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Posts Tagged ‘childhood leukemia’


 

Leaders in the CAR-T Field Are Proceeding With Cautious Hope

Reporter: Stephen J. Williams, Ph.D.

It wasn’t a long time ago, in fact the May 26, 2014 Cover Story in Forbes entitled “Is This How We’ll Cure Cancer” with cover photo of Novartis CEO Joseph Jimenez and subtitle “Will This man Cure Cancer?” highlighted the promise of CAR-T therapy as the ‘magic bullet’ therapy which will eventually cure all cancer. However, over the years, the pioneers of such therapy, while offering impressive clinical results, caution not to get to eager in calling CAR-T as the end-all-be-all cure but insist there are many issues that need be resolved.

The Allogenic Approach

In an interview for LabBiotech.eu Phillip Hemme had a discussion (and wonderful writeup) with André Choulika, the CEO of the French CAR-T miracle Cellectis on the current state of CAR-T therapy for cancer. Below is the interview in full as ther ae multiple important point Dr. Choulika mentioned, including how much is needed to be done in the field.

Cellectis’ CEO: “I’m just trying to be realistic, CAR-T is not THE miracle cure for Cancer”

 

 

Cellectis

CAR-T is solidifying in everybody’s mind as the next revolution in Cancer treatment. But there is still a lot to do…That’s basically what came out from my discussion with André Choulika, the CEO of the French CAR-T miracle Cellectis.

Cellectis is probably the most successful Biotech in France. It was founded in 1999 by Choulika himself (not alone though), following the discovery of meganucleases ability to change gene editing. Today, Cellectis is a well-known Biotech company counting over 100 employees end of October and having a market cap north of 1 Billion euros.

The company is now focused on the development of allogenic CAR-T (from generic donors  – i.e. not from the patient themself). With these universal CAR-T candidates (UCARTs). Cellectis has signed a massive partnership with the French pharma Servier, as well as Pfizer (which owns 8% of Cellectis), and has just announced two big milestones for the company within the last few weeks.

It is now able to produce it’s allogenic CAR-T in a GMP settings and it releases results from the “miracle” treatment of a 11-month old girl from the UK with multi-resistant leukemia.

 

Let’s start directly with the latest news…People seemed over-enthusiastic about UCART19…even the New York Times wrote about it. What do you think?

It’s a great news for Cellectis even though it’s still a very early result, in a single patient only. What’s important for us is that the first human patient received our treatment without showing any adverse effects (such as no cytokinetic storm) and our CAR-T cells were still active in the body 3 months after the injections.

Now, we have to expand the clinical trials to several patients and showing data from a cohort of patients. We are now on track to file the clinical trial application by the end of the year.

Your approach in the CAR-T is pretty unique. You are using donor’s cells to treat many different patients, whereas most CAR-T approaches are autologous (i.e. engineered the patient’s own cells).  Is the future in CAR-T the allogenic approach alone?

When we started to move into the CAR-T field we were pretty reluctant because there are not many examples of commercial success in the field yet. But CAR-T has still attracted many big players such as Novartis, Celgene, Juno or Kite. These each have a strong involvement in making autologous therapies work commercially (Celgene especially, which makes most of its revenue from groundbreaking and pricey cancer drugs).

On our side, we want to make this therapy accessible to a larger population and have good market access at the end. We have already pretty good reason to think it could work out well for us. We’ll see though…

Comment: Reuters published a report a few weeks ago estimating the cost of autologous CAR-T could be above $450K per treatment, which would make it economically not realistic for the healthcare payers.

CAR-T seems to be extremely hype right now. At BIO-Europe 2015, I had the impression everybody was talking about CAR-T. Do you think it could have the same impact as monoclonal antibodies?

What’s interesting with CAR-T is that you can target cells which expresses less receptors (10k receptors instead of 100k for monoclonal antibodies). This increases the targets for CAR-T and the possibilities linked.

But there are also downsides. Tissues with low expressions can become targets too and CAR-T cells would start attacking healthy cells.

