential Interpretation

Larry H. Bernstein, Gil David, James Rucinski and Ronald R. Coifman
In Hematology – Science and Practice
Lawrie CH, Ch 22. Pp541-552.
InTech Feb 2012, ISBN 978-953-51-0174-1
https://www.researchgate.net/profile/Larry_Bernstein/publication/221927033_Converting_Hematology_Based_Data_into_an_Inferential_Interpretation/links/0fcfd507f28c14c8a2000000.pdf

6.2.4.1.5 A model for Thalassemia Screening using Hematology Measurements

https://www.researchgate.net/profile/Larry_Bernstein/publication/258848064_A_model_for_Thalassemia_Screening_using_Hematology_Measurements/links/0c9605293c3048060b000000.pdf

A model for automated screening of thalassemia in hematology (math study).

Kneifati-Hayek J, Fleischman W, Bernstein LH, Riccioli A, Bellevue R.
Lab Hematol. 2007; 13(4):119-23. http://dx.doi.org:/10.1532/LH96.07003.

The results of 398 patient screens were collected. Data from the set were divided into training and validation subsets. The Mentzer ratio was determined through a receiver operating characteristic (ROC) curve on the first subset, and screened for thalassemia using the second subset. HgbA2 levels were used to confirm beta-thalassemia.

RESULTS: We determined the correct decision point of the Mentzer index to be a ratio of 20. Physicians can screen patients using this index before further evaluation for beta-thalassemia (P < .05).

CONCLUSION: The proposed method can be implemented by hospitals and laboratories to flag positive matches for further definitive evaluation, and will enable beta-thalassemia screening of a much larger population at little to no additional cost.

6.2.4.1.6 Measurement of granulocyte maturation may improve the early diagnosis of the septic state.

Bernstein LH, Rucinski J. Clin Chem Lab Med. 2011 Sep 21;49(12):2089-95.
http://dx.doi.org:/10.1515/CCLM.2011.688.

6.2.4.1.7 The automated malnutrition assessment.

David G, Bernstein LH, Coifman RR. Nutrition. 2013 Jan; 29(1):113-21.
http://dx.doi.org:/10.1016/j.nut.2012.04.017

6.2.4.2 Molecular Diagnostics

6.2.4.2.1 Genomic Analysis of Hematological Malignancies

Acute lymphoblastic leukemia (ALL) is the most common hematologic malignancy that occurs in children. Although more than 90% of children with ALL now survive to adulthood, those with the rarest and high-risk forms of the disease continue to have poor prognoses. Through the Pediatric Cancer Genome Project (PCGP), investigators in the Hematological Malignancies Program are identifying the genetic aberrations that cause these aggressive forms of leukemias. Here we present two studies on the genetic bases of early T-cell precursor ALL and acute megakaryoblastic leukemia.

  • Early T-Cell Precursor ALL Is Characterized by Activating Mutations
  • The CBFA2T3-GLIS2Fusion Gene Defines an Aggressive Subtype of Acute Megakaryoblastic Leukemia in Children

Early T-cell precursor ALL (ETP-ALL), which comprises 15% of all pediatric T-cell leukemias, is an aggressive disease that is typically resistant to contemporary therapies. Children with ETP-ALL have a high rate of relapse and an extremely poor prognosis (i.e., 5-year survival is approximately 20%). The genetic basis of ETP-ALL has remained elusive. Although ETP-ALL is associated with a high burden of DNA copy number aberrations, none are consistently found or suggest a unifying genetic alteration that drives this disease.

Through the efforts of the PCGP, Jinghui Zhang, PhD (Computational Biology), James R. Downing, MD (Pathology), Charles G. Mullighan, MBBS(Hons), MSc, MD (Pathology), and colleagues analyzed the whole-genome sequences of leukemic cells and matched normal DNA from 12 pediatric patients with ETP-ALL. The identified genetic mutations were confirmed in a validation cohort of 52 ETP-ALL specimens and 42 non-ETP T-lineage ALLs (T-ALL).

In the journal Nature, the investigators reported that each ETP-ALL sample carried an average of 1140 sequence mutations and 12 structural variations. Of the structural variations, 51% were breakpoints in genes with well-established roles in hematopoiesis or leukemogenesis (e.g., MLH2,SUZ12, and RUNX1). Eighty-four percent of the structural variations either caused loss of function of the gene in question or resulted in the formation of a fusion gene such as ETV6-INO80D. The ETV6 gene, which encodes a protein that is essential for hematopoiesis, is frequently mutated in leukemia. Among the DNA samples sequenced in this study, ETV6 was altered in 33% of ETP-ALL but only 10% of T-ALL cases.

6.2.4.2.2 Next-generation sequencing in hematologic malignancies: what will be the dividends?

Jason D. MerkerAnton Valouev, and Jason Gotlib
Ther Adv Hematol. 2012 Dec; 3(6): 333–339.
http://dx.doi.org:/10.1177/2040620712458948

The application of high-throughput, massively parallel sequencing technologies to hematologic malignancies over the past several years has provided novel insights into disease initiation, progression, and response to therapy. Here, we describe how these new DNA sequencing technologies have been applied to hematolymphoid malignancies. With further improvements in the sequencing and analysis methods as well as integration of the resulting data with clinical information, we expect these technologies will facilitate more precise and tailored treatment for patients with hematologic neoplasms.

6.2.4.2.3 Leveraging cancer genome information in hematologic malignancies.

Rampal R1Levine RL.
J Clin Oncol. 2013 May 20; 31(15):1885-92.
http://dx.doi.org:/10.1200/JCO.2013.48.7447

The use of candidate gene and genome-wide discovery studies in the last several years has led to an expansion of our knowledge of the spectrum of recurrent, somatic disease alleles, which contribute to the pathogenesis of hematologic malignancies. Notably, these studies have also begun to fundamentally change our ability to develop informative prognostic schema that inform outcome and therapeutic response, yielding substantive insights into mechanisms of hematopoietic transformation in different tissue compartments. Although these studies have already had important biologic and translational impact, significant challenges remain in systematically applying these findings to clinical decision making and in implementing new technologies for genetic analysis into clinical practice to inform real-time decision making. Here, we review recent major genetic advances in myeloid and lymphoid malignancies, the impact of these findings on prognostic models, our understanding of disease initiation and evolution, and the implication of genomic discoveries on clinical decision making. Finally, we discuss general concepts in genetic modeling and the current state-of-the-art technology used in genetic investigation.

6.2.4.2.4 p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies

E Wattel, C Preudhomme, B Hecquet, M Vanrumbeke, et AL.
Blood, (Nov 1), 1994; 84(9): pp 3148-3157
http://www.bloodjournal.org/content/bloodjournal/84/9/3148.full.pdf

We analyzed the prognostic value of p53 mutations for response to chemotherapy and survival in acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and chronic lymphocytic leukemia (CLL). Mutations were detected by single-stranded conformation polymorphism (SSCP) analysis of exons 4 to 10 of the P53 gene, and confirmed by direct sequencing. A p53 mutation was found in 16 of 107 (15%) AML, 20 of 182 (11%) MDS, and 9 of 81 (11%) CLL tested. In AML, three of nine (33%) mutated cases and 66 of 81 (81%) nonmutated cases treated with intensive chemotherapy achieved complete remission (CR) (P = .005) and none of five mutated cases and three of six nonmutated cases treated by low-dose Ara C achieved CR or partial remission (PR) (P = .06). Median actuarial survival was 2.5 months in mutated cases, and 15 months in nonmutated cases (P < lo-‘). In the MDS patients who received chemotherapy (intensive chemotherapy or low-dose Ara C), 1 of 13 (8%) mutated cases and 23 of 38 (60%) nonmutated cases achieved CR or PR (P = .004), and median actuarial survival was 2.5 and 13.5 months, respectively (P C lo-’). In all MDS cases (treated and untreated), the survival difference between mutated cases and nonmutated cases was also highly significant. In CLL, 1 of 8 (12.5%) mutated cases treated by chemotherapy (chlorambucil andlor CHOP andlor fludarabine) responded, as compared with 29 of 36 (80%) nonmutated cases (P = .02). In all CLL cases, survival from p53 analysis was significantly shorter in mutated cases (median 7 months) than in nonmutated cases (median not reached) (P < IO-’). In 35 of the 45 mutated cases of AML, MDS, and CLL, cytogenetic analysis or SSCP and sequence findings showed loss of the nonmutated P53 allele. Our findings show that p53 mutations are a strong prognostic indicator of response to chemotherapy and survival in AML, MDS, and CLL. The usual association of p53 mutations to loss of the nonmutated P53 allele, in those disorders, ie, to absence of normal p53 in tumor cells, suggests that p53 mutations could induce drug resistance, at least in part, by interfering with normal apoptotic pathways in tumor cells.

6.2.4.2.5 Genomic approaches to hematologic malignancies

Benjamin L. Ebert and Todd R. Golub
Blood. 2004; 104:923-932
https://www.broadinstitute.org/mpr/publications/projects/genomics/Review%20Genomics%20of%20Heme%20Malig,%20Blood%202004.pdf

In the past several years, experiments using DNA microarrays have contributed to an increasingly refined molecular taxonomy of hematologic malignancies. In addition to the characterization of molecular profiles for known diagnostic classifications, studies have defined patterns of gene expression corresponding to specific molecular abnormalities, oncologic phenotypes, and clinical outcomes. Furthermore, novel subclasses with distinct molecular profiles and clinical behaviors have been identified. In some cases, specific cellular pathways have been highlighted that can be therapeutically targeted. The findings of microarray studies are beginning to enter clinical practice as novel diagnostic tests, and clinical trials are ongoing in which therapeutic agents are being used to target pathways that were identified by gene expression profiling. While the technology of DNA microarrays is becoming well established, genome-wide surveys of gene expression generate large data sets that can easily lead to spurious conclusions. Many challenges remain in the statistical interpretation of gene expression data and the biologic validation of findings. As data accumulate and analyses become more sophisticated, genomic technologies offer the potential to generate increasingly sophisticated insights into the complex molecular circuitry of hematologic malignancies. This review summarizes the current state of discovery and addresses key areas for future research.

6.2.4.3 Flow cytometry

Introduction to Flow Cytometry: Blood Cell Identification

Dana L. Van Laeys
https://www.labce.com/flow_cytometry.aspx

No other laboratory method provides as rapid and detailed analysis of cellular populations as flow cytometry, making it a valuable tool for diagnosis and management of several hematologic and immunologic diseases. Understanding this relevant methodology is important for any medical laboratory scientist.

Whether you have no previous experience with flow cytometry or just need a refresher, this course will help you to understand the basic principles, with the help of video tutorials and interactive case studies.

Basic principles include:

  1. Immunophenotypic features of various types of hematologic cells
  2. Labeling cellular elements with fluorochromes
  3. Blood cell identification, specifically B and T lymphocyte identification and analysis
  4. Cell sorting to isolate select cell population for further analysis
  5. Analyzing and interpreting result reports and printouts

6.2.5 Treatments

6.2.5.1 Treatments for leukemia by type

6.2.5.1.1 Acute lymphocytic leukemias

6.2.5.1.1.1 Treatment of Acute Lymphoblastic Leukemia

Ching-Hon Pu, and William E. Evans
N Engl J Med Jan 12, 2006; 354:166-178
http://dx.doi.org:/10.1056/NEJMra052603

Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.

6.2.5.1.1.2 Acute Lymphoblastic Leukemia

Ching-Hon Pui, Mary V. Relling, and James R. Downing
N Engl J Med Apr 8, 2004; 350:1535-1548
http://dx.doi.org:/10.1056/NEJMra023001

This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.

6.2.5.1.1.3 Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Amy Holleman, Meyling H. Cheok, Monique L. den Boer, et al.
N Engl J Med 2004; 351:533-42

Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.

Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.

Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.

Conclusions  Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

6.2.5.1.1.4 Leukemias Treatment & Management

Author: Lihteh Wu, MD; Chief Editor: Hampton Roy Sr
http://emedicine.medscape.com/article/1201870-treatment

The treatment of leukemia is in constant flux, evolving and changing rapidly over the past few years. Most treatment protocols use systemic chemotherapy with or without radiotherapy. The basic strategy is to eliminate all detectable disease by using cytotoxic agents. To attain this goal, 3 phases are typically used, as follows: remission induction phase, consolidation phase, and maintenance therapy phase.

Chemotherapeutic agents are chosen that interfere with cell division. Tumor cells usually divide more rapidly than host cells, making them more vulnerable to the effects of chemotherapy. Primary treatment will be under the direction of a medical oncologist, radiation oncologist, and primary care physician. Although a general treatment plan will be outlined, the ophthalmologist does not prescribe or manage such treatment.

  • The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.
  • Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.
  • Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS varies from facility to facility.
  • Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.
  • Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.
  • Presently, treatment of CLL is palliative.
  • CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis sometimes is necessary when leukostastic complications are present. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.
  • When CML converts to the blastic phase, approximately one third of cases behave as ALL and respond to treatment with vincristine and prednisone. The remaining two thirds resemble AML but respond poorly to AML therapy.
  • Allogeneic bone marrow transplant is the only curative therapy for CML. However, it carries a high early mortality rate.
  • Leukemic retinopathy usually is not treated directly. As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve. There are reports that leukopheresis for hyperviscosity also may alleviate intraocular manifestations.
  • When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.
  • Relapse, manifested by anterior segment involvement, should be treated by radiation. In certain cases, subconjunctival chemotherapeutic agents have been injected.
  • Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.

6.2.5.1.1.5 Treatments and drugs

http://www.mayoclinic.org/diseases-conditions/leukemia/basics/
treatment/con-20024914

Common treatments used to fight leukemia include:

  • Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.

Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.

  • Biological therapy. Biological therapy works by using treatments that help your immune system recognize and attack leukemia cells.
  • Targeted therapy. Targeted therapy uses drugs that attack specific vulnerabilities within your cancer cells.

For example, the drug imatinib (Gleevec) stops the action of a protein within the leukemia cells of people with chronic myelogenous leukemia. This can help control the disease.

  • Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.

You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a stem cell transplant.

  • Stem cell transplant. A stem cell transplant is a procedure to replace your diseased bone marrow with healthy bone marrow.

Before a stem cell transplant, you receive high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive an infusion of blood-forming stem cells that help to rebuild your bone marrow.

You may receive stem cells from a donor, or in some cases you may be able to use your own stem cells. A stem cell transplant is very similar to a bone marrow transplant.

6.2.5.1.2 Acute Myeloid Leukemia

6.2.5.1.2.1 New treatment approaches in acute myeloid leukemia: review of recent clinical studies.

Norsworthy K1Luznik LGojo I.
Rev Recent Clin Trials. 2012 Aug; 7(3):224-37.
http://www.ncbi.nlm.nih.gov/pubmed/22540908

Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.

6.2.5.1.2.2 Novel approaches to the treatment of acute myeloid leukemia.

Roboz GJ1
Hematology Am Soc Hematol Educ Program. 2011:43-50.
http://dx.doi.org:/10.1182/asheducation-2011.1.43.

Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.

Age ≥ 60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group.5 Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, increased incidence of antecedent myelodysplastic syndrome and myeloproliferative disorders, and higher frequency of adverse cytogenetics.28 Older patients with multiple poor-risk factors have a high probability of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥ 75 years, unfavorable karyotype, poor performance status, creatinine > 1.3 mg/dL, duration of antecedent hematologic disorder > 6 months, and treatment outside a laminar airflow room as adverse prognostic indicators.29 Patients with 3 or more of these factors had expected complete remission rates of < 20%, 8-week mortality > 50%, and 1-year survival < 10%. The Medical Research Council (MRC) identified cytogenetics, WBC count at diagnosis, age, and de novo versus secondary disease as critical factors influencing survival in > 2000 older patients with AML, but cautioned in their conclusions that less objective factors, such as clinical assessment of “fitness” for chemotherapy, may be equally important in making treatment decisions in this patient population.30 It is hoped that data from comprehensive geriatric assessments of functional status, cognition, mood, quality of life, and other measures obtained during ongoing cooperative group trials will improve our ability to predict how older patients will tolerate treatment.

