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Posts Tagged ‘Non-Hodgkin lymphoma’


Steroids, Inflammation, and CAR-T Therapy [6.3.8]

 

Reporter: Stephen J. Williams, Ph.D.

Corticosteroids have been used as anticancer agents since the 1940s, with activity reported in a wide variety of solid tumors, including breast and prostate cancer, and the lymphoid hematologic malignancies. They are commonly found in regimens for acute lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, myeloma, and chronic lymphocytic leukemia.

 

A great review on the mechanism of action of prednisone’s antitumoral activity is seen in

Corticosteroids in the Treatment of Neoplasms Lorraine I. McKay, PhD and John A. Cidlowski, PhD. in Holland-Frei Cancer Medicine. 6th edition.

 

It was first discovered that cortisone caused tumor regression in a transplantable mouse lymphosarcoma,81 a finding soon extended to a wide variety of murine lymphatic tumors. The effects of corticosteroids were also evaluated on many nonendocrine and nonlymphoid transplantable rodent tumors. Pharmacologic doses of steroid inhibited growth of various tumor systems.82 Tissue culture studies confirmed that lymphoid cells were the most sensitive to glucocorticoids, and responded to treatment with decreases in DNA, ribonucleic acid (RNA), and protein synthesis.83 Studies of proliferating human leukemic lymphoblasts supported the hypothesis that glucocorticoids have preferential lymphocytolytic effects. The mechanism of action was initially thought to be caused by impaired energy use via decreased glucose transport and/or phosphorylation; it was later discovered that glucocorticoids induce apoptosis, or programmed cell death, in certain lymphoid cell populations.84,85

 

 

–For review on corticosteroids in cancer therapy see more at: http://www.cancernetwork.com/review-article/corticosteroids-advanced-cancer#sthash.IwHbekuI.dpuf

However, as Dana Farber’s Dr. George Canellos, M.D. ponders in Can MOPP be replaced in the treatment of advanced Hodgkin’s disease? Semin Oncol. Canellos GP1. 1990 Feb;17(1 Suppl 2):2-6., many dose-limiting toxicities occur with MOPP (mechlorethamine, vincristine, procarbazine, prednisone) therapy used in advanced Hodgkin’s disease.  Although, at the time, he generally was looking to establish combination therapies with less side effect, the advent of more personalized therapies as well as immunotherapies may indeed replace the older regimens for B-cell malignancies and Hodgkin’s disease, and their panels of toxicities.

Short-term side effects of prednisone (Cancer.gov prednisone description with side effects) as with all glucocorticoids, include high blood glucose levels (especially in patients with diabetes mellitus or on other medications that increase blood glucose, such as tacrolimus) and mineralocorticoid effects such as fluid retention.[10] The mineralocorticoid effects of prednisone are minor, which is why it is not used in the management of adrenal insufficiency, unless a more potent mineralocorticoid is administered concomitantly.

Long-term side effects include Cushing’s syndrome, steroid dementia syndrome, truncal weight gain, osteoporosis, glaucoma and cataracts, type II diabetes mellitus, and depression upon dose reduction or cessation.

Therefore the oncology world has been moving toward therapies which are more selective with less dose-limiting toxicities (e.g. Rituximab), and are looking to CAR-T therapies as a possible replacement for standard chemotherapeutic regimens. However, as with prednisone, there have been serious adverse events in some CAR-T clinical trials. Luckily clinicians, as discussed below, have found supportive therapies to alleviate the most severe side effects to CAR-T.

This section will be refer to supportive therapies as those adjuvant therapy given to alleviate patient discomfort, reduce toxicities and adverse event, or support patient well-being during their course of chemotherapy, not adjuvant therapy to enhance antitumoral effect.

For more background information of CAR-T therapies and related issues please see my previous post

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

The following is a brief re-post of some of the important points for reference to this new posting.