People should not overemphasise CAR-T. We are still at the beginning of the beginning of this technology. And it will probably have to be combined with surgery or checkpoint inhibitors.

 

You seem pessimistic about CAR-T…?

I am just trying to be more realistic, even though I am super positive about the technology. It will bring something really great to Haematology field, but is not a cure for Cancer. It’s more of a long-haul race in the right direction as opposed to fast results, and we expect great things perhaps 20 years down the line as opposed to 2016.

But yes, it will probably not be the miracle product some people are talking about.

As for every early technology, there are many challenges associated with its development. What are the main ones worth discussing?

I would say you have four main challenges…

The administration of the cells will be challenging. We have to find way of injecting repeated doses of the product (to ensure the therapy is fully effective seeing as CAR-T cells have a limited lifespan). This is difficult because of immunogenicty against the therapy.

Secondly, combination will play an essential role too and checkpoint inhibitors should be involved.

The last two are linked to the targets.

As I mentioned before, CAR-T can be too sensitive and one way to control that would be to induce “logic gates” where the cells would only act if a combination of receptors would be present. The last challenge is to find other antigens.

Most of the CAR-T cells today target the same antigen: CD19+. We should find new antigens and many companies are on the track, including us.

 

CD19 CART

An anti-CD19 CAR-expressing T cell recognizing a CD19+ (Source: Kochenderfer et al., Nature Reviews Clinical Oncology 10, 267-276, doi: 10.1038/nrclinonc.2013.46)

Autologous CART therapy

Dr. Carl June of University of Pennsylvania, who has helped pioneer the field of CAR-T therapy for leukemia, has also been cautiously hopeful on the progress of the therapy. In his 2015 AACR National Meeting address, he highlighted some achievements they had with CAR-T therapy in both hematologic as well as solid tumors however it was stressed that there is much work to do with regards to optimization of the system, characterization of new tumor antigens for diverse tumor types, as well as the need to develop optimal treatment strategies to mitigate toxicities. Indeed many of the pioneers in the field have been proactive in helping to develop pharmacovigilance, safety, and regulatory strategies (highlighted in a post found here: NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee and mitigating toxicities in a post Steroids, Inflammation, and CAR-T Therapy) and much credit should be given to these researchers.

https://youtu.be/1sA_oz_1P5E

Cancer Research Institute’s Breakthroughs in Cancer Immunotherapy Webinar Series are offered free to the public and feature informative updates from leaders in cancer immunotherapy, followed by a moderated Q&A. On June 10, 2013, Carl H. June, M.D., a specialist in T cell biology and lymphocyte activation at the Perelman School of Medicine, University of Pennsylvania, discussed his groundbreaking work that has led to remarkable remissions of advanced cancer. He focused on recent and ongoing successes in developing treatments with T cells that have been genetically engineered to target cancer. Called chimeric antigen receptor T cells (CAR T cells), these modified immune cells have proven effective at eliminating cancer in some patients, and offer great hope for this emerging strategy in cancer immunotherapy. For more information on this webinar, or to register for upcoming webinars, please visit www.cancerresearch.org/webinars.

Below are reports from the 2015 American Society of Hematology Conference by Novartis on results from CTL109 CART therapy trials. One trial is on response rate in B-cell lymphomas and follicular cell lymphomas while the second report is ongoing trial results in childhood refractory ALL, both conducted at University of Pennsylvania.

Novartis presents response rate data for CART therapy CTL019 in lymphoma

(Ref: Global Post, NASDAQ, PR Newswire)

posted on FirstWorldPharma.com December 6th, 2015

By: Matthew Dennis

Novartis announced Sunday data from an ongoing Phase IIa study demonstrating that the experimental chimaeric antigen receptor T-cell (CART) therapy CTL019 led to an overall response rate (ORR) at three months of 47 percent in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and an ORR of 73 percent in adults with follicular lymphoma. The results of the trial were presented at the American Society of Hematology annual meeting.