6.5.1.2.3 Current treatment of acute myeloid leukemia.

Roboz GJ1.
Curr Opin Oncol. 2012 Nov; 24(6):711-9.
http://dx.doi.org:/10.1097/CCO.0b013e328358f62d.

The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia.

RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient’s ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially ‘druggable’ molecular targets are reviewed.

SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future.

6.5.1.2.4  Adult Acute Myeloid Leukemia Treatment (PDQ®)
http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page9

About This PDQ Summary

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Treatment Option Overview for AML

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[13]

Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] Postremission therapy appears to be effective when given immediately after remission is achieved.[4]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions and for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients older than 60 years.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF because of a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival (DFS) in the group receiving GM-CSF (median DFS for patients who achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]

References

  1. Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
  2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
  3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia–results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992. [PUBMED Abstract]
  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992. [PUBMED Abstract]
  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
  6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. N Engl J Med 337 (26): 1870-5, 1997. [PUBMED Abstract]
  7. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997. [PUBMED Abstract]
  8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996. [PUBMED Abstract]
  9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995. [PUBMED Abstract]
  10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995. [PUBMED Abstract]
  11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995. [PUBMED Abstract]
  12. Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998. [PUBMED Abstract]
  13. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
  14. Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997. [PUBMED Abstract]
  15. Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998. [PUBMED Abstract]

6.2.5.1.3 Treatment for CML

6.2.5.1.3.1 Chronic Myelogenous Leukemia Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/CML/Patient/page4

Treatment Option Overview

Key Points for This Section

There are different types of treatment for patients with chronic myelogenous leukemia.

Six types of standard treatment are used:

  1. Targeted therapy
  2. Chemotherapy
  3. Biologic therapy
  4. High-dose chemotherapy with stem cell transplant
  5. Donor lymphocyte infusion (DLI)
  6. Surgery

New types of treatment are being tested in clinical trials.

Patients may want to think about taking part in a clinical trial.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Follow-up tests may be needed.

There are different types of treatment for patients with chronic myelogenous leukemia.

Different types of treatment are available for patients with chronic myelogenous leukemia (CML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information about new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Six types of standard treatment are used:

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Tyrosine kinase inhibitors are targeted therapy drugs used to treat chronic myelogenous leukemia.

Imatinib mesylate, nilotinib, dasatinib, and ponatinib are tyrosine kinase inhibitors that are used to treat CML.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Biologic therapy

Biologic therapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

See Drugs Approved for Chronic Myelogenous Leukemia for more information.

Donor lymphocyte infusion (DLI)

Donor lymphocyte infusion (DLI) is a cancer treatment that may be used after stem cell transplant.Lymphocytes (a type of white blood cell) from the stem cell transplant donor are removed from the donor’s blood and may be frozen for storage. The donor’s lymphocytes are thawed if they were frozen and then given to the patient through one or more infusions. The lymphocytes see the patient’s cancer cells as not belonging to the body and attack them.

Surgery

Splenectomy

6.2.5.1.3.2 What`s new in chronic myeloid leukemia research and treatment?

http://www.cancer.org/cancer/leukemia-chronicmyeloidcml/detailedguide/leukemia-chronic-myeloid-myelogenous-new-research

Combining the targeted drugs with other treatments

Imatinib and other drugs that target the BCR-ABL protein have proven to be very effective, but by themselves these drugs don’t help everyone. Studies are now in progress to see if combining these drugs with other treatments, such as chemotherapy, interferon, or cancer vaccines (see below) might be better than either one alone. One study showed that giving interferon with imatinib worked better than giving imatinib alone. The 2 drugs together had more side effects, though. It is also not clear if this combination is better than treatment with other tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib. A study going on now is looking at combing interferon with nilotinib.

Other studies are looking at combining other drugs, such as cyclosporine or hydroxychloroquine, with a TKI.

New drugs for CML

Because researchers now know the main cause of CML (the BCR-ABL gene and its protein), they have been able to develop many new drugs that might work against it.

In some cases, CML cells develop a change in the BCR-ABL oncogene known as a T315I mutation, which makes them resistant to many of the current targeted therapies (imatinib, dasatinib, and nilotinib). Ponatinib is the only TKI that can work against T315I mutant cells. More drugs aimed at this mutation are now being tested.

Other drugs called farnesyl transferase inhibitors, such as lonafarnib and tipifarnib, seem to have some activity against CML and patients may respond when these drugs are combined with imatinib. These drugs are being studied further.

Other drugs being studied in CML include the histone deacetylase inhibitor panobinostat and the proteasome inhibitor bortezomib (Velcade).

Several vaccines are now being studied for use against CML.

6.2.5.1.4. Chronic Lymphocytic Leukemia

6.2.5.1.4.1 Chronic Lymphocytic Leukemia Treatment (PDQ®)

General Information About Chronic Lymphocytic Leukemia

Key Points for This Section

  1. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).
  2. Leukemia may affect red blood cells, white blood cells, and platelets.
  3. Older age can affect the risk of developing chronic lymphocytic leukemia.
  4. Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.
  5. Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.
  6. Certain factors affect treatment options and prognosis (chance of recovery).
  7. Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

http://www.cancer.gov/images/cdr/live/CDR755927-750.jpg

Anatomy of the bone; drawing shows spongy bone, red marrow, and yellow marrow. A cross section of the bone shows compact bone and blood vessels in the bone marrow. Also shown are red blood cells, white blood cells, platelets, and a blood stem cell.

Anatomy of the bone. The bone is made up of compact bone, spongy bone, and bone marrow. Compact bone makes up the outer layer of the bone. Spongy bone is found mostly at the ends of bones and contains red marrow. Bone marrow is found in the center of most bones and has many blood vessels. There are two types of bone marrow: red and yellow. Red marrow contains blood stem cells that can become red blood cells, white blood cells, or platelets. Yellow marrow is made mostly of fat.

Leukemia may affect red blood cells, white blood cells, and platelets.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

  1. Red blood cells that carry oxygen and other substances to all tissues of the body.
  2. White blood cells that fight infection and disease.
  3. Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  1. B lymphocytes that make antibodies to help fight infection.
  2. T lymphocytes that help B lymphocytes make antibodies to fight infection.
  3. Natural killer cells that attack cancer cells and viruses.
Blood cell development. CDR526538-750

Blood cell development. CDR526538-750

http://www.cancer.gov/images/cdr/live/CDR526538-750.jpg

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.

Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

  • Adult Acute Lymphoblastic Leukemia Treatment.
  • Childhood Acute Lymphoblastic Leukemia Treatment.
  • Adult Acute Myeloid Leukemia Treatment.
  • Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
  • Chronic Myelogenous Leukemia Treatment.
  • Hairy Cell Leukemia Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

  • Being middle-aged or older, male, or white.
  • A family history of CLL or cancer of the lymph system.
  • Having relatives who are Russian Jews or Eastern European Jews.

Signs and symptoms of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:

  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Feeling very tired.
  • Pain or fullness below the ribs.
  • Fever and infection.
  • Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

Physical exam and history : An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.

Complete blood count (CBC) with differential : A procedure in which a sample of blood is drawn and checked for the following:

The number of red blood cells and platelets.

The number and type of white blood cells.

The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.

The portion of the blood sample made up of red blood cells.

6.2.5.1.4.2 Results from the Phase 3 Resonate™ Trial

Significantly improved progression free survival (PFS) vs ofatumumab in patients with previously treated CLL

  • Patients taking IMBRUVICA® had a 78% statistically significant reduction in the risk of disease progression or death compared with patients who received ofatumumab1
  • In patients with previously treated del 17p CLL, median PFS was not yet reached with IMBRUVICA® vs 5.8 months with ofatumumab (HR 0.25; 95% CI: 0.14, 0.45)1

Significantly prolonged overall survival (OS) with IMBRUVICA® vs ofatumumab in patients with previously treated CLL

  • In patients with previously treated CLL, those taking IMBRUVICA® had a 57% statistically significant reduction in the risk of death compared with those who received ofatumumab (HR 0.43; 95% CI: 0.24, 0.79; P<0.05)1

6.2.5.1.4.3 Typical treatment of chronic lymphocytic leukemia

http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/detailedguide/leukemia-chronic-lymphocytic-treating-treatment-by-risk-group

Treatment options for chronic lymphocytic leukemia (CLL) vary greatly, depending on the person’s age, the disease risk group, and the reason for treating (for example, which symptoms it is causing). Many people live a long time with CLL, but in general it is very difficult to cure, and early treatment hasn’t been shown to help people live longer. Because of this and because treatment can cause side effects, doctors often advise waiting until the disease is progressing or bothersome symptoms appear, before starting treatment.

If treatment is needed, factors that should be taken into account include the patient’s age, general health, and prognostic factors such as the presence of chromosome 17 or chromosome 11 deletions or high levels of ZAP-70 and CD38.

Initial treatment

Patients who might not be able to tolerate the side effects of strong chemotherapy (chemo), are often treated with chlorambucil alone or with a monoclonal antibody targeting CD20 like rituximab (Rituxan) or obinutuzumab (Gazyva). Other options include rituximab alone or a corticosteroid like prednisione.

In stronger and healthier patients, there are many options for treatment. Commonly used treatments include:

  • FCR: fludarabine (Fludara), cyclophosphamide (Cytoxan), and rituximab
  • Bendamustine (sometimes with rituximab)
  • FR: fludarabine and rituximab
  • CVP: cyclophosphamide, vincristine, and prednisone (sometimes with rituximab)
  • CHOP: cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone
  • Chlorambucil combined with prednisone, rituximab, obinutuzumab, or ofatumumab
  • PCR: pentostatin (Nipent), cyclophosphamide, and rituximab
  • Alemtuzumab (Campath)
  • Fludarabine (alone)

Other drugs or combinations of drugs may also be also used.

If the only problem is an enlarged spleen or swollen lymph nodes in one region of the body, localized treatment with low-dose radiation therapy may be used. Splenectomy (surgery to remove the spleen) is another option if the enlarged spleen is causing symptoms.

Sometimes very high numbers of leukemia cells in the blood cause problems with normal circulation. This is calledleukostasis. Chemo may not lower the number of cells until a few days after the first dose, so before the chemo is given, some of the cells may be removed from the blood with a procedure called leukapheresis. This treatment lowers blood counts right away. The effect lasts only for a short time, but it may help until the chemo has a chance to work. Leukapheresis is also sometimes used before chemo if there are very high numbers of leukemia cells (even when they aren’t causing problems) to prevent tumor lysis syndrome (this was discussed in the chemotherapy section).

Some people who have very high-risk disease (based on prognostic factors) may be referred for possible stem cell transplant (SCT) early in treatment.

Second-line treatment of CLL

If the initial treatment is no longer working or the disease comes back, another type of treatment may help. If the initial response to the treatment lasted a long time (usually at least a few years), the same treatment can often be used again. If the initial response wasn’t long-lasting, using the same treatment again isn’t as likely to be helpful. The options will depend on what the first-line treatment was and how well it worked, as well as the person’s health.

Many of the drugs and combinations listed above may be options as second-line treatments. For many people who have already had fludarabine, alemtuzumab seems to be helpful as second-line treatment, but it carries an increased risk of infections. Other purine analog drugs, such as pentostatin or cladribine (2-CdA), may also be tried. Newer drugs such as ofatumumab, ibrutinib (Imbruvica), and idelalisib (Zydelig) may be other options.

If the leukemia responds, stem cell transplant may be an option for some patients.

Some people may have a good response to first-line treatment (such as fludarabine) but may still have some evidence of a small number of leukemia cells in the blood, bone marrow, or lymph nodes. This is known as minimal residual disease. CLL can’t be cured, so doctors aren’t sure if further treatment right away will be helpful. Some small studies have shown that alemtuzumab can sometimes help get rid of these remaining cells, but it’s not yet clear if this improves survival.

Treating complications of CLL

One of the most serious complications of CLL is a change (transformation) of the leukemia to a high-grade or aggressive type of non-Hodgkin lymphoma called diffuse large cell lymphoma. This happens in about 5% of CLL cases, and is known as Richter syndrome. Treatment is often the same as it would be for lymphoma (see our document called Non-Hodgkin Lymphoma for more information), and may include stem cell transplant, as these cases are often hard to treat.

Less often, CLL may transform to prolymphocytic leukemia. As with Richter syndrome, these cases can be hard to treat. Some studies have suggested that certain drugs such as cladribine (2-CdA) and alemtuzumab may be helpful.

In rare cases, patients with CLL may have their leukemia transform into acute lymphocytic leukemia (ALL). If this happens, treatment is likely to be similar to that used for patients with ALL (see our document called Leukemia: Acute Lymphocytic).

Acute myeloid leukemia (AML) is another rare complication in patients who have been treated for CLL. Drugs such as chlorambucil and cyclophosphamide can damage the DNA of blood-forming cells. These damaged cells may go on to become cancerous, leading to AML, which is very aggressive and often hard to treat (see our document calledLeukemia: Acute Myeloid).

CLL can cause problems with low blood counts and infections. Treatment of these problems were discussed in the section “Supportive care in chronic lymphocytic leukemia.”

6.2.5.1.5 Lymphoma treatment

 6.2.5.1.5.1 Overview

http://www.emedicinehealth.com/lymphoma/page8_em.htm#lymphoma_treatment

The most widely used therapies are combinations of chemotherapyand radiation therapy.

  • Biological therapy, which targets key features of the lymphoma cells, is used in many cases nowadays.

The goal of medical therapy in lymphoma is complete remission. This means that all signs of the disease have disappeared after treatment. Remission is not the same as cure. In remission, one may still have lymphoma cells in the body, but they are undetectable and cause no symptoms.

  • When in remission, the lymphoma may come back. This is called recurrence.
  • The duration of remission depends on the type, stage, and grade of the lymphoma. A remission may last a few months, a few years, or may continue throughout one’s life.
  • Remission that lasts a long time is called durable remission, and this is the goal of therapy.
  • The duration of remission is a good indicator of the aggressiveness of the lymphoma and of the prognosis. A longer remission generally indicates a better prognosis.

Remission can also be partial. This means that the tumor shrinks after treatment to less than half its size before treatment.

The following terms are used to describe the lymphoma’s response to treatment:

  • Improvement: The lymphoma shrinks but is still greater than half its original size.
  • Stable disease: The lymphoma stays the same.
  • Progression: The lymphoma worsens during treatment.
  • Refractory disease: The lymphoma is resistant to treatment.

The following terms to refer to therapy:

  • Induction therapy is designed to induce a remission.
  • If this treatment does not induce a complete remission, new or different therapy will be initiated. This is usually referred to as salvage therapy.
  • Once in remission, one may be given yet another treatment to prevent recurrence. This is called maintenance therapy.

6.2.5.1.5.2 Chemotherapy

Many different types of chemotherapy may be used for Hodgkin lymphoma. The most commonly used combination of drugs in the United States is called ABVD. Another combination of drugs, known as BEACOPP, is now widely used in Europe and is being used more often in the United States. There are other combinations that are less commonly used and not listed here. The drugs that make up these two more common combinations of chemotherapy are listed below.

ABVD: Doxorubicin (Adriamycin), bleomycin (Blenoxane), vinblastine (Velban, Velsar), and dacarbazine (DTIC-Dome). ABVD chemotherapy is usually given every two weeks for two to eight months.

BEACOPP: Bleomycin, etoposide (Toposar, VePesid), doxorubicin, cyclophosphamide (Cytoxan, Neosar), vincristine (Vincasar PFS, Oncovin), procarbazine (Matulane), and prednisone (multiple brand names). There are several different treatment schedules, but different drugs are usually given every two weeks.