1. Evolution of Chimeric Antigen Receptors

Early evidence had suggested that adoptive transfer of tumor-infiltrating lymphocytes, after depletion of circulating lymphocytes, could result in a clinical response in some tumor patients however developments showed autologous T-cells (obtained from same patient) could be engineered to express tumor-associated antigens (TAA) and replace the TILS in the clinical setting.

A brief history of construction of 2nd and 3rd generation CAR-T cells given by cancer.gov:

http://www.cancer.gov/cancertopics/research-updates/2013/CAR-T-Cells

cartdiagrampic

Differences between  second- and third-generation chimeric antigen receptor T cells. (Adapted by permission from the American Association for Cancer Research: Lee, DW et al. The Future Is Now: Chimeric Antigen Receptors as New Targeted Therapies for Childhood Cancer. Clin Cancer Res; 2012;18(10); 2780–90. doi:10.1158/1078-0432.CCR-11-1920)

Constructing a CAR T Cell (from cancer.gov)

The first efforts to engineer T cells to be used as a cancer treatment began in the early 1990s. Since then, researchers have learned how to produce T cells that express chimeric antigen receptors (CARs) that recognize specific targets on cancer cells.

The T cells are genetically modified to produce these receptors. To do this, researchers use viral vectors that are stripped of their ability to cause illness but that retain the capacity to integrate into cells’ DNA to deliver the genetic material needed to produce the T-cell receptors.

The second- and third-generation CARs typically consist of a piece of monoclonal antibody, called a single-chain variable fragment (scFv), that resides on the outside of the T-cell membrane and is linked to stimulatory molecules (Co-stim 1 and Co-stim 2) inside the T cell. The scFv portion guides the cell to its target antigen. Once the T cell binds to its target antigen, the stimulatory molecules provide the necessary signals for the T cell to become fully active. In this fully active state, the T cells can more effectively proliferate and attack cancer cells.

2. Consideration for Design of Trials and Mitigating Toxicities

  • Early Toxic effectsCytokine Release Syndrome– The effectiveness of CART therapy has been manifested by release of high levels of cytokines resulting in fever and inflammatory sequelae. One such cytokine, interleukin 6, has been attributed to this side effect and investigators have successfully used an IL6 receptor antagonist, tocilizumab (Acterma™), to alleviate symptoms of cytokine release syndrome (see review Adoptive T-cell therapy: adverse events and safety switches by Siok-Keen Tey).
  • Early Toxic effects – Over-activation of CAR T-cells; mitigation by dose escalation strategy (as authors in reference [3] proposed). Most trials give billions of genetically modified cells to a patient.
  • Late Toxic Effectslong-term depletion of B-cells . For example CART directing against CD19 or CD20 on B cells may deplete the normal population of CD19 or CD20 B-cells over time; possibly managed by IgG supplementation

References

  1. Ertl HC, Zaia J, Rosenberg SA, June CH, Dotti G, Kahn J, Cooper LJ, Corrigan-Curay J, Strome SE: Considerations for the clinical application of chimeric antigen receptor T cells: observations from a recombinant DNA Advisory Committee Symposium held June 15, 2010. Cancer research 2011, 71(9):3175-3181.
  2. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA: Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Molecular therapy : the journal of the American Society of Gene Therapy 2010, 18(4):843-851.
  3. Kandalaft LE, Powell DJ, Jr., Coukos G: A phase I clinical trial of adoptive transfer of folate receptor-alpha redirected autologous T cells for recurrent ovarian cancer. Journal of translational medicine 2012, 10:157.

 

3. Case Reports of Adverse Events and Their Amelioration During CAR-T Therapy

CAR-T Therapy have Had reports of Serious Adverse Events

From FierceBiotech UPDATED: Two deaths force MSK to hit the brakes on engineered T cell cancer study

April 6, 2014 | By John Carroll

Safety concerns forced investigators at Memorial Sloan-Kettering Cancer Center to suspend patient recruitment for an early-stage study of a closely watched approach to reengineering the immune system to fight cancer. Several days ago MSK updated a site on clinicaltrials.gov to note that it was halting recruitment for a small study using T cells reengineered with chimeric antigen receptors (CARs) against CD19-positive B cells for aggressive non-Hodgkin lymphoma, triggering concerns about the potential fallout at Juno Therapeutics, the biotech formed to commercialize the effort. And Sunday evening representatives for MSK revealed at the meeting of the American Association for Cancer Research in San Diego that the deaths of two patients spurred investigators to rethink the trial protocol on recruitment, revamping the patient profile to account for the threat of comorbidities while adjusting the dose “based on the extent of disease at the time of treatment.”