Findings from the study, which was conducted by the University of Pennsylvania’s Perelman School of Medicine, include 15 adults with DLBCL and 11 with follicular lymphoma who were evaluable for response. Results showed that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with follicular lymphoma who achieved a PR at three months converted to CR by six months.

Novartis added that one DLBCL patient with a PR at three months experienced disease progression at six months after treatment. Further, one follicular lymphoma patient with a PR at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. The company indicated that median progression-free survival was 11.9 months for patients with follicular lymphoma and 3 months for those with DLBCL.

In the study, four patients developed cytokine release syndrome (CRS) of grade 3 or higher. Novartis noted that during CRS, patients typically experience varying degrees of influenza-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. Meanwhile, neurologic toxicity occurred in two patients in the trial, including one grade three episode of delirium and one possibly related grade five encephalopathy.

“These data add to the growing body of clinical evidence on CTL019 and illustrate its potential benefit in the treatment of relapsed and refractory non-Hodgkin lymphoma,” commented lead investigator Stephen Schuster. Novartis indicated that the findings keep CTL019 on track for submission to the FDA in 2017. Usman Azam, global head of Novartis’ cell and gene therapies unit, said “we remain consistent again with the data set.”

“It’s an attractive population, it’s a population that continues to have a huge unmet need, it’s a cornerstone of our investments,” Azam remarked. Analysts expect CART therapies, once approved, to cost up to $450 000 per patient. Novartis acknowledged that prices will be high, but declined to give further details. “With any disruptive innovation that comes, initially, cost of goods is very challenging,” Azam said, adding “as time goes on, and more patients are treated, we will simplify that cost base.”

Source: http://www.firstwordpharma.com/node/1338217?tsid=28&region_id=2#axzz3tfDVaT1f

 

 

Novartis AG (NVS)’s Experimental Therapy Wipes Out Blood Cancer in 93 Percent of Patients

Reported in Biospace.com (for full article see here)

Novaritis and University of Pennsylvania reported results of the CTL019 CART trials for the treatment of children with relapsed/refractory acute lymphoblastic leukemia at the 2015 Annual Hemotologic Society Meeting. 55 of 59 patients, or 93 percent, experienced complete remissions with CTL019. The study did show that at the end of one year, 55 percent of patients had a remission-free survival rate and that 18 patients continued to show complete remission following one year

 

Other posts on the Open Access Journal on CAR-T therapy include

 

CAR-T therapy in leukemia

Steroids, Inflammation, and CAR-T Therapy

NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee

 

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Hematological Cancer Classification

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

 

 

Introduction to leukemias and lymphomas

 

2.4.1 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

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

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

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

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

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

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

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

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

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

platelets and the immune continuum nri2956-f3

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

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

2.4.2.1 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

2.4.2.2 Secondary Classification

2.4.2.3 Nuance – PathologyOutlines
Nat Pernick, Ed.

Leukemia – Acute

Primary referencesacute leukemia-generalAML generalAML classificationtransient abnormal myelopoiesis

Recurrent genetic abnormalities: AML with t(6;9)AML with t(8;21)AML with 11q23 abnormalitiesAML with inv(16) or t(16;16)AML with Down syndromeAML with FLT3 mutationsAML with myelodysplastic related changesAML therapy relatedAPL microgranular variantAPL with t(15;17)APL with t(V;17)APL therapy related

AML not otherwise categorized: minimally differentiated (M0)without maturation (M1)with maturation (M2)M3myelomonocyticmonoblastic and monocyticerythroidmegakaryoblasticCD13/CD33 negativebasophilicmyeloid sarcomaacute panmyelosis with myelofibrosiswith Philadelphia chromosomewith pseudo Chediak-Higashi anomalyhypocellular

ALL: generalWHO classificationwith eosinophilia

PreB ALL: generalt(9;22)t(v;11q23)t(1;19)t(5;14)t(12;21)hyperdiploidyhypodiploidymature B ALL/Burkitt