The type of chemotherapy, number of cycles of chemotherapy, and the additional use of radiation therapy are based on the stage of the Hodgkin lymphoma and the type and number of prognostic factors.

6.2.5.1.5.3 Adult Non-Hodgkin Lymphoma Treatment (PDQ®)

http://www.cancer.gov/cancertopics/pdq/treatment/adult-non-hodgkins/Patient/page1

Key Points for This Section

Adult non-Hodgkin lymphoma is a disease in which malignant (cancer) cells form in the lymph system.

Because lymph tissue is found throughout the body, adult non-Hodgkin lymphoma can begin in almost any part of the body. Cancer can spread to the liver and many other organs and tissues.

Non-Hodgkin lymphoma in pregnant women is the same as the disease in nonpregnant women of childbearing age. However, treatment is different for pregnant women. This summary includes information on the treatment of non-Hodgkin lymphoma during pregnancy

Non-Hodgkin lymphoma can occur in both adults and children. Treatment for children, however, is different than treatment for adults. (See the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for more information.)

There are many different types of lymphoma.

Lymphomas are divided into two general types: Hodgkin lymphoma and non-Hodgkin lymphoma. This summary is about the treatment of adult non-Hodgkin lymphoma. For information about other types of lymphoma, see the following PDQ summaries:

Age, gender, and a weakened immune system can affect the risk of adult non-Hodgkin lymphoma.

If cancer is found, the following tests may be done to study the cancer cells:

  • Immunohistochemistry : A test that uses antibodies to check for certain antigens in a sample of tissue. The antibody is usually linked to a radioactive substance or a dye that causes the tissue to light up under a microscope. This type of test may be used to tell the difference between different types of cancer.
  • Cytogenetic analysis : A laboratory test in which cells in a sample of tissue are viewed under a microscope to look for certain changes in the chromosomes.
  • Immunophenotyping : A process used to identify cells, based on the types of antigens ormarkers on the surface of the cell. This process is used to diagnose specific types of leukemia and lymphoma by comparing the cancer cells to normal cells of the immune system.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options depend on the following:

  • The stage of the cancer.
  • The type of non-Hodgkin lymphoma.
  • The amount of lactate dehydrogenase (LDH) in the blood.
  • The amount of beta-2-microglobulin in the blood (for Waldenström macroglobulinemia).
  • The patient’s age and general health.
  • Whether the lymphoma has just been diagnosed or has recurred (come back).

Stages of adult non-Hodgkin lymphoma may include E and S.

Adult non-Hodgkin lymphoma may be described as follows:

E: “E” stands for extranodal and means the cancer is found in an area or organ other than the lymph nodes or has spread to tissues beyond, but near, the major lymphatic areas.

S: “S” stands for spleen and means the cancer is found in the spleen.

Stage I adult non-Hodgkin lymphoma is divided into stage I and stage IE.

  • Stage I: Cancer is found in one lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen).
  • Stage IE: Cancer is found in one organ or area outside the lymph nodes.

Stage II adult non-Hodgkin lymphoma is divided into stage II and stage IIE.

  • Stage II: Cancer is found in two or more lymph node groups either above or below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIE: Cancer is found in one or more lymph node groups either above or below the diaphragm. Cancer is also found outside the lymph nodes in one organ or area on the same side of the diaphragm as the affected lymph nodes.

Stage III adult non-Hodgkin lymphoma is divided into stage III, stage IIIE, stage IIIS, and stage IIIE+S.

  • Stage III: Cancer is found in lymph node groups above and below the diaphragm (the thin muscle below the lungs that helps breathing and separates the chest from the abdomen).
  • Stage IIIE: Cancer is found in lymph node groups above and below the diaphragm and outside the lymph nodes in a nearby organ or area.
  • Stage IIIS: Cancer is found in lymph node groups above and below the diaphragm, and in the spleen.
  • Stage IIIE+S: Cancer is found in lymph node groups above and below the diaphragm, outside the lymph nodes in a nearby organ or area, and in the spleen.

In stage IV adult non-Hodgkin lymphoma, the cancer:

  • is found throughout one or more organs that are not part of a lymphatic area (lymph node group, tonsils and nearby tissue, thymus, or spleen), and may be in lymph nodes near those organs; or
  • is found in one organ that is not part of a lymphatic area and has spread to organs or lymph nodes far away from that organ; or
  • is found in the liver, bone marrow, cerebrospinal fluid (CSF), or lungs (other than cancer that has spread to the lungs from nearby areas).

Adult non-Hodgkin lymphomas are also described based on how fast they grow and where the affected lymph nodes are in the body.  Indolent & aggressive.

The treatment plan depends mainly on the following:

  • The type of non-Hodgkin’s lymphoma
  • Its stage (where the lymphoma is found)
  • How quickly the cancer is growing
  • The patient’s age
  • Whether the patient has other health problems
  • If there are symptoms present such as fever and night sweats (see above)

6.2.5.1.6 Primary treatments

6.2.5.1.6.1 Radiation Therapy for leukemias and lymphomas

http://www.lls.org/treatment/types-of-treatment/radiation-therapy

Radiation therapy, also called radiotherapy or irradiation, can be used to treat leukemia, lymphoma, myeloma and myelodysplastic syndromes. The type of radiation used for radiotherapy (ionizing radiation) is the same that’s used for diagnostic x-rays. Radiotherapy, however, is given in higher doses.

Radiotherapy works by damaging the genetic material (DNA) within cells, which prevents them from growing and reproducing. Although the radiotherapy is directed at cancer cells, it can also damage nearby healthy cells. However, current methods of radiotherapy have been improved upon, minimizing “scatter” to nearby tissues. Therefore its benefit (destroying the cancer cells) outweighs its risk (harming healthy cells).

When radiotherapy is used for blood cancer treatment, it’s usually part of a treatment plan that includes drug therapy. Radiotherapy can also be used to relieve pain or discomfort caused by an enlarged liver, lymph node(s) or spleen.

Radiotherapy, either alone or with chemotherapy, is sometimes given as conditioning treatment to prepare a patient for a blood or marrow stem cell transplant. The most common types used to treat blood cancer are external beam radiation (see below) and radioimmunotherapy.
External Beam Radiation

External beam radiation is the type of radiotherapy used most often for people with blood cancers. A focused radiation beam is delivered outside the body by a machine called a linear accelerator, or linac for short. The linear accelerator moves around the body to deliver radiation from various angles. Linear accelerators make it possible to decrease or avoid skin reactions and deliver targeted radiation to lessen “scatter” of radiation to nearby tissues.

The dose (total amount) of radiation used during treatment depends on various factors regarding the patient, disease and reason for treatment, and is established by a radiation oncologist. You may receive radiotherapy during a series of visits, spread over several weeks (from two to 10 weeks, on average). This approach, called dose fractionation, lessens side effects. External beam radiation does not make you radioactive.

6.2.5.1.6.2 bone marrow (BM) transplantation

http://www.nlm.nih.gov/medlineplus/ency/article/003009.htm

There are three kinds of bone marrow transplants:

Autologous bone marrow transplant: The term auto means self. Stem cells are removed from you before you receive high-dose chemotherapy or radiation treatment. The stem cells are stored in a freezer (cryopreservation). After high-dose chemotherapy or radiation treatments, your stems cells are put back in your body to make (regenerate) normal blood cells. This is called a rescue transplant.

Allogeneic bone marrow transplant: The term allo means other. Stem cells are removed from another person, called a donor. Most times, the donor’s genes must at least partly match your genes. Special blood tests are done to see if a donor is a good match for you. A brother or sister is most likely to be a good match. Sometimes parents, children, and other relatives are good matches. Donors who are not related to you may be found through national bone marrow registries.

Umbilical cord blood transplant: This is a type of allogeneic transplant. Stem cells are removed from a newborn baby’s umbilical cord right after birth. The stem cells are frozen and stored until they are needed for a transplant. Umbilical cord blood cells are very immature so there is less of a need for matching. But blood counts take much longer to recover.

Before the transplant, chemotherapy, radiation, or both may be given. This may be done in two ways:

Ablative (myeloablative) treatment: High-dose chemotherapy, radiation, or both are given to kill any cancer cells. This also kills all healthy bone marrow that remains, and allows new stem cells to grow in the bone marrow.

Reduced intensity treatment, also called a mini transplant: Patients receive lower doses of chemotherapy and radiation before a transplant. This allows older patients, and those with other health problems to have a transplant.

A stem cell transplant is usually done after chemotherapy and radiation is complete. The stem cells are delivered into your bloodstream usually through a tube called a central venous catheter. The process is similar to getting a blood transfusion. The stem cells travel through the blood into the bone marrow. Most times, no surgery is needed.

Donor stem cells can be collected in two ways:

Bone marrow harvest. This minor surgery is done under general anesthesia. This means the donor will be asleep and pain-free during the procedure. The bone marrow is removed from the back of both hip bones. The amount of marrow removed depends on the weight of the person who is receiving it.

Leukapheresis. First, the donor is given 5 days of shots to help stem cells move from the bone marrow into the blood. During leukapheresis, blood is removed from the donor through an IV line in a vein. The part of white blood cells that contains stem cells is then separated in a machine and removed to be later given to the recipient. The red blood cells are returned to the donor.

Why the Procedure is Performed

A bone marrow transplant replaces bone marrow that either is not working properly or has been destroyed (ablated) by chemotherapy or radiation. Doctors believe that for many cancers, the donor’s white blood cells can attach to any remaining cancer cells, similar to when white cells attach to bacteria or viruses when fighting an infection.

Your doctor may recommend a bone marrow transplant if you have:

Certain cancers, such as leukemia, lymphoma, and multiple myeloma

A disease that affects the production of bone marrow cells, such as aplastic anemia, congenital neutropenia, severe immunodeficiency syndromes, sickle cell anemia, thalassemia

Had chemotherapy that destroyed your bone

6.2.5.1.6.2.1 Autologous stem cell transplantation

6.2.5.1.6.2.1.1 Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas

O.W Press,  F Appelbaum,  P.J Martin, et al.
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(95)92225-3/abstract

25 patients with relapsed B-cell lymphomas were evaluated with trace-labelled doses (2·5 mg/kg, 185-370 MBq [5-10 mCi]) of 131I-labelled anti-CD20 (B1) antibody in a phase II trial. 22 patients achieved 131I-B1 biodistributions delivering higher doses of radiation to tumor sites than to normal organs and 21 of these were treated with therapeutic infusions of 131I-B1 (12·765-29·045 GBq) followed by autologous hemopoietic stem cell reinfusion. 18 of the 21 treated patients had objective responses, including 16 complete remissions. One patient died of progressive lymphoma and one died of sepsis. Analysis of our phase I and II trials with 131I-labelled B1 reveal a progression-free survival of 62% and an overall survival of 93% with a median follow-up of 2 years. 131I-anti-CD20 (B1) antibody therapy produces complete responses of long duration in most patients with relapsed B-cell lymphomas when given at maximally tolerated doses with autologous stem cell rescue.

6.2.5.2.6.2.1.2 Autologous (Self) Transplants

http://www.leukaemia.org.au/treatments/stem-cell-transplants/autologous-self-transplants

An autologous transplant (or rescue) is a type of transplant that uses the person’s own stem cells. These cells are collected in advance and returned at a later stage. They are used to replace stem cells that have been damaged by high doses of chemotherapy, used to treat the person’s underlying disease.

In most cases, stem cells are collected directly from the bloodstream. While stem cells normally live in your marrow, a combination of chemotherapy and a growth factor (a drug that stimulates stem cells) called Granulocyte Colony Stimulating Factor (G-CSF) is used to expand the number of stem cells in the marrow and cause them to spill out into the circulating blood. From here they can be collected from a vein by passing the blood through a special machine called a cell separator, in a process similar to dialysis.

Most of the side effects of an autologous transplant are caused by the conditioning therapy used. Although they can be very unpleasant at times it is important to remember that most of them are temporary and reversible.

6.2.5.2.6.2.1.3  Hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood. It may be autologous (the patient’s own stem cells are used) or allogeneic (the stem cells come from a donor).

Hematopoietic Stem Cell Transplantation

Author: Ajay Perumbeti, MD, FAAP; Chief Editor: Emmanuel C Besa, MD
http://emedicine.medscape.com/article/208954-overview

Hematopoietic stem cell transplantation (HSCT) involves the intravenous (IV) infusion of autologous or allogeneic stem cells to reestablish hematopoietic function in patients whose bone marrow or immune system is damaged or defective.

The image below illustrates an algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy.

An algorithm for typically preferred hematopoietic stem cell transplantation cell source for treatment of malignancy: If a matched sibling donor is not available, then a MUD is selected; if a MUD is not available, then choices include a mismatched unrelated donor, umbilical cord donor(s), and a haploidentical donor.

6.2.5.3 Supportive Therapies

6.2.5.3.1  Blood transfusions – risks and complications of a blood transfusion

  • Allogeneic transfusion reaction (acute or delayed hemolytic reaction)
  • Allergic reaction
  • Viruses Infectious Diseases

The risk of catching a virus from a blood transfusion is very low.

HIV. Your risk of getting HIV from a blood transfusion is lower than your risk of getting killed by lightning. Only about 1 in 2 million donations might carry HIV and transmit HIV if given to a patient.

Hepatitis B and C. The risk of having a donation that carries hepatitis B is about 1 in 205,000. The risk for hepatitis C is 1 in 2 million. If you receive blood during a transfusion that contains hepatitis, you’ll likely develop the virus.

Variant Creutzfeldt-Jakob disease (vCJD). This disease is the human version of Mad Cow Disease. It’s a very rare, yet fatal brain disorder. There is a possible risk of getting vCJD from a blood transfusion, although the risk is very low. Because of this, people who may have been exposed to vCJD aren’t eligible blood donors.

  • Fever
  • Iron Overload
  • Lung Injury
  • Graft-Versus-Host Disease

Graft-versus-host disease (GVHD) is a condition in which white blood cells in the new blood attack your tissues.

6.2.5.3.2  Erythropoietin

Erythropoietin, (/ɨˌrɪθrɵˈpɔɪ.ɨtɨn/UK /ɛˌrɪθr.pˈtɪn/) also known as EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. It is a cytokine (protein signaling molecule) for erythrocyte (red blood cell) precursors in the bone marrow. Human EPO has a molecular weight of 34 kDa.

Also called hematopoietin or hemopoietin, it is produced by interstitial fibroblasts in the kidney in close association with peritubular capillary and proximal convoluted tubule. It is also produced in perisinusoidal cells in the liver. While liver production predominates in the fetal and perinatal period, renal production is predominant during adulthood. In addition to erythropoiesis, erythropoietin also has other known biological functions. For example, it plays an important role in the brain’s response to neuronal injury.[1] EPO is also involved in the wound healing process.[2]

Exogenous erythropoietin is produced by recombinant DNA technology in cell culture. Several different pharmaceutical agents are available with a variety ofglycosylation patterns, and are collectively called erythropoiesis-stimulating agents (ESA). The specific details for labelled use vary between the package inserts, but ESAs have been used in the treatment of anemia in chronic kidney disease, anemia in myelodysplasia, and in anemia from cancer chemotherapy. Boxed warnings include a risk of death, myocardial infarction, stroke, venous thromboembolism, and tumor recurrence.[3]

6.2.5.3.4  G-CSF (granulocyte-colony stimulating factor)

Granulocyte-colony stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.

There are different types, including

  • Lenograstim (Granocyte)
  • Filgrastim (Neupogen, Zarzio, Nivestim, Ratiograstim)
  • Long acting (pegylated) filgrastim (pegfilgrastim, Neulasta) and lipegfilgrastim (Longquex)

Pegylated G-CSF stays in the body for longer so you have treatment less often than with the other types of G-CSF.