For more on this story please see

Source: http://www.fiercebiotech.com/story/memorial-sloan-kettering-hits-brakes-engineered-t-cell-cancer-study/2014-04-06

Keynote presentation by Carl H. June, recipient of The Richard V. Smalley MD 2013 Award

 

As reported in 2013 in Highlights and summary of the 28th annual meeting of the Society for Immunotherapy of Cancer by Paolo A Ascierto1, David H Munn2, Anna K Palucka34 and Paul M Sondel in Journal of ImmunoTherapy of Cancer

Since 2005, SITC honors a luminary in the field who has significantly contributed to the advancement of cancer immunotherapy research by presenting the annual Richard V. Smalley MD Memorial Award, which is associated with the Smalley keynote lecture at the Annual SITC meeting. The awardee this year Carl H. June of the University of Pennsylvania, has led innovative translational research for over 25 years, with the most recent focus being the development of the Chimeric Antigen Receptor modified T-cell (CART) approach. Carl June summarized how the past 15 years of progress have expanded upon the original concept presented by Zelig Eshhar [4], in which variable regions of tumor-reactive monoclonal antibodies (mAbs) (VH and VL) are linked to transmembrane and signaling domains of T cell activating molecules to create membrane based receptors with specificity for the tumor antigen recognized by the original mAb [4]. These receptors can be transfected into T cells, for example with lentiviruses. Pre-clinical work demonstrated how CD3-ζ and 41BB signaling components enhanced proliferation and survival of T cells in hypoxic conditions. The initial clinical work has been done with CART reactive to CD-19 on malignant B cells, with progress particularly in chronic lymphocytic leukemia (CLL) in adults and acute lymphoblastic leukemia (ALL) in children [5,6]. As of the SITC meeting, CarlJune’s team had treated 35 patients with CLL and 20 with ALL. Of the 20 with ALL, ½ had relapsed after allogeneic BMT. Of these 20 children, 17 were in complete remission, and with persistent B cell aplasia; documenting the persistent effects of the CART cells. Toxicities included the persistent B cell aplasia and profound tumor lysis and cytokine storm, seen 1–2 weeks into the treatment for ALL. This cytokine storm has been ameliorated by using anti-IL6 mAb. The B cell aplasia, while undesired, is acceptable, as patients can receive passive replacement of IgG, thus making their B cells “expendable”. These CART cells can traffic into the CNS. In ALL patients, it appears that each individual CART cell (or its progeny) can destroy 1000 tumor cells. Ongoing efforts in CarlJune’s program, and at other centers, are now moving into analyses of CART reactive with other tumor targets, by using mAbs that recognize antigens expressed on other tumors. Among these are EGFR on glioblastoma, PSMA on prostate cancer, mesothelin on ovarian cancer, HER2 on breast (and other) cancers, and several other targets. Because some of these targets are also expressed on normal tissues that are “not expendable”, novel approaches are being developed to decrease the potency or longevity of the CART effect, to decrease potential toxicity. This includes generating “short lived” CART cells by inducing CAR expression with short-lived RNA, rather than transfecting with a DNA construct that remains permanently.