Other ALL: T ALLambiguous lineagemixed phenotype

AML and related malignancies

Acute myeloid leukemias with recurrent genetic abnormalities:

  • AML with t(8;21)(q22;q22); RUNX1-RUNX1T1
  • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBF&beta-MYH11
  • Acute promyelocytic leukemia with t(15;17)(q22;q12); PML/RAR&alpha and variants
  • AML with t(9;11)(p22;q23); MLLT3-MLL
  • AML with t(6;9)(p23;q34); DEK-NUP214
  • AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1
  • AML (megakaryoblastic) with t(1;22)(p13;q13); RBM15-MKL1
  • AML with mutated NPM1*
  • AML with mutated CEBPA*

* provisional

Acute myeloid leukemia with myelodysplasia related changes

Therapy related acute myeloid leukemia

  • Alkylating agent related
  • Topoisomerase II inhibitor related (some maybe lymphoid)

Acute myeloid leukemia not otherwise categorized:

  • AML minimally differentiated (M0)
  • AML without maturation (M1)
  • AML with maturation (M2)
  • Acute myelomonocytic leukemia (M4)
  • Acute monoblastic and monocytic leukemia (M5a, M5b)
  • Acute erythroid leukemia (M6)
  • Acute megakaryoblastic leukemia (M7)
  • Acute basophilic leukemia
  • Acute panmyelosis with myelofibrosis

Myeloid Sarcoma

Myeloid proliferations related to Down syndrome:

  • Transient abnormal myelopoeisis
  • Myeloid leukemia associated with Down syndrome

Blastic plasmacytoid dentritic cell neoplasm:

Acute leukemia of ambiguous lineage:

  • Acute undifferentiated leukemia
  • Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1
  • Mixed phenotype acute leukemia with t(v;11q23); MLL rearranged
  • Mixed phenotype acute leukemia, B/myeloid, NOS
  • Mixed phenotype acute leukemia, T/myeloid, NOS
  • Mixed phenotype acute leukemia, NOS, rare types
  • Other acute leukemia of ambiguous lineage
  • References: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue (IARC, 2008), Discovery Medicine 2010, eMedicine

Acute lymphocytic leukemia

General
=================================================================

  • WHO classification system includes former FAB classifications ALL-L1 and L2
    ● FAB L3 is now considered Burkitt lymphoma

WHO classification of acute lymphoblastic leukemia
=================================================================

Precursor B lymphoblastic leukemia / lymphoblastic lymphoma:
● ALL with t(9;22)(q34;q11.2); BCR-ABL (Philadelphia chromosome)
● ALL with t(v;11q23) (MLL rearranged)
● ALL with t(1;19)(q23;p13.3); TCF3-PBX1 (E2A-PBX1)
● ALL with t(12;21)(p13;q22); ETV6-RUNX1 (TEL-AML1)
● Hyperdiploid > 50
● Hypodiploid
● t(5;14)(q31;q32); IL3-IGH

Precursor T lymphoblastic leukemia / lymphoma

Additional references
=================================================================

Mixed phenotype acute leukemia (MPAL)

General
=================================================================

  • De novo acute leukemia containing separate populations of blasts of more than one lineage (bilineal or bilineage), or a single population of blasts co-expressing antigens of more than one lineage (biphenotypic)Excludes:
    ● Acute myeloid leukemia (AML) with recurrent translocations t(8;21), t(15;17) or inv(16)
    ● Leukemias with FGFR1 mutations
    ● Chronic myelogenous leukemia (CML) in blast crisis
    ● Myelodysplastic syndrome (MDS)-related AML and therapy-related AML, even if they have MPAL immunophenotypeCriteria for biphenotypic leukemia:
    ● Score of 2 or more for each of two separate lineages:The European Group for the Immunological Classification of Leukemias (EGIL) scoring system2008 WHO classification of acute leukemias of ambiguous lineage 

Prognosis
=================================================================

  • Poor, overall survival of 18 months
    ● Young age, normal karyotype and ALL induction therapy are associated with favorable survival
    ● Ph+ is a predictor for poor prognosis
    ● Bone marrow transplantation should be considered in first remission