6.2.5.3.5  Plasma exchange (plasmapheresis)

http://emedicine.medscape.com/article/1895577-overview

Plasmapheresis is a term used to refer to a broad range of procedures in which extracorporeal separation of blood components results in a filtered plasma product.[1, 2] The filtering of plasma from whole blood can be accomplished via centrifugation or semipermeable membranes.[3] Centrifugation takes advantage of the different specific gravities inherent to various blood products such as red cells, white cells, platelets, and plasma.[4] Membrane plasma separation uses differences in particle size to filter plasma from the cellular components of blood.[3]

Traditionally, in the United States, most plasmapheresis takes place using automated centrifuge-based technology.[5] In certain instances, in particular in patients already undergoing hemodialysis, plasmapheresis can be carried out using semipermeable membranes to filter plasma.[4]

In therapeutic plasma exchange, using an automated centrifuge, filtered plasma is discarded and red blood cells along with replacement colloid such as donor plasma or albumin is returned to the patient. In membrane plasma filtration, secondary membrane plasma fractionation can selectively remove undesired macromolecules, which then allows for return of the processed plasma to the patient instead of donor plasma or albumin. Examples of secondary membrane plasma fractionation include cascade filtration,[6] thermofiltration, cryofiltration,[7] and low-density lipoprotein pheresis.

The Apheresis Applications Committee of the American Society for Apheresis periodically evaluates potential indications for apheresis and categorizes them from I to IV based on the available medical literature. The following are some of the indications, and their categorization, from the society’s 2010 guidelines.[2]

  • The only Category I indication for hemopoietic malignancy is Hyperviscosity in monoclonal gammopathies

6.2.5.3.6  Platelet transfusions

6.2.5.3.6.1 Indications for platelet transfusion in children with acute leukemia

Scott Murphy, Samuel Litwin, Leonard M. Herring, Penelope Koch, et al.
Am J Hematol Jun 1982; 12(4): 347–356
http://onlinelibrary.wiley.com/doi/10.1002/ajh.2830120406/abstract;jsessionid=A6001D9D865EA1EBC667EF98382EF20C.f03t01
http://dx.doi.org:/10.1002/ajh.2830120406

In an attempt to determine the indications for platelet transfusion in thrombocytopenic patients, we randomized 56 children with acute leukemia to one of two regimens of platelet transfusion. The prophylactic group received platelets when the platelet count fell below 20,000 per mm3 irrespective of clinical events. The therapeutic group was transfused only when significant bleeding occurred and not for thrombocytopenia alone. The time to first bleeding episode was significantly longer and the number of bleeding episodes were significantly reduced in the prophylactic group. The survival curves of the two groups could not be distinguished from each other. Prior to the last month of life, the total number of days on which bleeding was present was significantly reduced by prophylactic therapy. However, in the terminal phase (last month of life), the duration of bleeding episodes was significantly longer in the prophylactic group. This may have been due to a higher incidence of immunologic refractoriness to platelet transfusion. Because of this terminal bleeding, comparison of the two groups for total number of days on which bleeding was present did not show a significant difference over the entire study period.

6.2.5.3.6.2 Clinical and laboratory aspects of platelet transfusion therapy
Yuan S, Goldfinger D
http://www.uptodate.com/contents/clinical-and-laboratory-aspects-of-platelet-transfusion-therapy

INTRODUCTION — Hemostasis depends on an adequate number of functional platelets, together with an intact coagulation (clotting factor) system. This topic covers the logistics of platelet use and the indications for platelet transfusion in adults. The approach to the bleeding patient, refractoriness to platelet transfusion, and platelet transfusion in neonates are discussed elsewhere.

Pooled platelets – A single unit of platelets can be isolated from every unit of donated blood, by centrifuging the blood within the closed collection system to separate the platelets from the red blood cells (RBC). The number of platelets per unit varies according to the platelet count of the donor; a yield of 7 x 1010 platelets is typical [1]. Since this number is inadequate to raise the platelet count in an adult recipient, four to six units are pooled to allow transfusion of 3 to 4 x 1011 platelets per transfusion [2]. These are called whole blood-derived or random donor pooled platelets.

Advantages of pooled platelets include lower cost and ease of collection and processing (a separate donation procedure and pheresis equipment are not required). The major disadvantage is recipient exposure to multiple donors in a single transfusion and logistic issues related to bacterial testing.

Apheresis (single donor) platelets – Platelets can also be collected from volunteer donors in the blood bank, in a one- to two-hour pheresis procedure. Platelets and some white blood cells are removed, and red blood cells and plasma are returned to the donor. A typical apheresis platelet unit provides the equivalent of six or more units of platelets from whole blood (ie, 3 to 6 x 1011 platelets) [2]. In larger donors with high platelet counts, up to three units can be collected in one session. These are called apheresis or single donor platelets.

Advantages of single donor platelets are exposure of the recipient to a single donor rather than multiple donors, and the ability to match donor and recipient characteristics such as HLA type, cytomegalovirus (CMV) status, and blood type for certain recipients.

Both pooled and apheresis platelets contain some white blood cells (WBC) that were collected along with the platelets. These WBC can cause febrile non-hemolytic transfusion reactions (FNHTR), alloimmunization, and transfusion-associated graft-versus-host disease (ta-GVHD) in some patients.

Platelet products also contain plasma, which can be implicated in adverse reactions including transfusion-related acute lung injury (TRALI) and anaphylaxis. (See ‘Complications of platelet transfusion’ .)

6.2. +  Steroids

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Genomics and Medicine: The Physician’s View


Genomics and Medicine: The Physician’s View

Author and Curator: Larry H. Bernstein, MD, FCAP

 

Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease.  This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market.   Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured.  That is the first issue of concern.

Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked.  It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects.  In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.

A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon.  Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient.  Historically, insurance is an actuarial discipline.  But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention.  Only the timing cannot be predicted.  As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.

How does this compute for the physician provider.  The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm.   Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today.  It may provide assessment of risk, or of survival expectation.  The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams.  Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid.  They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.

The relevant questions are:

1. acuity of symptoms and signs.
2. actions to be taken.
3. tests that are needed to clarify the examination findings.

once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.

Where does genetic testing fit into this? At this point, it will only be used

  1. to confirm a restricted list of diagnoses that have a high association with the condition, and
  2. only with the participation of a medical geneticist, when
  3. profiling the patient and other members of the family is required.

10d0de1 Vitruvian Man by Leonardo da Vinci

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Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker

 

Co-Author of the FIRST Article: Larry H. Bernstein, MD, FCAP

Reviewer and Curator of the SECOND and of the THIRD Articles: Larry H. Bernstein, MD, FCAP

and

Article Architecture Curator: Aviva Lev-Ari, PhD, RN

This article presents Advances in the Treatment using Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe) for IMPROVEMENT of Severe and Resistant Congestive Heart Failure and its resultant Anemia.  The Leading Biomarker for Congestive Heart Failure is an Independent Predictor identified as an Elevated N-terminal proBNP.

NT-proBNP schematic diagram-Copy.pdf_page_1

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

Perspective

This THREE article sequence is related by investigations occurring by me, a very skilled cardiologist and his resident, and my premedical student at New York Methodist Hospital-Weill Cornell, in Brooklyn, NY, while a study had earlier been done applying the concordant discovery, which the team in Israel had though was knowledge neglected.  There certainly was no interest in the problem of the effect of anemia on the patient with severe congestive heart failure, even though erythropoietin was used widely in patients with end-stage renal disease requiring dialysis, and also for patients with myelofibrosis.  The high cost of EPO was only one factor, the other being a guideline to maintain the Hb concentration at or near 11 g/dl – not higher.  In the first article, the authors sought to determine whether the amino terminal pro– brain type natriuretic peptide (NT-pro BNP) is affected by anemia, and to determine that they excluded all patients who had renal insufficiency and/or CHF, since these were associated with elevated NT-proBNP.  It was already well established that this pro-peptide is secreted by the heart with the action as a urinary sodium retention hormone on the kidney nephron, the result being an increase in blood volume.  Perhaps the adaptation would lead to increased stroke volume from increased venous return, but that is not conjectured.  However, at equilibrium, one would expect there to be increased red cell production to maintain the cell to plasma volume ratio, thereby, resulting in adequate oxygen exchange to the tissues.  Whether that is always possible is uncertain because any reduction in the number of functioning nephrons would make the kidney not fully responsive at the Na+ exchange level, and the NT-pro BNP would rise.  This introduces complexity into the investigation, requiring a removal of confounders to establish the effect of anemia.

The other two articles are related studies by the same group in Israel.  They surmised that there was evidence that was being ignored as to the effect of anemia, and the treatment of anemia was essential in addition to other treatments.  They carried out a randomized trial to determine just that, a benefit to treating the anemia.  But they also conjectured that an anemia with a Hb concentration below 12 g/dl has an deleterious effect on the targeted population.  Treatment by intermittent transfusions could potentially provide the added oxygen-carrying capacity, but the fractionation of blood, the potential for transfusion-transmitted disease and transfusion-reactions, combined with the need for the blood for traumatic blood loss made EPO a more favorable alternative to packed RBCs.  The proof-of-concept is told below.  Patients randomized to receive EPO at a lower than standard dose + iron did better.

 

Introduction

In this article, Erythropoietin (EPO) and Intravenous Iron (Fe) as Therapeutics for Anemia in Severe and Resistant CHF: The Elevated N-terminal proBNP Biomarker we provides a summary of three articles on the topic and we shading new light on the role that Anemia Hb < 12 g%  plays as a Biomarker for CHF and for

  • prediction of elevated BNP, known as an indicator for the following Clinical Uses:
Clinical Use
  • Rule out congestive heart failure (CHF) in symptomatic individuals
  • Determine prognosis in individuals with CHF or other cardiac disease
  • Maximize therapy in individuals with heart failure by the use of Subcutaneous Erythropoietin (EPO) and Intravenous Iron (Fe)
Evaluation of BNP and NT-proBNP Clinical Performance
Study Sensitivity(%) Specificity(%) PPV(%) NPV(%)
Diagnose impaired LVEF3
BNP 73 77 70 79
NT-proBNP 70 73 61 80
Diagnose LV systolic dysfunction after MI2
BNP 68 69 56 79
NT-proBNP 71 69 56 80
Diagnose LV systolic dysfunction after MI12
BNP 94 40 NG 96
NT-proBNP 94 37 NG 96
Prognosis in newly diagnosed heart failure patients: prediction of mortality/survival1
BNP 98 22 42 94
NT-proBNP 95 37 47 93
Prognosis post myocardial infarction: prediction of mortality2
BNP 86 72 39 96
NT-proBNP 91 72 39 97
Prognosis post myocardial infarction: prediction of heart failure2
BNP 85 73 54 93
NT-proBNP 82 69 50 91
PPV, positive predictive value; NPV, negative predictive value; LVEF, left ventricular ejection fraction; NG, not given.
Reference Range
BNP: < 100 pg/mL13
proBNP, N-terminal: 300 pg/mL
The NT-proBNP reference range is based on EDTA plasma. Other sample types will produce higher values.
Interpretive Information
Symptomatic patients who present with a BNP or NT-proBNP level within the normal reference range are highly unlikely to have CHF. Conversely, an elevated baseline level indicates the need for further cardiac assessment and indicates the patient is at increased risk for future heart failure and mortality.BNP levels increase with age in the general population, with the highest concentrations seen in those greater than 75 years of age.14 Heart failure is unlikely in individuals with a BNP level <100 pg/mL and proBNP level ≤300 pg/mL. Heart failure is very likely in individuals with a BNP level >500 pg/mL and proBNP level ≥450 pg/mL who are <50 years of age, or ≥900 pg/mL for patients ≥50 years of age. Patients in between are either hypertensive or have mild ischemic or valvular disease and should be observed closely.15BNP is increased in CHF, left ventricular hypertrophy, acute myocardial infarction, atrial fibrillation, cardiac amyloidosis, and essential hypertension. Elevations are also observed in right ventricular dysfunction, pulmonary hypertension, acute lung injury, subarachnoid hemorrhage, hypervolemic states, chronic renal failure, and cirrhosis.NT-proBNP levels are increased in CHF, left ventricular dysfunction, myocardial infarction, valvular disease, hypertensive pregnancy, and renal failure, even after hemodialysis.Although levels of BNP and NT-proBNP are similar in normal individuals, NT-proBNP levels are substantially greater than BNP levels in patients with cardiac disease due to increased stability (half-life) of NT-proBNP in circulation. Thus, results from the two tests are not interchangeable.
References
  1. Cowie MR and Mendez GF. BNP and congestive heart failure. Prog Cardiovasc Dis. 2002;44:293-321.
  2. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin. New neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998:97:1921-1929.
  3. Hammerer-Lercher A, Neubauer E, Muller S, et al. Head-to-head comparison of N-terminal pro-brain natriuretic peptide, brain natriuretic peptide and N-terminal pro-atrial natriuretic peptide in diagnosing left ventricular dysfunction. Clin Chim Acta. 2001;310:193-197.
  4. McDonagh TA, Robb SD, Murdoch DR, et al. Biochemical detection of left-ventricular systolic dysfunction. Lancet. 1998;351:9-13.
  5. Mukoyama Y, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans: Evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest. 1991;87:1402-1412.
  6. Hunt PJ, Richards AM, Nicholls MG, et al. Immunoreactive amino-terminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endocrinol. 1997;47:287-296.
  7. Davis M, Espiner E, Richards G, et al. Plasma brain natriuretic peptide in assessment of acute dyspnoea. Lancet. 1994;343:440-444.
  8. Kohno M, Horio T, Yokokawa K, et al. Brain natriuretic peptide as a cardiac hormone in essential hypertension. Am J Med. 1992;92:29-34.
  9. Bettencourt P, Ferreira A, Pardal-Oliveira N, et al. Clinical significance of brain natriuretic peptide in patients with postmyocardial infarction. Clin Cardiol. 2000;23:921-927.
  10. Jernberg T, Stridsberg M, Venge P, et al. N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation. J Am Coll Cardiol. 2002;40:437-445.
  11. Richards AM, Troughton RW. Use of natriuretic peptides to guide and monitor heart failure therapy. Clin Chem. 2012;58:62-71.
  12. Pfister R, Scholz M, Wielckens K, et al. The value of natriuretic peptides NT-pro-BNP and BNP for the assessment of left-ventricular volume and function. A prospective study of 150 patients.Dtsch Med Wochenschr. 2002;127:2605-2609.
  13. Siemens ADVIA Centaur® BNP directional insert; 2003.
  14. Redfield MM, Rodeheffer RJ, Jacobsen SJ, et al. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40:976-982.
  15. Weber M, Hamm C. Role of B-type natriuretic peptid (BNP) and NT-proBNP in clinical routine.Heart. 2006;92:843-849.

SOURCE

B-type Natriuretic Peptide and proBNP, N-terminal

http://www.questdiagnostics.com/testcenter/testguide.action?dc=TS_BNP_proBNP

FIRST ARTICLE

Anemia as an Independent Predictor of Elevated N-terminal proBNP

Salman A. Haq, MD1, Mohammad E. Alam2, Larry Bernstein, MD, FCAP3,  LB Banko 1, Leonard Y. Lee, MD, FACS4, Barry I. Saul, MD, FACC5, Terrence J. Sacchi, MD, FACC6,  John F. Heitner, MD, FACC7
1Cardiology Fellow,  2  Clinical Chemistry Laboratories, 3 Program Director, Cardiothoracic Surgery, 4 Division of Cardiology,  Department of Medicine, New York Methodist Hospital-Weill Cornell, Brooklyn, NY

(Unpublished manuscript)  Poster Presentation:

Anemia as an Independent Predictor of Elevated N-Terminal proBNP Levels in
Patients without Evidence of Heart Failure and Normal Renal Function.

Haq SA, Alam ME, Bernstein L, Banko LB, Saul BI, Lee LY, Sacchi TJ, Heitner JF.