In T-Cell Immunotherapy: Looking Forward Molecular Therapy (2014); 22 9, 1564–1574. doi:10.1038/mt.2014.148 many of the leading CAR-T clinicians and investigators reported on some of the adverse events related o CAR-T therapy including

  • 40 severe adverse events (SAE) had been reported from 2010 to 2013.
  • B-cell aplasia
  • Systemic inflammatory release syndrome (CRS) {the most sever toxicity seen}
  • Tumor lysis syndrome
  • CNS toxicity
  • Macrophage activation syndrome

According to the investigators the systemic inflammatory release syndrome (CRS) is the most severe toxicity seen

The most commonly reported adverse event is CRS,49 with about three-quarters of the patients with CRS requiring admission to an intensive care unit. In the case of CAR therapy, the onset of CRS is related to the particular signaling domain in the CAR, with early-onset CRS in the first several days after infusion related to CARs that encode a CD28 signaling domain.4,16 By contrast, CARs encoding a 4-1BB signaling domain tend to have delayed-onset CRS (range, 7 to 50 days) after CAR T-cell infusion.6 CRS has also been reported after the infusion of TCR-modified T cells, with onset typically five to seven days after infusion. The development of CRS is often, but not invariably, associated with clinically beneficial tumor regression. Several cytokines have been reported to be elevated in the serum—most commonly, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-6. Management of CRS has included supportive care, corticosteroids, etanercept, tocilizumab, and alemtuzumab. The role of suicide genes in the management of CRS remains unknown.50

This supportive therapy have now been included in all protocols now and sites are engaged in developing pharmacovigilance protocol development for CAR-T therapy.

 

Other posts on this site on Immunotherapy and Cancer include

Combined anti-CTLA4 and anti-PD1 immunotherapy shows promising results against advanced melanoma

Molecular Profiling in Cancer Immunotherapy: Debraj GuhaThakurta, PhD

Pancreatic Cancer: Genetics, Genomics and Immunotherapy

$20 million Novartis deal with ‘University of Pennsylvania’ to develop Ultra-Personalized Cancer Immunotherapy

Upcoming Meetings on Cancer Immunogenetics

Tang Prize for 2014: Immunity and Cancer

ipilimumab, a Drug that blocks CTLA-4 Freeing T cells to Attack Tumors @DM Anderson Cancer Center

Juno’s approach eradicated cancer cells in 10 of 12 leukemia patients, indicating potential to transform the standard of care in oncology

Report on Cancer Immunotherapy Market & Clinical Pipeline Insight

New Immunotherapy Could Fight a Range of Cancers

 

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Treatments for Lymphomas and Leukemias

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

 

2.4.4 Treatments for leukemia by type

2.4.4.1 Acute Lymphocytic Leukemias

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.

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.

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.

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.

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.

2.4.4.2 Acute Myeloid Leukemia

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.

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.

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.

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]

2.4.4.3 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.

2.4.4.4. 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.”

2.4.4.5  Lymphoma treatment

Overview

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

The most widely used therapies are combinations of chemotherapy and 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.

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.

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)

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Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia.

Duvelisib is a dual phosphoinositide-3-kinase (PI3K) delta and PI3K gamma inhibitor.  The delta and gamma isozymes are selectively expressed in leukocytes.    This article (at Dr. Melvin Crasto’s blog newdrugapprovals.org) discusses the synthesis of Duvelisib and mentions additional clinical trials underway including a phase II trial for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma).  The drug was originally developed at Takeda subsidiary Intellikine.

Read Full Post »


Reporter: Aviva Lev-Ari, PhD, RN

Based on the results of a new study, researchers are developing a clinical trial to test imatinib(Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

http://www.cancer.gov/ncicancerbulletin/103012/page3#b

VIEW VIDEO by  Mayo Clinic Dr. Tim Call describes Chronic Lymphocytic Leukemia (CLL), its diagnosis, and treatment options for patients with CLL.

http://www.youtube.com/watch?v=GCMuizn980c&feature=related

VIEW VIDEO  by Leading CLL researcher Dr. Thomas Kipps discusses the latest in the course of the disease including: symptoms, causes, and risk factors. Dr. Kipps also highlights discoveries made in his lab that may lead to developing new therapies to treat this disease. Series: “Stein Institute for Research on Aging” [9/2010] [Health and Medicine] [Show ID: 19345]

http://www.youtube.com/watch?v=QToR46370OI&feature=related

Understanding the Molecular Basis of Imatinib Mesylate Therapy in Chronic Myelogenous Leukemia and the Related Mechanisms of Resistance1

Commentary re: A. N. Mohamed et al., The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations. Clin. Cancer Res., 9: 1333–1337, 2003.