Major Categories

MPAL with t(9;22)(q34;q11.2); BCR-ABL1
=================================================================

  • 20% of all MPAL
    ● Blasts with t(9;22)(q34;q11.2) translocation or BCR-ABL1 rearrangement (Ph+) without history of CML
    ● Majority in adults
    ● High WBC counts● Most of the cases B/myeloid phenotype
    ● Rare T/myeloid, B and T lineage, or trilineage leukemiasMorphology:
    ● Many cases show a dimorphic blast population, one resembling myeloblasts and the other lymphoblastsCytogenetic abnormalities:
    ● Conventional karyotyping for t(9;22), FISH or PCR for BCR-ABL1 translocation
    ● Additional complex karyotypes
    ● Ph+ is a poor prognostic factor for MPAL, with a reported median survival of 8 months
    ● Worse than patients of all other types of MPAL

MPAL with t(v;11q23); MLL rearranged
=================================================================

  • Meeting the diagnostic criteria for MPAL with blasts bearing a translocation involving the 11q23 breakpoint (MLL gene)
    ● MPAL with MLL rearranged rare
    ● More often seen in children and relatively common in infancy
    ● High WBC counts
    ● Poor prognosis
    ● Dimorphic blast population, with one resembling monoblasts and the other resembling lymphoblasts
    ● Lymphoblast population often shows a CD19+, CD10- B precursor immunophenotype, frequently CD15+
    ● Expression of other B markers usually weak
    ● Translocations involving MLL gene include t(4;11)(q21;q23), t(11;19)(q23;p13), and t(9;11)(p22;q23)
    ● Cases with chromosome 11q23 deletion should not be classified in this category

B cell acute lymphoblastic leukemia (ALL) / lymphoblastic lymphoma (LBL)

General

=================================================================

  • Current 2008 WHO classification: B lymphoblastic leukemia / lymphoma, NOS or B lymphoblastic leukemia / lymphoma with recurrent genetic abnormalities
  • See also lymphomas: B cell chapter
  • Also called B cell acute lymphoblastic leukemia / lymphoblastic lymphoma, pre B ALL / LBL
  • Usually children
  • B acute lymphoblastic leukemia presents with pancytopenia due to extensive marrow involvement, stormy onset of symptoms, bone pain due to marrow expansion, hepatosplenomegaly due to neoplastic infiltration, CNS symptoms due to meningeal spread and testicular involvement
  • B acute lymphoblastic lymphoma often presents with cutaneous nodules, bone or nodal involvement, < 25% lymphoblasts in bone marrow and peripheral blood; aleukemic cases are usually asymptomatic
  • Depending on specific leukemia, arises in either hematopoietic stem cell or B-cell progenitor
  • Tumors are derived from pre-germinal center naive B cells with unmutated VH region genes
  • Have multiple immunophenotyping aberrancies relative to normal B cell precursors (hematogones); at relapse, 73% show loss of 1+ aberrance and 60% show new aberrancies (Am J Clin Pathol 2007;127:39)

Prognostic features

=================================================================

  • Favorable prognosis: age 1-10 years, female, white; preB phenotype, hyperdiploidy>50, t(12,21), WBC count at presentation <50×108/L, non-traumatic tap with no blasts in CNS, rapid response to chemotherapy < 5% blasts on morphology on day 15, remission status after induction <5% blasts on morphology and <0.01% blast on flow or PCR, CD10+
  • Intermediate prognosis: hyperdiploidy 47-50, diploid, 6q- and rearrangements of 8q24
  • Unfavorable prognosis: under age 1 (usually have 11q23 translocations) or over age 10; t(9;22) (but not if age 59+ years, Am J Clin Pathol 2002;117:716); male, > 50×108/L WBC at presentation, hypodiploidy, near tetraploidy, 17p- and MLL rearrangements t(v;11q23); CD10-; non-traumatic tap with > 5% blasts or traumatic tap (7%); also increased microvessel staining using CD105 in children (Leuk Res 2007;31:1741), MDR1 expression in children (Oncol Rep 2004;12:1201) and adults (Blood 2002;100:974), 25%+ blasts on morphology on day 15, remission status after induction ≥ 5% blasts on morphology and ≥ 0.1% blasts on flow or PCR