Table 1.  Patient Characteristics

Variable No Anemia(n=138) Anemia(n=80)
Median Age (years) 63 76
Men (%) 35 33
Creatinine (mg/dl) 0.96 1.04
Hemoglobin (g/dl) 13.7 10.2
LVEF (%) 67 63
Median NT-proBNP (pg/ml) 321.6 1896.0

Poster-ProBNP_final[1]

A series of slide showing the determination of the representation of normal NT-proBNP range
after removal of patient confounders.

Slide1

Slide10

Slide5

Slide8

ABSTRACT

Introduction

N-terminal proBNP (NT-proBNP) has emerged as a primary tool for diagnosing congestive heart failure (CHF). Studies have shown that the level of

  • NT-proBNP is affected by renal insufficiency (RI) and age, independent of the diagnosis of CHF.

There is some suggestion from recent studies that

  • anemia may also independently affect NT-proBNP levels.

Objective

To assess the affect of anemia on NT-proBNP independent of CHF, RI, and age.

Methods

We evaluated 746 consecutive patients presenting to the Emergency Department (ED) with shortness of breath and underwent evaluation with serum NT-proBNP.

All patients underwent a trans-thoracic echocardiogram (TTE) and clinical evaluation for CHF. Patients were included in this study if they had a normal TTE (normal systolic function, mitral inflow pattern and left ventricular (LV) wall thickness) and no evidence of CHF based on clinical evaluation. Patients were excluded if they had RI (creatinine > 2 mg/dl) or a diagnosis of sepsis. Anemia was defined using the World Health Organization (W.H.O.) definition of

  • hemoglobin (hgb) < 13 g/dl for males and hgb < 12 g/dl for females.

Results

Of the 746 consecutive patients, 218 patients (138 anemia, 80 no anemia) met the inclusion criteria. There was a markedly significant difference between

  • NT- proBNP levels based on the W.H.O. diagnosis of anemia.

Patients with anemia had a

  • mean NT- proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p=0.0001).

There was a markedly

  • significant difference in patients who had a hgb > 12 (median 295 pg/ml) when compared to
  • both patients with an hgb of 10.0 to 11.9 (median 2,102 pg/ml; p = 0.0001) and
  • those with a hgb < 10 (median 2,131 pg/ml; p = 0.001).

Linear regression analysis comparing hgb with log NT-proBNP was statistically significant (r = 0.395; p = 0.0001). MANOVA demonstrated that

  • elevated NT- proBNP levels in patients with anemia was independent of age.

Conclusion

This study shows that NT-proBNP is associated with anemia independent of CHF, renal insufficiency, sepsis or age.

INTRODUCTION

B-type natriuretic peptide (BNP) is secreted from the myocardium in response to myocyte stretch. 1-2 BNP is released from the myocytes as a 76 aminoacid N-terminal fragment (NT-proBNP) and a 32-amino acid active hormone (BNP). 3 These peptides have emerged as a primary non-invasive modality for the diagnosis of congestive heart failure (CHF). 4- 7 In addition, these peptides have demonstrated prognostic significance in patients with invasive modality for the diagnosis of

  • congestive heart failure (CHF). 4- 7
  • heart failure 8-9,
  • stable coronary artery disease 10, and
  • in patients with acute coronary syndromes. 11-14

Studies have shown that the level of NT- proBNP is affected by

  • age and renal insufficiency (RI) independent of the diagnosis of CHF. 15,16

There is some suggestion from the literature that

  • anemia may also independently affect NT-proBNP levels. 17-20

Willis et al. demonstrated in a cohort of 209 patients without heart failure that anemia was associated with an elevated NT- proBNP. 17 Similarly, in 217 patients undergoing cardiac catheterization, blood samples were drawn from the descending aorta prior to contrast ventriculography for BNP measurements and

  • anemia was found to be an independent predictor of plasma BNP levels. 18

The objective of this study is to assess the effect of anemia on NT-proBNP independent of CHF, sepsis, age or renal insufficiency.

METHODS

Patient population

The study population consisted of 746 consecutive patients presenting to the emergency room who underwent NT-proBNP evaluation for the evaluation of dyspnea. Transthoracic echocardiogram (TTE) was available on 595 patients. Patients were included in this study if they had a normal TTE, which was defined as normal systolic function (left ventricular ejection fraction [LVEF] > 45%), normal mitral inflow pattern and normal LV wall thickness. CHF was excluded based on thorough clinical evaluation by the emergency department attending and the attending medical physician. Patients with disease states that may affect the NT- proBNP levels were also excluded:

  1. left ventricular systolic dysfunction (LVEF < 45%),
  2. renal insufficiency defined as a creatinine > 2 mg/dl and
  3. sepsis (defined as positive blood cultures with two or more of the following systemic inflammatory response syndrome (SIRS) criteria: heart rate > 90 beats per minute;
  4. body temperature < 36 (96.8 °F) or > 38 °C (100.4 °F);
  5. hyperventilation (high respiratory rate) > 20 breaths per minute or, on blood gas, a PaCO2 less than 32 mm Hg;
  6. white blood cell count < 4000 cells/mm3 or > 12000 cells/mm³ (< 4 x 109 or > 12 x 109 cells/L), or greater than 10% band forms (immature white blood cells). 21

The study population was then divided into two groups, anemic and non- anemic. Anemia was defined using the world health organization (W.H.O.) definition of hemoglobin (hgb) < 13 g/dl for males and < 12 g/dl for females.The data was also analyzed by dividing the patients into three groups based on hgb levels i.e. hgb > 12, hgb 10 to 11.9 and hgb < 10.

Baseline patient data

Patient’s baseline data including age, gender, ethnicity, hemoglobin (hgb), hematocrit (hct), creatinine, NT- proBNP were recorded from the electronic medical record system in our institution. Chemistry results were performed on the Roche Modular System (Indianapolis, IN), with the NT- proBNP done by chemiluminescence assay. The hemogram was performed on the Beckman Coulter GenS. All TTE’s were performed on Sonos 5500 machine. TTE data collected included LVEF, mitral inflow pattern and LV wall thickness assessment.

Statistical analysis

The results are reported in the means with p < 0.05 as the measure of significance for difference between means. Independent Student’s t-tests were done comparing NT proBNP and anemia. Univariate ANOVAs and multivariate ANOVA (MANOVA) with post hoc tests using the Bonferroni method were used to compare NT- proBNP levels with varying ranges of hgb and age using SPSS 13.0 (SPSS, Chicago, IL). A linear regression analysis was performed using SYSTAT. Calculations included Wilks’Lamda, Pillai trace and Hotelling-Lawley trace. A GOLDMineR® plot was constructed to estimate the effects of age and anemia on NT- proBNP levels. The GOLDMineR® effects plot displays the odds-ratios for predicted NT-proBNP elevation versus the predictor values. Unlike the logistic regression, the ordinal regression, which the plot is derived from, can have polychotomous as well as dichotomous values, as is the case for NT-proBNP.

RESULTS

Of the 746 consecutive patients, 218 patients met the inclusion criteria (fig 1). Baseline characteristics of patients are listed in table 1. The median age for anemic patients was 76 years and 63 years for patients without anemia. One third of patients in both groups were men. The mean hemoglobin for

  • anemic patients was 10.2 g/dl as compared to 13.7 g/dl for non-anemic patients.
  • The mean LVEF of patients with anemia was 64% as compared to 67% for non-anemic patients.

Based on the WHO definition of anemia, 138 patients were determined to be anemic while 80 patients were diagnosed as non-anemic. There was a markedly  significant difference between NT-proBNP levels based on the WHO diagnosis of anemia.

Patients with anemia had a

  • mean NT-proBNP of 4,735 pg/ml compared to 1,230 pg/ml in patients without anemia (p = 0.0001).

Of the 218 patients in the study, 55 patients had a hgb of < 10 g/dl. Analysis using

  • hgb < 10 g/dl for anemia demonstrated a statistically significant difference in the NT-proBNP values.

Patients with a hgb < 10 g/dl had a mean NT- proBNP of 5,130 pg/ml

  • compared to 2,882 pg/ml in patients with a hgb of > 10 g/dl (p = 0.01)

The groups were also divided into three separate categories of hgb for subset analysis:

  • hgb > 12 g/dl,
  • hgb 10 to 11.9 g/dl and
  • hgb < 10 g/dl.

There was a markedly significant difference in

  •  the NT- ProBNP levels of patients who had a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to those with a hgb range of 10.0 g/dl to 11.9 g/dl (median 2,102 pg/ml) (p = 0.0001),

and also a significant difference in

  • NT- proBNP levels of patients with a hgb > 12 g/dl (median 295 pg/ml) when
  • compared to a hgb of < 10 g/dl (median 2,131 pg/ml) (p = 0.001).

However, there was no statistically significant difference in NT-proBNP levels of patients with hgb 10 g/dl to 11.9 g/dl

  • when compared to those with a hgb of < 10 g/dl (p = 1.0).

A scatter plot comparing hgb with log NT-proBNP and fitting of a line to the data by ordinary least squares regression was significant (p = 0.0001) and demonstrated

  • a correlation between anemia and NT-proBNP levels (r = 0.395) (fig. 2).

MANOVA demonstrated that elevated NT- proBNP levels in patients with anemia was independent of age (Wilks’ Lambda [p = 0.0001]). In addition, using GOLDMineR® plots (figure 3a and 3b) with a combination of age and hb scaled as predictors of elevated NT-proBNP,

  • both age and hgb were required as independent predictors.

What about the effect of anemia? The GOLDminer analysis of ordinal regression was carried out in a database from which renal insufficiency and CHF were removed. The anemia would appear to have an independent effect on renal insufficiency. Figure 4 is a boxplot comparison of NT – proBNP, the age normalized function NKLog (NT- proBNP)/eGFR formed from taking 1000*Log(NT- proBNP) divided by the MDRD at eGFR exceeding 60 ml/min/m2 and exceeding 30 ml/min/m2. The transformed variable substantially makes the test independent of age and renal function. The boxplot shows the medians, 97.5, 75, 25 and 2.5 percentiles. There appears to be no significance in the NKLog(NT pro-BNP)/MDRD plot. Table II compares the NT-proBNP by WHO criteria at eGFR 45, 60 and 75 ml/mln/m2 using the t-test with unequal variance assumed, and the Kolmogorov-Smirnov test for nonparametric measures of significance. The significance at 60 ml/min/m2 is marginal and nonexistent at 75 ml/min/m2. This suggests that the contribution from renal function at above 60 ml/min2 can be ignored. This is consistent with the findings using the smaller, trimmed database, but there is an interaction between

  •  anemia, and
  •  eGFR at levels below 60 ml/min/m2

DISCUSSION

The findings in this study indicate that

  • anemia was associated with elevated NT-proBNP levels independent of CHF, renal insufficiency, sepsis or age.

These findings have been demonstrated with NT-proBNP in only one previous study. Wallis et al. demonstrated that after adjusting for age, sex, BMI, GFR, LVH and valvular disease;

  1. only age,
  2. valvular disease and
  3. low hemoglobin

were significantly associated with increased NT-proBNP. 18.

In our study, CHF was excluded based on both a normal TTE and a thorough clinical evaluation. In the only other study directly looking at NT- proBNP levels in anemic patients without heart failure

  • only 25% of patients had TTEs, with one patient having an LVEF of 40%. 17

BNP, the active molecule released after cleavage along with NT- proBNP, has also been studied in relation to blood hemoglobin levels. 18 In 263 patients undergoing cardiac catheterization  blood samples were drawn from the descending aorta prior to contrast ventriculography to determine the value of BNP. Anemia was present in 217 patients. Multivariate linear regression model adjusting for

  1.  age,
  2.  gender,
  3.  body mass index,
  4.  history of myocardial infarction,
  5.  estimated creatinine clearance, and
  6.  LVEF
  • found hgb to be an independent predictor of BNP levels.

In our study, patients with anemia were slightly older than those without anemia. However, both MANOVA and GOLDMineR® plot demonstrated that

  • elevated NT-proBNP levels in patients with anemia was independent of age.

Other studies have found that BNP is dependent on renal insufficiency and age. Raymond et al. randomly selected patients to complete questionnaires regarding CHF and

  1. then underwent pulse and blood pressure measurements,
  2.  electrocardiogram (ECG),
  3.  echocardiography and
  4.  blood sampling. 15

A total of 672 subjects were screened and 130 were determined to be normal, defined as

  • no CHF or ischemic heart disease,
  • normal LVEF,
  • no hypertension,
  • diabetes mellitus,
  • lung disease, and
  • not on any cardiovascular drugs.

They found

  1. older age,
  2. increasing dyspnea,
  3. high plasma creatinine and a
  4. LVEF < 45%

to be independently associated with an elevated NT-proBNP plasma level by multiple linear regression analysis. In another study, McCullough et al. evaluated the patients from the Breathing Not Properly Multinational Study

  • looking at the relationship between BNP and renal function in CHF. 16

Patients were excluded if they were on hemodialysis or had a estimated glomerular filteration rate (eGFR) of < 15 ml/min. They found that the BNP levels correlated significantly with the eGFR, especially in patients without CHF, suggesting

  1. chronic increased blood volume and
  2. increased left ventricular wall tension as a possible cause. 16

Our study was designed to exclude patients with known diseases such as CHF and renal insufficiency in order to demonstrate

  • the independent effect of anemia on elevated NT-proBNP levels.

The mechanism for elevated NT-proBNP levels in patients with anemia is unknown. Some possible mechanisms that have been reported in the literature include

  • hemodilution secondary to fluid retention in patients with CHF 18,
  • decreased oxygen carrying capacity with accompanying tissue hypoxia which
  • stimulates the cardio-renal compensatory mechanism leading to increased release of NT-proBNP. 17

The findings from our study suggest that

  •  NT-proBNP values should not be interpreted in isolation of hemoglobin levels and
  • should be integrated with other important clinical findings for the diagnosis of CHF.

Further studies are warranted

  1.  to assess the relationship between anemia and plasma natriuretic peptides, and
  2. possibly modify the NT-proBNP cutoff points for diagnosing acutely decompensated CHF in patients with anemia.

CONCLUSION

This study shows that elevated NT-proBNP levels are associated with anemia independent of

  •   CHF,
  •  renal insufficiency,
  •  sepsis and
  •  age.

NT-proBNP levels should be interpreted with caution in patients who have anemia.

 REFERENCES

1. Brunea BG, Piazza LA, de Bold AJ. BNP gene expression is specifically modulated by stretch and ET-1 in a new model of isolated rat atria.Am J Physiol  1997; 273:H2678-86.

2. Wiese S, Breyer T, Dragu A, et al. Gene expression of brain natriuretic peptide  in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circ 2000; 102:3074-79.

3. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003; 362:316-22.

4.   Dao Q, Krishnaswamy P, Kazanegra R, et al. Utility of B-type natriuretic  peptide in the diagnosis of congestive heart failure in an urgent care setting. J Am  Coll Cardiol 2001; 37:379-85.

5. Morrison LK, Harrison A, Krishnaswamy P, Kazanegra R, Clopton P, Maisel A. Utility of rapid natriuretic peptide assay in differentiating congestive heart failure from lung  disease in patients presenting with dyspnea.
J Am Coll Cardiol  2003; 39:202-09.

6.  Maisel AS, Krishnaswamy P, Nowak RM, et al.  Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002; 347:161-67.

7. Januzzi JL, Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J  Cardiol 2005; 95:948-954.

8.  Tsutamoto T, Wada A, Meada K, et al.   Attenuation of compensation of  endogenous cardiac natriuretic peptide system  in chronic heart failure: prognostic role  of plasma  brain natriuretic peptide concentration in patients with chronic  symptomatic  left ventricular dysfunction.
Circulation 1997; 96(2): 509-16.

9.  Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HEFT). Circulation 2003; 107:1278-1283.

10. Omland T, Richards AM, Wergeland R and Vik-Mo H. B-type natriuretic peptide and long term survival in patients with stable coronary artery disease.
Am J Cardiol 2005; 95:24-28.