Case reports

=================================================================

  • 12 month old girl and 13 month old boy with mature phenotype but no translocations (Arch Pathol Lab Med 2003;127:1340)
  • 56 year old man with ALL arising from follicular lymphoma (Arch Pathol Lab Med 2002;126:997)
  • 76 year old man with basal cell carcinoma (Diagn Pathol 2007;2:32)
  • With hemophagocytic lymphohistiocytosis (Pediatr Blood Cancer 2008;50:381)

Treatment

================================================================

  • Chemotherapy cures more children than adults; adolescents benefit from intensive regimens (Hematology Am Soc Hematol Educ Program 2005:123)

Micro description

=================================================================

  • Bone marrow smears: small to intermediate blast-like cells with scant, variably basophilic cytoplasm, round / oval or convoluted nuclei, fine chromatin and indistinct nucleoli; frequent mitotic figures; may have “starry sky” appearance similar to Burkitt lymphoma; may have large lymphoblasts with 1-4 prominent nucleoli resembling myeloblasts; usually no sclerosis
  • Bone marrow biopsy: usually markedly hypercellular with reduction of trilinear maturation; cells have minimal cytoplasm, medium sized nuclei that are often convoluted, moderately dense chromatin and indistinct nucleoli, brisk mitotic activity
  • Other tissues: may have “starry sky” appearance similar to Burkitt lymphoma; collagen dissection, periadipocyte growth pattern and single cell linear filing

Chronic Leukemia

Chronic Myeloid Neoplasms

Myelodysplastic syndromes (MDS): general, WHO classification, childhood, refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess blasts, 5q-syndrome, therapy related, unclassified, arsenic toxicity

Myeloproliferative neoplasms (MPN): general, WHO classification, chronic eosinophilic leukemia, chronic myelogenous leukemia, chronic neutrophilic leukemia, essential thrombocythemia, hypereosinophilic syndrome, mast cell disease, polycythemia vera, primary myelofibrosis, unclassifiable

MDS/MPN: general, WHO classification, atypical CML, chronic myelomonocytic leukemia (CMML), chronic myelomonocytic leukemia with eosinophilia, juvenile myelomonocytic leukemia, unclassifiable

Myeloid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1: PDGFRA, PDGFRB, FGFR1

Miscellaneous: transient myeloproliferative disorder of Downís syndrome

Lymphoma and plasma cell neoplasms

Lymph nodes: normal development-generalB cellsT cellsNK cellsnormal histologygrossing lymph nodesfeatures to report

Molecular testing: theoryFISHnorthern blotPCRsouthern blot

Non-Hodgkin lymphoma: generalcytogeneticsstagingstaging-pediatricmorphologic clueshemophagocytic syndromechemotherapeutic atypia

B cell disorders: generalpost-rituximabbone marrow biopsyclassification-historicalWHO classification

B cell lymphoma subtypes: age-related EBV-associatedALK positive large cellBurkittunclassifiable-intermediate between Burkitt and diffuse large B cell lymphomaCLL
diffuse large B cell: 
diffuse-NOSCD5+T cell / histiocyte richprimary cutaneous-generalprimary cutaneous-legprimary sites-other
follicular: 
generalchildhoodcutaneousGI
hairy cell leukemiaHCL variantintravascular large B celllymphomatoid granulomatosislymphoplasmacyticmantle cell-classicmantle cell-blastoidmarginal zone-generalmarginal zone-MALTMALT-primary sitesmarginal zone-nodalmediastinal (thymic)plasmablasticpre B lymphoblastic leukemia/lymphomaprimary effusionprolymphocytic leukemiapyothorax associatedSLLsplenic marginal zonesplenic lymphoma with villous lymphocytes

Plasma cell neoplasms: generalmyelomaplasmacytomaheavy chain diseaseprimary amyloidosisMGUSOsteosclerotic myeloma (POEMS)cryoglobulinemia

T/NK cell disorders: generalWHO classificationadult T cellaggressive NK cell leukemiaanaplastic large cell ALK+ALK-angioimmunoblastic T cellblastic plasmacytoidchronic lymphoproliferative disorders of NK cellscutaneous CD4+ small/medium sized T cell lymphomacutaneous CD30 positive T cell lymphoproliferative disorderscutaneous gamma delta T cell lymphomaenteropathyepidermotropic CD8+ T cell lymphomahepatosplenicindolent T cell proliferationsmycosis fungoidesNK/T cell lymphoma-nasal typenodal CD8+ cytotoxic T cellnonB nonT lymphoblasticperipheral T cell lymphoma, NOSprimary effusion lymphomaSezary syndromestagingsubcutaneous panniculitis-likeT cell large granular lymphocytic leukemiaT cell lymphoblastic leukemia/lymphomaT cell prolymphocytic leukemia

Hodgkin lymphoma: general/stagingclassiclymphocyte depletedlymphocyte rich classicalmixed cellularitynodular lymphocyte predominantnodular sclerosis

Post-transplantation: generalWHO classificationplasmacytic hyperplasia/IM-like lesionspolymorphic B cell lymphoproliferative disordersmonomorphic B cell lymphoproliferative disordersothergraft versus host disease

Other: AIDS associated-generalAIDS associated-examplesEBV+ T cell lymphoproliferative disorders of childhoodprimary immune disorders related

Myeloproliferative neoplasms (MPN)

WHO 2008 – Myeloproliferative neoplasms (MPN) 

General
=================================================================

  • Chronic myelogenous leukemia
    ● Polycythemia vera
    ● Essential thrombocythemia
    ● Primary myelofibrosis
    ● Chronic neutrophilic leukemia
    ● Chronic eosinophilic leukemia, not otherwise categorized
    ● Mast cell disease
    ● MPNs, unclassifiable

WHO 2001 – Chronic myeloproliferative diseases 

Definition
=================================================================

  • Chronic myelogenous leukemia (Philadelphia chromosome, t(9;22)(q34;q11), BCR-ABL positive)
    ● Chronic neutrophilic leukemia
    ● Chronic eosinophilic leukemia (and the hypereosinophilic syndrome)
    ● Polycythemia vera
    ● Chronic idiopathic myelofibrosis (with extramedullary hematopoiesis)
    ● Essential thrombocythemia
    ● Chronic myeloproliferative disease, unclassifiable

Additional references
=================================================================

The World Health Organization (WHO) classification of the myeloid neoplasms  James W. Vardiman, Nancy Lee Harris, and Richard D. Brunning
Blood 2002; 100(7)  http://dx.doi.org/10.1182/blood-2002-04-1199

Lymphoma – Non B cell neoplasms

T/NK cell disorders/WHO classification (2008)

Principles of classification
=================================================================

  • Based on all available information (morphology, immunophenotype, genetics, clinical)
    ● No one antigenic marker is specific for any neoplasm (except ALK1)
    ● Immune profiling less helpful in subclassification of T cell lymphomas then B cell lymphomas
    ● Certain antigens commonly associated with specific disease entities but not entirely disease specific
    ● CD30: common in anaplastic large cell lymphoma but also classic Hodgkin lymphoma and other B and T cell lymphomas
    ● CD56: characteristic for nasal NK/T cell lymphoma, but also other T cell neoplasms and plasma cell disorders
    ● Variation of immunophenotype within a given disease (hepatosplenic T cell lymphoma: usually γδ but some are αβ)
    ● Recurrent genetic alterations have been identified for many B cell lymphomas but not for most T cell lymphomas
    ● No attempt to stratify lymphoid malignancies by grade
    ● Recognize the existence of grey zone lymphomas
    ● This multiparameter approach has been validated in international studies as highly reproducible