11. Omland T, Aakvaag A, Bonarjee VV. et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic dysfunction and long term prognosis after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.
Circulation 1996; 93:1963-1969.

12. de Lemos JA, Morrow DA, Bently JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001; 345:1014-1021.

13. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and  ejection fraction for prognosis after myocardial infarction. Circulation 2003; 107:2786-2792.

14. Sabatine MS, Morrow DA, de Lemos JA, et al.  Multimarker approach to risk  stratification in non-ST elevation acute coronary syndromes: simultaneous  assessment of troponin I, C-reactive protein and B-type natriuretic peptide.
Circulation 2002; 105:1760-1763.

15. Raymond I, Groenning BA, Hildebrandt PR, Nilsson JC, Baumann M, Trawinski   J, Pedersen F.  The influence of age, sex andother variables on the plasma level of N-terminal pro brain natriureticpeptide in a large sample of the general  population. Heart 2003; 89:745-751.

16. McCollough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, et al. B-type natriuretic peptide and renal function in the diagnosis of heartfailure:  an analysis from the  Breathing Not Properly Multinational Study.
Am J Kidney Dis 2003; 41:571-579.

17. Willis MS, Lee ES, Grenache DG. Effect of anemia on plasma concentrations of  NT-proBNP.
Clinica Chim Acta 2005; 358:175-181.

18. Wold Knudsen C, Vik-Mo H, Omland T. Blood hemoglobin is an independent  predictor of B-type natriuretic peptide.
Clin Sci 2005; 109:69-74.

19. Tsuji H, Nishino N, Kimura Y, Yamada K, Nukui M, et al. Haemoglobin level influences plasma brain natriuretic peptide concentration. Acta Cardiol 2004;59:527-31.

20. Wu AH, Omland T, Wold KC, McCord J, Nowak RM, et al. Relationship  of B-type natriuretic peptide and anemia  in patients withand without heart failure:  A substudy from the Breathing Not Properly(BNP) Multinational Study.
Am J  Hematol 2005; 80:174-80.

22. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al.  Definitions for sepsis and organ failure and guidelines for theuse of innovative therapies in sepsis.  The ACCP/SCCM Consensus Conference Committee. Chest. 1992;101(6):1644-55.

Table Legends

Table I. Clinical characteristics of the study population

Table II. Comparison of NT- proBNP means under WHO criteria at different GFR

Table I
Variable No Anemia(n=80) Anemia(n=138)
Median age (years) 63 76
Gender
    Men (%) 27 (34) 47 (34)
    Women (%) 53 (66) 91 (66)
Weight (kg) 82.9 80.1
Chest Pain 21 (26) 3 (2)
Hemoglobin (g/dl) 13.7 10.2
Hematocrit (%) 40.5 30.5
Mean Corpuscular Volume 97 87
Creatinine (mg/dl) 0.99 1.07
Median NT-proBNP (pg/ml) 321 1896
Medical History
    HTN (%) 12 (15) 51 (37)
    Prior MI (%) 11 (14) 5 (4)
    ACS (%) 16 (20) 3 (2)
    CAD (%) 2 (1) 3 (2)
     DM (%) 18 (22) 11 (8)
Medication
   Clopidogrel 58 (72) 15 (11)
   Beta Blockers 68 (85) 27 (20)
   Ace Inhibitors 45 (56) 18 (13)
   Statins 57 (71) 17 (12)
   Calcium Channel Blocker 17 (21) 8 (6)
LVEF (%) 67 64

HTN: Hypertension CAD: Coronary Artery Disease
MI: Myocardial Infarction DM: Diabetes Mellitus
ACS: Acute Coronary Syndrome LVEF: Left Ventricular Ejection Fraction

Table II
GFR WHO Mean P (F) N NPar
> 45 0 3267 0.022 (4.33) 661
1 4681
> 60* 0 2593 0.031 (5.11) 456 0.018
1 4145
> 60r 0 786 0.203 (3.63) 303 0.08
1 3880
> 75 0 2773 > 0.80 320 0.043
1 3048

*AF, valve disease and elevated troponin T included
r AF, valve disease and elevated troponin T removed

FIGURE LEGENDS

FIGURE 1. Study population flow chart. (see poster)
FIGURE 2. Relationship between proBNP and hemoglobin. (see above)
FIGURE 3. NT-proBNP levels in relation to anemia (see above)

Supplementary Material

Table based on LatentGOLD Statistical Innovations, Inc., Belmont, MA., 2000: Jeroen Vermunt & Jay Magidson)

4-Cluster Model

Number of cases                                   408
Number of parameters (Npar)             24

Chi-squared Statistics
Degrees of freedom (df)                          71                     p-value
L-squared (L²)                                    80.2033                    0.21
X-squared                                            80.8313                     0.20
Cressie-Read                                        76.6761                     0.30
BIC (based on L²)                          -346.5966
AIC3 (based on L²)                        -132.7967
CAIC (based on L²)                       -417.5966

Model for Clusters
 Intercept                Cluster1      Cluster2     Cluster3     Cluster4     Wald     p-value
————–           0.1544           0.1434        0.0115        -0.3093     1.1981     0.75
Cluster Size           0.2870          0.2838       0.2487          0.1805
(across)

LogNTpr
< 1.5                       0.0843           0.2457       0.0006          0.0084
1.6-2.5                   0.6179            0.6458       0.0709          0.2809
2.5-3.5                  0.2848           0.1067         0.5319          0.5883
> 3.5                      0.0130           0.0018         0.3966         0.1224
MDRD
> 90                     0.1341             0.7919         0.0063         0.6106
61-90                  0.6019            0.2040          0.1633         0.3713
41-60                  0.2099            0.0041          0.3317         0.0175
< 41                     0.0542            0.0001         0.4987        0.0006
age
under 51           0.0668           0.5646          0.0568        0.0954
51-70                 0.3462            0.3602          0.3271         0.3880
over 70             0.5870            0.0752          0.6161         0.5166
WHO
No anemia      0.7518             0.6556          0.2041         0.0998
Anemia            0.2482             0.3444          0.7959         0.9002

———          Cluster1          Cluster2      Cluster3      Cluster4
Overall           0.2870            0.2838         0.2487        0.1805
(down)

LogNTpro
< 1.5                0.2492              0.7379           0.0013         0.0116
1.6-2.5            0.4163               0.4243           0.0427        0.1167
2.6-3.5           0.2296               0.0887          0.3723        0.3095
> 3.5              0.0328                0.0023          0.7982        0.1666
MDRD
> 90              0.1001                0.5998           0.0043        0.2958
61-90           0.5198                 0.1716           0.1136         0.1950
41-60           0.3860                 0.0055          0.5847         0.0238
< 41             0.1205                  0.0002          0.8785         0.0008
 age
< 51            0.0720                 0.7458           0.0910          0.0912
51-70         0.3036                 0.3084           0.2013          0.1867
over 70     0.3773                  0.0409          0.3633           0.2186
 WHO
No anemia 0.4589              0.3957           0.1076           0.0378
Anemia     0.1342                 0.1844            0.3742           0.3073

Hemoglobin on NT proBNP 3

SECOND ARTICLE

The effect of correction of mild anemia in severe, resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a randomized controlled study

Donald S Silverberg, MDa; Dov Wexler, MDa; David Sheps, MDa; Miriam Blum, MDa; Gad Keren, MDa; Ron Baruch, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Shoshana Steinbruch, RNa; Itzhak Shapira, MDa; Shlomo Laniado, MDa; Adrian Iaina, MDa

J Am Coll Cardiol. 2001;37(7):1775-1780. doi:10.1016/S0735-1097(01)01248-7

http://content.onlinejacc.org/article.aspx?articleid=1127229

OBJECTIVES

This is a randomized controlled study of anemic patients with severe congestive heart failure (CHF) to assess the effect of correction of the anemia on cardiac and renal function and hospitalization.

BACKGROUND

Although mild anemia occurs frequently in patients with CHF, there is very little information about the effect of correcting it with erythropoietin (EPO) and intravenous iron.

METHODS

Thirty-two patients with moderate to severe CHF (New York Heart Association [NYHA] class III to IV)
who had a left ventricular ejection fraction (LVEF) of 40% despite maximally tolerated doses of CHF medications and
  • whose hemoglobin (Hb) levels were persistently between 10.0 and 11.5 g% were randomized into two groups.
Group A (16 patients) received subcutaneous EPO and IV iron to increase the level of Hb to at least 12.5 g%. In Group B (16 patients) the anemia was not treated. The doses of all the CHF medications were maintained at the maximally tolerated levels except for oral and intravenous (IV) furosemide, whose doses were increased or decreased according to the clinical need.

RESULTS

Over a mean of 8.2 +/- 2.6 months,
  • four patients in Group B and none in Group A died of CHF-related illnesses.
  • The mean NYHA class improved by 42.1% in A and worsened by 11.4% in B.
  • The LVEF increased by 5.5% in A and decreased by 5.4% in B.
  • The serum creatinine did not change in A and increased by 28.6% in B.
  • The need for oral and IV furosemide decreased by 51.3% and 91.3% respectively in A and increased by 28.5% and 28.0% respectively in B.
  • The number of days spent in hospital compared with the same period of time before entering the study decreased by 79.0% in A and increased by 57.6% in B.

CONCLUSIONS

When anemia in CHF is treated with EPO and IV iron, a marked improvement in cardiac and patient function is seen,
  • associated with less hospitalization and renal impairment and less need for diuretics. (J Am Coll Cardiol 2001;37:1775– 80)

Anemia of any cause is known to be capable of causing congestive heart failure (CHF) (1). In patients hospitalized with CHF the 

  • mean hemoglobin (Hb) is about 12 g% (2,3),

which is considered the lower limit of normal in adults (4). Thus, anemia appears to be

common in CHF. Recently, in 142 patients in our special CHF outpatient clinic, we found that

  • as the CHF worsened, the mean Hb concentration decreased, from 13.7 g% in mild CHF (New York Heart Association [NYHA] class I) to 10.9 g% in severe CHF (NYHA 4), and
  • the prevalence of a Hb 12 g% increased from 9.1% in patients with NYHA 1 to 79.1% in those with NYHA 4 (5).
The Framingham Study has shown that anemia is an
  • independent risk factor for the production of CHF (6).
Despite this association of CHF with anemia,
  • its role is not mentioned in the 1999 U.S. guidelines for the diagnosis and treatment of CHF (7), and
  • many studies consider anemia to be only a rare contributing cause of hospitalization for CHF (8,9).
Recently, we performed a study in which the anemia of severe CHF that was resistant to maximally tolerated doses of standard medications
  • was corrected with a combination of subcutaneous (sc) erythropoietin (EPO) and intravenous iron (IV Fe) (5).
We have found this combination to be safe, effective and additive
  • in the correction of the anemia of chronic renal failure (CRF) in both
  • the predialysis period (10) and the dialysis period (11).
The IV Fe appears to be more effective than oral iron (12,13). In our previous study of CHF patients (5), the treatment resulted in
  • improved cardiac function,
  • improved NYHA functional class,
  • increased glomerular filtration rate,
  • a marked reduction in the need for diuretics and
  • a 92% reduction in the hospitalization rate
compared with a similar time period before the intervention. In the light of these positive results, a prospective randomized study was undertaken
  • to determine the effects of the correction of anemia in severe symptomatic CHF resistant to maximally tolerated CHF medication.

Abbreviations and Acronyms

CABG coronary artery bypass graft
CHF congestive heart failure
CRF chronic renal failure
EPO erythropoietin
%Fe Sat percent iron saturation
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IU international units
IV intravenous
LVEF left ventricular ejection fraction
NYHA New York Heart Association
PA pulmonary artery
sc subcutaneous
SOLVD Studies Of Left Ventricular Dysfunction

MATERIALS AND METHODS

Patients.Thirty-two patients with CHF were studied. Before the study, the patients were treated for least six months in the CHF clinic with

  • maximally tolerated doses of angiotensin-converting enzyme inhibitors, the beta-blockers bisoprolol or carvedilol, aldospirone, long-acting nitrates, digoxin and oral and intravenous (IV) furosemide.

In some patients these agents could not be given because of contraindications and in others they had to be stopped because of side effects. Despite this maximal treatment

  • the patients still had severe CHF  (NYHA classIII), with  fatigue and/or shortness of breath  on even mild exertion or at rest.  All had levels of
  • Hb in the range of 10 to 11.5 g%  on at least three consecutive visits over a three-week period.
  • All had a LVEF of 40%.

Secondary causes of anemia including hypothyroidism, and folic acid and vitamin B12 deficiency were ruled out and

  • there was no clinical evidence of gastrointestinal bleeding.

The patients were randomized consecutively into two groups:

  • Group A, 16 patients, was treated with sc EPO and IV Fe to achieve a target Hb of at least 12.5 g%.
  • Group B, 16 patients, did not receive the EPO and IV Fe.

Treatment protocol for correction of anemia.

All patients in Group A received the combination of sc EPO and IV Fe. The EPO was given once a week at a starting dose of 4,000 international units (IU) per week  and
the dose was increased  to two  or  three  times a week or decreased to once every few weeks as  necessary

  • to achieve and maintain a target Hb of 12.5 g%.

The IV Fe (Venofer-Vifor International, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every two weeks

  • until the serum ferritin reached 400 g/l or
  • the %Fe saturation (%Fe Sat is serum iron/total iron binding capacity 100) reached 40% or
  • the Hb reached 12.5g%. 

The IV Fe was then given at longer intervals as needed to maintain these levels.

Investigations. 

Visits to the clinic were at two- to three week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before then,

  • potassium and ferritin and %Fe Sat were performed on every visit.
  • blood pressure was measured by an electronic device on every visit.
  • LVEF was measured initially and at four- to six-month intervals by MUGA radioisotope ventriculography.

This technique measures

  • the amount of blood in the ventricle at the end of systole and at the end of diastole, thus giving
  • a very accurate assessment of the ejection fraction.

It has been shown to be an accurate and reproducible method of measuring the ejection fraction (14).  Hospital records were reviewed at the end of the intervention period to compare

  • the number of days hospitalized during the study with 
  • the number of days hospitalized during a similar period 
    • when the patients were treated in the CHF clinic before the initial randomization and entry into the study.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study. The mean follow-up for patients was 8.2 +/-  2.7 months (range 5 to 12 months).  The study was done with the approval of the local ethics committee.Statistical analysis.

An analysis of variance with repeated measures (over time) was performed to compare the two study groups (control vs. treatment) and

  • to assess time trend and the interactions between the two factors.
  • A separate analysis was carried out for each of the outcome parameters.
  • The Mann-Whitney test was used to compare the change in NYHA class between two groups.

All the statistical analysis was performed by SPSS (version 10).

RESULTS

The mean age in Group A (EPO and Fe) was 75.3 +/-  14.6 years and in group B was 72.2 +/-  9.9 years. There were 11 and 12 men in Groups A and B, respectively.
Before the study the two groups were similar in
  1. cardiac function,
  2. comorbidities,
  3. laboratory investigations and
  4. medications
  • (Tables 1, 2 and 3), except for IV furosemide (Table 3),
which was higher in the treatment group. The mean NYHA class of Group A before the study was 3.8  0.4 and was 3.5  0.5 in Group B. The contributing factors to CHF in Groups A and B, respectively, are seen in Table 1 and were similar.
Table 1. Medical Conditions and Contributing Factors to Congestive Heart Failure in the 16 Patients Treated for the Anemia and in the 16 Controls

Table 1 medical conditions heart failure anemia

Table 2. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 2 medications to treat heart failure anemia

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

The main contributing factors to CHF were considered to be

  • ischemic heart disease (IHD) in 11 and 10 patients respectively,
  • hypertension in two and two patients,
  • valvular heart disease in twoand two patients, and
  • idiopathic cardiomyopathy in one and two patients, respectively.

A significant change after treatment was observed in the two groups in the following parameters:

  • IV furosemide,
  • days in hospital,
  • Hb,
  • ejection fraction,
  • serum creatinine and
  • serum ferritin.
In addition, the interaction between the study group and time trend was significant in all measurements except for blood pressure and %Fe Sat. This interaction indicates that
  • the change over time was significantly different in the two groups.
Table 3. The Effect of Correction of Anemia by Intravenous Iron and Erythropoietin Therapy on Various Parameters in 16 Patients in the Treatment (A) and 16 in the Control (B) Group

Table 3  CHF aneia EPO

p values are given for analysis of variance with repeated measures and for independent t tests for comparison of baseline levels between the two groups.
BP  blood pressure; Fe Sat  iron saturation; Hb  hemoglobin; IV  intravenous; NS  not stated; Std Dev.  standard deviation.

We find in the comparisons of Tables 2 and 3:

  1. before treatment the level of oral furosemide was higher in the control group (136.2 mg/day) compared with the treatment group (132.2 mg/day).
  2. after treatment, while the dose of oral furosemide of the treated patients was reduced  to 64.4 mg/day
  • the dose of the nontreated patients was increased to 175 mg/day.

The same results of improvement in the treated group and deterioration in the control group are expressed in the following parameters:

  1. IV furosemide, days in hospital,
  2. Hb,
  3. ejection fraction and
  4. serum creatinine.

The NYHA class was

  • 3.8 +/- 0.4 before treatment and 2.2 +/- 0.7 after treatment in Group A  (delta mean = – 1.6) and
  • 3.5 +/-  0.7 before treatment and 3.9 +/- 0.3 after treatment in Group B. (delta mean = 0.4)

The improvement in NYHA class was significantly higher (p < 0.0001) in the treatment group compared with the control group (Table 4).

Table 4. Changes from Baseline to Final New York Heart Association (NYHA) Class
Initial minus final

Table 4  changes from NYHA baseline  CHF anemia

The improvement in NYHA class was statistically higher (p <  0.0001) in the treatment group compared with control.

There were no deaths in Group A and four deaths in Group B.

Case 1: A 71-year-old woman with severe mitral insufficiency and severe pulmonary hypertension  (a pulmonary artery [PA] pressure of 75 mm Hg) had persistent NYHA 4 CHF  and died during mitral valve surgery  seven months after onset of the study. She was hospitalized for 21 days  in the seven months before randomization and for 28 days  during the seven months after randomization.

Case 2:

A 62-year-old man with a longstanding history of hypertension complicated by IHD, coronary artery bypass graft (CABG) and atrial fibrillation had persistent NYHA 4 CHF  and a PA pressure of 35 mm Hg,  and died from pneumonia and septic shock eight months after onset of the study. He was hospitalized for seven days in the eight months before randomization and for 21 days during the eight months  after
randomization.

Case 3:
A 74-year old man with IHD, CABG, chronic obstructive pulmonary disease, a history of heavy smoking and diabetes had persistent NYHA 4 CHF and a PA pressure of  28 mm Hg, and died of pulmonary  edema and cardiogenic shock nine months after onset of the study. He was hospitalized for 14 days in the nine months before  randomization and for 41 days during the nine months after randomization.

Case 4:
A 74-year-old man with a history of IHD, CABG, diabetes, dyslipidemia, hypertension and atrial fibrillation, had persistent NYHA 4 CHF and a PA pressure of 30 mm Hg,  and died of pneumonia and septic shock   six months after onset of the study. He was hospitalized for five days in the six months before randomization and for 16 days during the nine months after randomization.

DISCUSSION

 Main findings.

The main finding of the present study is that the correction of

  • even mild anemia in patients with symptoms of very severe CHF despite being on maximally tolerated drug therapy
  • resulted in a significant improvement in their cardiac function and NYHA functional class.

There  was also a large

  • reduction in the number of days of  hospitalization compared with a similar period before the  intervention.
  • all this was achieved despite a marked reduction in the dose of oral and IV furosemide.

In the group in whom the anemia was not treated, four  patients died during the study. In all four cases

  • the CHF was unremitting and contributed to the deaths. 

In addition,  for the group as a whole, 

  • the LVEF, the NYHA class and  the renal function worsened.

There was also need for

  • increased oral and IV furosemide as well as increased  hospitalization.

Study limitations.

The major limitations of this study are

  1. the smallness of the sample size and
  2. the fact that randomization and treatment were not done in a blinded fashion.

Nevertheless, the two groups were almost identical in

  1. cardiac, renal and anemia status;
  2. in the types and doses of medication they were taking before and during the intervention and
  3. in the number of hospitalization days before the intervention.

Although the results of this study, like those of  our previous uncontrolled study (5), suggest that

  • anemia may play an important role in the mortality and morbidity of  CHF,
  • a far larger double-blinded controlled study should be carried out to verify our findings.

Anemia as a risk factor for hospitalization and death in CHF.

Our results are consistent with a recent analysis of 91,316 patients hospitalized with CHF (15). Anemia was found to be a stronger predictor of

  • the need for early rehospitalization than  was hypertension,  IHD or the presence of a previous CABG.  

A recent analysis of the Studies Of Left Ventricular Dysfunction (SOLVD) (16) showed that

  • the level of hematocrit (Hct) was an independent risk factor for mortality.

During a mean follow-up of 33 months the mortality was

  • 22%, 27% and 34% for those with a Hct of 40, 35 to 40 and 35 respectively.

The striking response of our patients to

  • correction of mild anemia suggests that the failing heart may be very susceptible to anemia.

It has, in fact, been found in both animal (17) and human studies (17–19) that

  • the damaged heart is more vulnerable to anemia and/or ischemia than is the normal heart.

These stimuli may result in a more marked reduction in cardiac function than occurs in the normal heart and may explain why,  in our study,

  • the patients were so resistant to high doses of CHF medications and
  • responded so well when the anemia was treated.

Our findings about the importance of anemia in CHF are not surprising when one considers that, in dialysis patients,

  • anemia has been shown to be associated with an increased prevalence and incidence of CHF (20) and that
  • correction of anemia in these patients is associated with improved
    • cardiac function (21,22),
    • less mortality (23,24) and
    • fewer hospitalizations (23,25).

Effect of improvement of CHF on CRF.

Congestive heart failure can cause progressive renal failure (26,27). Renal ischemia is found very early on

  • in patients with cardiac dysfunction (28,29), and
  • chronic ischemia may cause progression of renal failure (30). Indeed, the development of
  • CHF in patients with essential hypertension has been found to be one of the most powerful predictors of
  • the eventual development of end-stage renal disease (31).

Patients who develop CHF after a myocardial infarction experience a

  • fall in the glomerular filtration rate (GFR) of about 1 ml/min/month if the CHF is not treated (32).

In another recent analysis of the SOLVD study, treating the CHF with

  • both angiotensin-converting enzyme inhibitors and beta-blockers resulted in better preservation of the renal function than did
  • angiotensin-converting enzyme inhibitors alone (26),
suggesting that the more aggressive the treatment of the CHF, the better the renal function is preserved. In the present study, as in our previous one (5), we found that the deterioration of GFR was prevented with
  • successful treatment of the CHF, including correction of the anemia, whereas
  • the renal function worsened when the CHF remained severe

All these findings suggest that early detection and treatment of CHF and systolic and/or diastolic dysfunction from whatever cause could prevent

  • the deterioration not only of the cardiac function
  • but of the renal function as well.

This finding has very broad implications in the prevention of CRFbecause most patients with advanced CRF have

  • either clinical evidence of CHF or at least some degree of systolic dysfunction (33).

Systolic and/or diastolic dysfunction can occur early on in many  conditions, such as

  • essential hypertension (34),
  • renal disease of any cause (35,36) or
  • IHD, especially after a myocardial infarction (37).

The early detection and adequate treatment of this cardiac dysfunction, including correction of the anemia, could prevent this cardiorenal insufficiency. To detect cardiac dysfunction early on, one would need  at least an echocardiogram and MUGA radio-nucleotide ventriculography. These tests should probably be done not only in patients with signs and symptoms of CHF,   but in all patients where CHF or systolic  and/or diastolic dysfunction are suspected, such as those with a history of heart disease or suggestive changes of ischemia or hypertrophy on the electrocardiogram, or in patients with hypertension or renal disease.

Other positive cardiovascular effects of EPO treatment.

Another possible explanation for the improved cardiac function in this study may be the direct effect that EPO itself has on improving cardiac muscle function (38,39) and myocardial cell growth (39,40) unrelated to its  effect of the anemia. In fact EPO may be  crucial in the formation of the heart muscle in utero (40). It may also improve  endothelial function (41).  Erythropoietin may be superior to blood transfusions  not only  because adverse reactions to EPO are infrequent, but also because

  • EPO causes the production and release of young cells from the bone marrow into the blood.

These cells have an oxygen dissociation curve that is shifted to the right of the normal curve, causing the release of

  • much greater amounts of oxygen into the tissues than occurs normally (42).

On the other hand, transfused blood consists of older red cells with an oxygen dissociation curve that is

  • shifted to the left, causing the release of much less oxygen into the tissues than occurs normally (42).

The combination of IV Fe and EPO. The use of IV Fe along with EPO has been found to have an additive effect, 

  • increasing the Hb even more than would occur with EPO alone while at the same time
  • allowing the dose of EPO to be reduced (10 –13).
  • The lower dose of EPO will be cost-saving and also reduce the chances of hypertension developing (43).
 We used iron sucrose (Venofer) as our IV Fe medication because, in our experience, it is extremely well tolerated (10,11) and  
  • has not been  associated  with any serious side effects in more than 1,200 patients over six years.

Implications of treatment of anemia in CHF. The correction of anemia is not a substitute for the well-documented effective therapy of CHF but seems to be  an important, if not vital,  addition to the therapy. It is surprising, therefore,  that judging from  the  literature  on CHF,

  • such an obvious treatment for improving CHF is so rarely considered.

We believe that correction of the anemia will have an important role to play in

  • the amelioration of cardiorenal insufficiency, and that this improvement will have
  • significant economic  implications as well.

Acknowledgments

The authors thank Rina Issaky, Miriam Epstein, Hava Ehrenfeld and Hava Rapaport for their secretarial assistance.
Reprint requests and correspondence: Dr. D. S. Silverberg, Department of Nephrology, Tel Aviv Medical Center, Weizman 6, Tel Aviv, 64239, Israel.

 THIRD ARTICLE

The use of subcutaneous erythropoietin and intravenous iron for the treatment of the anemia of severe, resistant congestive heart failure improves cardiac and renal function and functional cardiac class, and markedly reduces hospitalizations

Donald S Silverberg, MDa; Dov Wexler, MDa; Miriam Blum, MDa; Gad Keren, MDa; David Sheps, MDa; Eyal Leibovitch, MDa; David Brosh, MDa; Shlomo Laniado, MDa; Doron Schwartz, MDa; Tatyana Yachnin, MDa; Itzhak Shapira, MDa; Dov Gavish, MDa; Ron Baruch, MDa; Bella Koifman, MDa; Carl Kaplan, MDa; Shoshana Steinbruch, RNa; Adrian Iaina, MDa

J Am Coll Cardiol. 2000;35(7):1737-1744. doi:10.1016/S0735-1097(00)00613-6

http://content.onlinejacc.org/article.aspx?articleid=1126474

OBJECTIVES

This study evaluated the prevalence and severity of anemia in patients with congestive heart failure (CHF) and

  • the effect of its correction on cardiac and renal function and hospitalization.

BACKGROUND

The prevalence and significance of mild anemia in patients with CHF is uncertain, and the role of erythropoietin with intravenous iron supplementation in treating this anemia is unknown.

METHODS

In a retrospective study, the records of the 142 patients in our CHF clinic were reviewed to find
  • the prevalence and severity of anemia (hemoglobin [Hb]12 g).
In an intervention study, 26 of these patients, despite maximally tolerated therapy of CHF for at least six months, still had had severe CHF and were also anemic. They were treated with
  • subcutaneous erythropoietin and intravenous iron sufficient to increase the Hb to 12 g%.
The doses of the CHF medications, except for diuretics, were not changed during the intervention period.

RESULTS

The prevalence of anemia in the 142 patients increased with the severity of CHF,
  • reaching 79.1% in those with New York Heart Association class IV.
In the intervention study, the anemia of the 26 patients was treated for a mean of 7.2 5.5 months.
  • The mean Hb level and mean left ventricular ejection fraction increased significantly.
  • The mean number of hospitalizations fell by 91.9% compared with a similar period before the study.
  • The New York Heart Association class fell significantly,
  • as did the doses of oral and intravenous furosemide.
  • The rate of fall of the glomerular filtration rate slowed with the treatment.

CONCLUSIONS

Anemia is very common in CHF and its successful treatment is associated with a significant improvement in
  • cardiac function,
  • functional class,
  • renal function and
  • in a marked fall in the need for diuretics and hospitalization.
Abbreviations and Acronyms
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor
ACE Angiotensin-converting enzyme
CHF congestive heart failure
COPD chronic obstructive pulmonary disease
CRF chronic renal failure
CVA cerebrovascular accident
EPO erythropoietin
Fe iron
g% grams Hb /100 ml blood
GFR glomerular filtration rate
Hb hemoglobin
Hct hematocrit
IV intravenous
LVEF left ventricular ejection fraction
LVH left ventriculr hypertrophy
NYHA New York Heart Association
%Fe Sat percent iron saturation
sc subcutaneous
TNF tumor becrosis factor

The mean hemoglobin (Hb) in patients with congestive heart failure (CHF) is about 12 g Hb per 100 ml blood (g%) (1–3), which is considered to be the lower limit of normal in adult men and postmenopausal women (4). Thus, many patients with CHF are anemic, and

  • this anemia has been shown to worsen as the severity of the CHF progresses (5,6).
Severe anemia of any cause can produce CHF, and treatment of the anemia can improve it (7). In patients with chronic renal failure (CRF) who are anemic,
  • treatment of the anemia with erythropoietin (EPO) has improved many of the abnormalities seen in CHF,
  • reducing left ventricular hypertrophy (LVH) (8 –10),
  • preventing left ventricular dilation (11) and,
    • in those with reduced cardiac function, increasing the left ventricular ejection fraction (LVEF)(8 –10),
    • the stroke volume (12) and
    • the cardiac output (12).
In view of the high prevalence of anemia in CHF, it is surprising that we could find no studies in which EPO was used in the treatment of the anemia of CHF, and the use of EPO is not included in U.S. Public Health Service guide-lines of treatment of the anemia of CHF (13). In fact, anemia has been considered
  • only a rare contributing factor to the worsening of CHF, estimated as contributing to
  • no more than 0% to 1.5% of all cases (14 –16).
Perhaps for this reason, recent guidelines for the prevention and treatment of CHF do not mention treatment of anemia at all (17). If successful treatment of anemia could improve cardiac function and patient function in CHF,
  • this would have profound implications, because,
  • despite all the advances made in the treatment of CHF, it is still a major and steadily increasing cause of hospitalizations, morbidity and mortality (18 –20).
The purpose of this study is to examine
  • the prevalence of anemia (Hb 12 g%) in patients with different levels of severity of CHF and
  • to assess the effect of correction of this anemia in severe CHF patients
  • resistant to maximally tolerated doses of CHF medication.
A combination of subcutaneous (SC) EPO and intravenous (IV) iron (Fe) was used. We have found this combination to be additive in improving the anemia of CRF (21,22).

METHODS 

Patients.

The medical records of the 142 CHF patients being treated in our special outpatient clinic devoted to CHF were reviewed to determine the prevalence and severity of anemia and CRF in these patients. These patients were referred to the clinic either from general practice or from the various wards in the hospital.

Intervention study.