WHO 2008 classification of tumors of hematopoietic and lymphoid tissues (T/NK)
=================================================================

Precursor T-lymphoid neoplasms
● T lymphoblastic leukemia/lymphoma, 9837/3

Mature T cell and NK cell neoplasms
● T cell prolymphocytic leukemia, 9834/3
● T cell large granular lymphocytic leukemia, 9831/3
● Chronic lymphoproliferative disorder of NK cells, 9831/3
● Aggressive NK cell leukemia, 9948/3
● Systemic EBV-positive T cell lymphoproliferative disease of childhood, 9724/3
● Hydroa vacciniforme-like lymphoma, 9725/3
● Adult T cell leukemia/lymphoma, 9827/3
● Extranodal NK/T cell lymphoma, nasal type, 9719/3
● Enteropathy-associated T cell lymphoma, 9717/3
● Hepatosplenic T cell lymphoma, 9716/3
● Subcutaneous panniculitis-like T cell lymphoma, 9708/3
● Mycosis fungoides, 9700/3
● Sézary syndrome, 9701/3
● Primary cutaneous CD30-positive T cell lymphoproliferative disorders
● Lymphomatoid papulosis, 9718/1
● Primary cutaneous anaplastic large cell lymphoma, 9718/3
● Primary cutaneous gamma-delta T cell lymphoma, 9726/3
● Primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T cell lymphoma, 9709/3
● Primary cutaneous CD4-positive small/medium T cell lymphoma, 9709/3
● Peripheral T cell lymphoma, NOS, 9702/3
● Angioimmunoblastic T cell lymphoma, 9705/3
● Anaplastic large cell lymphoma, ALK-positive, 9714/3
● Anaplastic large cell lymphoma, ALK-negative, 9702/3

Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia Staging
Author: Sandy D Kotiah, MD; Chief Editor: Jules E Harris, MD
Medscape Sep 6, 2013
http://emedicine.medscape.com/article/2006578-overview

General considerations in the staging of chronic lymphocytic leukemia (CLL) and the revised Rai (United States) and Binet (Europe) staging systems for CLL are provided below.[1, 2, 3]

See Chronic Leukemias: 4 Cancers to Differentiate, a Critical Images slideshow, to help detect chronic leukemias and determine the specific type present.

General considerations

  • CLL and small lymphocytic lymphoma (SLL) are different manifestations of the same disease; SLL is diagnosed when the disease is mainly nodal, and CLL is diagnosed when the disease is seen in the blood and bone marrow
  • CLL is diagnosed by > 5000 monoclonal lymphocytes/mm3 for longer than 3mo; the bone marrow usually has more than 30% monoclonal lymphocytes and is either normocellular or hypercellular
  • Monoclonal B lymphocytosis is a precursor form of CLL that is defined by a monoclonal B cell lymphocytosis < 5000 monoclonal lymphocytes/mm3; all lymph nodes smaller than 1.5 cm; no anemia; and no thrombocytopenia

Revised Rai staging system (United States)

Low risk (formerly stage 0)[1] :

  • Lymphocytosis, lymphocytes in blood > 15000/mcL, and > 40% lymphocytes in the bone marrow

Intermediate risk (formerly stages I and II):

  • Lymphocytosis as in low risk with enlarged node(s) in any site, or splenomegaly or hepatomegaly or both

High risk (formerly stages III and IV):

  • Lymphocytosis as in low risk and intermediate risk with disease-related anemia (hemoglobin level < 11.0 g/dL or hematocrit < 33%) or platelets < 100,000/mcL

Binet staging system (Europe)

Stage A:

  • Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, and < 3 enlarged areas

Stage B:

  • Hemoglobin ≥ 10 g/dL, platelets ≥ 100,000/mm3, and ≥ 3 enlarged areas

Stage C:

  • Hemoglobin < 10 g/dL, platelets < 100,000/mm3, and any number of enlarged areas

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