Despite at least six months of treatment in the CHF clinic,
  • 26 of the above patients had persistent, severe CHF (New York Heart Association [NYHA] class III),
  • had a Hb level of 12 g% and were on
    • angiotensin-converting enzyme [ACE] inhibitors, the 
    • alpha-beta-blocker carvedilol,
    • long-acting nitrates,
    • digoxin, 
    • aldactone and
    • oral and IV furosemide.

These 26 patients participated in an intervention study. The mean age was 71.76  8.12 years. There were 21 men and 5 women. They  all had a

  • LVEF below 35%,
  • persistent fatigue and
  • shortness

    of breath on mild to moderate exertion and often at rest, and had

  • required hospitalizations at least once during their follow-up in the CHF clinic for pulmonary edema.
In 18 of the 26 patients, the CHF was associated with ischemic heart disease either
  • alone in four patients, or
  • with hypertension in six,
  • diabetes in four,
  • the two together in three, or with
  • valvular heart disease in one.
Of the remaining eight patients,
  • four had valvular heart disease alone and
  • four had essential hypertension alone.
Secondary causes of anemia including
  • gastrointestinal blood loss (as assessed by history and by three negative stool occult blood examinations),
  • folic acid and vitamin B12 deficiency and
  • hypothyroidism were ruled out.
Routine gastrointestinal endoscopy was not carried out. The study passed an ethics committee.
Table 1. Initial Characteristics of the 142 Patients With CHF Seen in the CHF Clinic
Age, yearsMale/female,  %Associated conditionsDiabetesHypertensionDyslipidemiaSmoking

Main cardiac diagnosis
Ischemic heart disease

Dilated CMP

Valvular heart disease

Hypertension

LVEF,  %

Left atrial area (n 15 cm2)

Pulmonary artery pressure  (15 mm Hg)

Previous hospitalizations/year

Serum Na, mEq/liter

Serum creatinine, mg%

Hemoglobin, g%

70.1 +/- 11.1

79/21

28%

64%

72%

40%

74%

15%

6%

5%

32.5 +/- 12.2

31.3  +/- 10.3

43.1  +/-14.9

3.2  +/- 1.5

139.8  +/- 4.0

1.6   +/-  1.1

11.9   +/- 1.5

CMP  cardiomyopathy; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association class.

Correction of the anemia.

All patients received the combination of SC EPO and IV Fe. The EPO was given once a week at a starting dose of 2,000 IU per week subcutaneously, and the dose was increased or decreased as necessary to achieve and maintain a target Hb of 12 g%. The IV Fe (Venofer-Vifor International, St. Gallen, Switzerland), a ferric sucrose product, was given in a dose of 200 mg IV in 150 ml saline over 60 min every week until the serum ferritin reached 400  g/liter or the percent Fe saturation (%Fe Sat: serum iron/total iron binding capacity   100) reached 40% or until the Hb reached 12 g%. The IV Fe was then given at longer intervals as needed to maintain these levels.

Medication dose.

Except for oral and IV furosemide therapy, the doses of all the other CHF medications, which were used in the maximum tolerated doses before the intervention, were kept unchanged during the intervention period.

Duration of the study.

The study lasted for a mean of 7.2  5.5 months (range four to 15 months).

Investigations.

Visits were at weekly intervals initially and then at two- to three-week intervals depending on the patient’s status. This was the same frequency of visits to the CHF clinic as before the intervention study.
  • A complete blood count, serum creatinine, serum ferritin and % Fe Sat were performed on every visit.
  •  An electronic device measured the blood pressure on every visit.
  • The LVEF was measured by a multiple gated ventricular angiography heart scan initially and at four- to six-month intervals.
Hospital records were reviewed to compare the number of hospitalizations during the time the patients were treated for the anemia with the number of hospitalizations
  • during a similar period of time that they were treated in the CHF clinic 
    before the anemia was treated.
Clinic records were reviewed to evaluate the types and doses of CHF medications used 
before and during the study.

Period of time that they were treated in the CHF clinic before the anemia was treated.

Clinic records were reviewed to evaluate the types and doses of CHF medications used before and during the study.  The glomerular filtration rate (GFR) was calculated from the serum creatinine by the formula: 1/serum creatinine in mg% x 100 GFR in ml/min. The rate of change of the GFR before and during the intervention period was calculated by comparing the change in GFR per month in the year before the intervention with that during the intervention.

Statistical analysis.

Mean standard deviation was calculated. One-way analysis of variance (ANOVA) was performed to compare parameter levels between the four NYHA groups. Hochberg’s method of multiple comparisons (23) was used for pair-wise comparison between two groups. A p value of less than 0.05 was considered statistically significant. In the intervention study, the significance of the difference between the initial values and those at the end of the study for the individual parameters in the 26 treated patients was assessed by paired student’s t test; p < 0.05 was considered statistically significant. All the statistical analysis was performed by the SPSS program (Version 9, Chicago, Illinois).

 RESULTS

CHF: the whole study group.

The clinical, biochemical and hematological characteristics of the 142 patients seen in the clinic are shown in Tables 1 and 2.

  • Sixty-seven patients (47%) had severe CHF as judged by a NYHA class of IV (Table 2).
  • Seventy- nine of the 142 patients (55.6%) were anemic (Hb  12 g%).

The mean Hb level fell progressively from 13.73 +/- 0.83 g% in class I NYHA to 10.90 +/- 1.70 g% in class IV NYHA (p  0.01). The percentage of patients with Hb  12 g% increased from 9.1% in class I to 79.1% in class IV.
Fifty eight patients (40.8%) had CRF as defined as a serum creatinine  1.5 mg%. The mean serum creatinine increased from 1.18 +/_  0.38 mg% in class I NYHA, to 2.0 +/-    1.89 mg% in class IV NYHA, p  0.001. The percentage of patients with an elevated serum creatinine ( 1.5 mg%)      increased from 18.2% in class I to 58.2% in class IV.

The mean ejection fraction fell from 37.67 +/-  15.74% in class I to 27.72 +/-  9.68% (p  0.005) in class IV.

Table 2. LVEF and Biochemical and Hematological Parameters by NYHA Class in 142 Patients With CHF 
NYHA Class I II III IV  Significantly Different Pairs*

 *p  0.05 at least between the two groups by pair-wise comparison between groups.

†p  0.05 at least between the groups by ANOVA.

No. of patients

11

26  

38

67

(total 142) (%)

    (7.7)    (18.3)    (26.8)    (47.2)

Hb, g%†

13.73 (0.83)

13.38 (1.26)

11.95 (1.48)

10.90 (1.70) 

1–3, 1–4, 2–3, 2–4

Serum creatinine,

1.18

1.22

1.32

2.00

1–2, 1–3, 1–4

mg%†

    (0.38)     (0.29)      (0.38)     (1.89)

LVEF, %†

37.67 (15.74)

32.88 (12.41)

32.02 (10.99)

27.72 (9.68)

1–4, 2–4

Hb 12 g%,  (%)

1
(9.1)

5 (19.2) 

20 (52.6) 

53 (79.1)

Serum creatinine

    2      5     12     39

1.5 mg%,  (%) 

 (18.2)

(19.2)

(31.6)

 (58.2)

The intervention study: medications.

The percentage of patients receiving each CHF medication before and after the intervention period and the reasons for not receiving  them are seen in Table 3.

Table 3. Number (%) of the 26 Patients Taking Each Type of Medication Before and During the Intervention Period and the Reason Why the Medication Was Not Used

Medication    No. of Patients  (%)         Reason for Not Receiving the Medications (No. of Patients)
BP  blood pressure; CRF  chronic renal failure; IV  intravenous.

The main reason for not receiving:

  • 1) ACE inhibitors was the presence of reduced renal function;
  • 2) carvedilol was the presence of chronic obstructive pulmonary disease (COPD);
  • 3) nitrates was low blood pressure and aortic stenosis and
  • 4) aldactone was hyperkalemia.
Table 4. Mean Dose of Each Medication Initially and at the End of the Intervention Period in the 26 Patients

                                       No. of Patients                                 Initial Dose ^                 Final Dose^
Carvedilol (mg/day)                      20                                                        26.9 15.5                                   28.8 14.5
Captopril (mg/day)                          7                                                        69.6 40.0                                 70.7 40.4
Enalapril (mg/day)                        13                                                        25.7 12.5                                   26.9 12.6
Digoxin (mg/day)                          25                                                       0.10 0.07                                    0.10 0.07
Aldactone (mg/day)                       19                                                        61.2 49.2                                   59.9 47.1
Long-acting nitrates                      23                                                        53.2 13.2                                   54.1 14.4
Oral furosemide (mg/day)           26                                                      200.9 120.4                                78.3 41.3*
IV furosemide (mg/month)         26                                                      164.7 178.9                                  19.8 47.0*
*p  0.05 at least vs. before by paired Student’s t test.
^  +/-

The mean doses of the medications are shown in Table 4. 

The mean dose of oral furosemide was 200.9 +/-  120.4 mg/day before and 78.3 +/-  41.3 mg/day after the intervention (p   0.05). The dose of IV furosemide was 164.7 +/-  19.8,  178.9 mg/month before and  7.0 mg/month after the intervention (p  0.05).  

The doses of the other CHF medications were almost identical in the two periods.

Clinical results.

DEATHS.
There were three deaths during the intervention period. An 83-year-old man died after eight months of respiratory failure after many years of COPD, a 65-year-old man at eight months of a CVA with subsequent pneumonia and septic shock and a 70-year-old man at four months of septicemia related to an empyema that developed after aortic valve replacement.
HEMODIALYSIS.
Three patients, a 76-year-old man, an 85-year-old woman and a 72-year-old man, required chronic hemodialysis after six, 16 and 18 months, respectively. The serum creatinines of these three patients at onset of the anemia treatment were 4.2, 3.5 and 3.6 mg%, respectively. All three had improvement in their NYHA status but
  • their uremia worsened as the renal function deteriorated, demanding the initiation of dialysis.

In no cases, however, was pulmonary congestion an indication for starting dialysis.

Functional results (Table 5).

During the treatment period, the NYHA class fell from a mean of 3.66 +/- 0.47 to 2.66 +/- 0.70 (p 0.05), and
  • 24 had some improvement in their functional class.
The mean LVEF increased from 27.7 +/- 4.8 to 35.4  +/- 7.6% (p 0.001), an increase of 27.8%.
Compared with a similar period of time before the onset of the anemia treatment, the mean number of hospitalizations fell from 2.72 +/-  1.21 to 0.22 +/-  0.65 per patient (p   0.05)a decrease of 91.9%.
No significant changes were found in the mean systolic/diastolic blood pressure.

Hematological results (Table 5).

  • The mean hematocrit (Hct) increased from 30.14 +/- 3.12%) to 35.9  +/- 4.22% (p < 0.001).
  • The mean Hb increased from 10.16 +/- 0.95 g%) to 12.10 +/-  1.21 g% (p <  0.001).
  • The mean serum ferritin increased from 177.07 +/-  113.80  g/liter to 346.73 +/- 207.40 g/liter (p  0.005).
  • The mean serum Fe increased from 60.4 +/- 19.0 g% to 74 +/- .80  20.7 g% (p  0.005). 
  • The mean %Fe Sat increased from 20.05   6.04% to 26.14 =/- 5.23% (p  0.005).
  • The mean dose of EPO used throughout the treatment period was 5,227  +/- 455 IU per week, and
  • the mean dose of IV Fe used was 185.1 +/- 57.1 mg per month.
In four of the patients, the target Hb of 12 g% was maintained despite stopping the EPO for at least four months.

Renal results (Table 5).

The changes in serum creatinine were not significant. The estimated creatinine clearance fell at a rate of 0.95 + 1.31 ml/min/month before the onset of treatment of the anemia and increased at a rate of 0.85 + 2.77 ml/min/month during the treatment period.
Table 5. The Hematological and Clinical Data of the 26 CHF Patients at Onset and at the End of the Intervention Period

————–                                         Initial ^                                    Final^
Hematocrit, vol%                              30.14 3.12                            35.90 4.22*
Hemoglobin, g%                                10.16 0.95                              2.10 1.21*
Serum ferritin, g/liter                    177.07 113.80                       346.73  207.40*
Serum iron, g%                                  60.4 19.0                               74.8  20.7*
% iron saturation                              20.5 6.04                               26.14 5.23*
Serum creatinine, mg%                   2.59 0.77                                 2.73 1.55
LVEF, %                                              27.7 4.8                                   35.4  7.6*
No. hospitalizations/patient          2.72 1.21                                 0.22   0.65*
Systolic BP, mm Hg                       127.1 19.4                                128.9  26.4
Diastolic BP, mm Hg                       73.9 9.9                                   74.0   12.7
NYHA (0–4)                                     3.66 0.47                                2.66 0.70*
*p  0.05 at least vs before by paired Student’s t test.     ^ +/-
BP  blood pressure; LVEF  left ventricular ejection fraction; NYHA  New York Heart Association.

DISCUSSION

The main findings in the present study are that anemia is common in CHF patients and becomes progressively more prevalent and severe as CHF progresses. In addition, for patients with resistant CHF, the treatment of the associated anemia causes a marked improvement in their

  1. functional status,
  2. ejection fraction and
  3. GFR.
        • All these changes were associated with a markedly
            • reduced need for hospitalization and
            • for oral and IV furosemide.

The effect of anemia on the ischemic myocardium.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39).
The Fe deficiency will cause

  • a resistance to EPO therapy and
  • increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may increase the blood pressure excessively (41). The IV Fe reduces the dose of EPO needed to correct the anemia, because

  • the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42).

Oral Fe, however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain why

  • the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

The Effect of Anemia Correction on Renal Function.

Congestive heart failure is often associated with some degree of CRF (1–3,27–29), and

  • this is most likely due to renal vasoconstriction and ischemia (28,29).

When the anemia is treated and the cardiac function improves,

  • an increase in renal blood flow and glomerular filtration is seen (7,28).

In the present study, renal function decreased as the CHF functional class worsened (Table 2). The rate of deterioration of renal function was slower during the intervention period. Treatment of anemia in CRF has been associated with

  • a rate of progression of the CRF that is either unchanged (30) or is slowed (31–33).

It is possible, therefore, that adequate treatment of the anemia in CHF may, in the long term, help slow down the progression of CRF.

Possible Adverse Effects of Correction of the Anemia.

There has been concern, in view of the recent Amgen study (34), that correction of the Hct to a mean 42% in hemodialysis patients might increase cardiovascular events in those receiving EPO compared with those maintained at a Hct of 30%. Although there is much uncertainty about how to interpret this study (35), there is a substantial body of evidence that shows

  • correction of the anemia up to a Hb of 12 g% (Hct 36%) in CRF on dialysis is safe and desirable (35–38), and
  • results in a reduction in mortality, morbidity and in the number and length of hospitalizations.

The same likely holds true for the anemia of CHF with or without associated CRF. Certainly, our patients’ symptoms were strikingly improved, as was their cardiac function (LVEF) and need for hospitalization and diuretics. It remains to be established

  • if correction of the anemia up to a normal Hb level of 14 g% might be necessary in order to further improve the patient’s clinical state.

The Role of Fe Deficiency and its Treatment in the Anemia of CHF.

We used the IV Fe together with EPO to avoid the Fe deficiency caused by the use of EPO alone (38,39). The Fe deficiency will cause

  • a resistance to EPO therapy and increase the need for higher and higher doses to maintain the Hb level (39,40).

These high doses will not only be expensive but may

  • increase the blood pressure excessively (41).

The IV Fe reduces the dose of EPO needed to correct the anemia, because the combination of SC EPO and IV Fe has been shown to have an additive effect on correction of the anemia of CRF (21,22,39,42). Oral Fe,  however, has no such additive effect (39,42). The relatively low dose of EPO needed to control the anemia in our study may explain

  • why the blood pressure did not increase significantly in any patient.

We used Venofer, an Fe sucrose product, as our IV Fe supplement because, in our experience (21,22,43), it has very few side effects and, indeed, no side effects with its use were encountered in this study.

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