  1. Guido Marcucci2,
  2. Danilo Perrotti, and
  3. Michael A. Caligiuri

+Author Affiliations


  1. Division of Hematology and Oncology, Department of Internal Medicine [G. M., M. A. C.], Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics [G. M., D. P., M. A. C.], The James Cancer Hospital and The Comprehensive Cancer Center at The Ohio State University, Columbus, Ohio 43210

Introduction

CML3 is a myeloproliferative disorder with an incidence of approximately 1–1.5 cases/100,000 population/year, a slight male predominance, and a peak between 50 and 60 years of age (1) . This condition arises from a transformed pluripotent hematopoietic precursor associated with t(9;22)(q34;q11.2) that gives rise to the Ph′ chromosome. At the molecular level, this cytogenetic aberration results in the fusion of the ABL gene at chromosome band 9q34 with the BCR gene at chromosome band 22q11.2. The resultantBCR/ABL fusion gene encodes a chimeric protein necessary and sufficient to confer the leukemic phenotype. In a minority of the cases, despite absence of the Ph′ chromosome, molecular methodologies (i.e., fluorescence in situ hybridization, Southern, or RT-PCR) can still detect BCR/ABL as the product of complex cytogenetic aberrations involving other chromosomes in addition to 9q34 and 22q11.2, or cryptic genomic rearrangements of the BCR and ABL genes. Taken all together, >95% of the CML cases are associated with BCR/ABL expression that, therefore, represents the hallmark of this condition.

CML is a bi- or triphasic disease (2) . Patients usually present in a chronic proliferative phase characterized by splenomegaly and accumulation of neutrophils in their various stages of maturation. Basophils and blasts are normally <20% and 10%, respectively, in CP CML. Evolution to the BP (or blast crisis) is defined by an increase (≥20%) in myeloid or lymphoid blasts in blood, BM, or extramedullary locations. In many cases, the transformation is characterized by a passage through an AP, in which the failure of a patient to respond to therapy is accompanied by an increase in percentage of blasts (10–19%); a ≥20% increase in basophils, uncontrolled thrombocytosis, or thrombocytopenia; and acquisition of new cytogenetic abnormalities such as trisomy 8, isochromosome 17q, or a second Ph chromosome and/or genetic inactivation of the p53 gene.

The ultimate goal of treatment for CML is prevention of blast crisis, because, once this occurs, the prognosis is dismal. Although a rapid reduction of the white cell count can be achieved with chemotherapy (i.e., busulfan or hydroxyurea) in CP CML, these drugs usually fail to prevent disease progression. IFN-α was the first agent proven capable of modifying the biological history of CML by prolonging survival in patients who achieved CHR and MCR (<35% of Ph′+cells; Ref. 3 ). A second breakthrough in the treatment of CML occurred when 60–80% of patients undergoing alloBMT in CP were reported to be disease free at 5 years (456) . However, both IFN-α and alloBMT have considerable treatment-induced toxicity that attenuated the initial enthusiasm for these results, and novel, less toxic therapeutic strategies are being explored. In 2001, Druker et al. (7)reported the first Phase I study with imatinib mesylate (STI571, Gleevec), a specific inhibitor of BCR/ABL oncogenic activity. In this study, the authors demonstrated that high rates of CHR and MCR were achieved with relatively few side effects in patients with CML refractory or intolerant to IFN-α, opening new avenues for molecularly targeted therapies in this disease. Subsequently, encouraging results were also obtained for CML patients in BP (8) .

Is BCR/ABLthe Driving Force for Leukemogenesis in CML?

The transforming activity of BCR/ABL has long been demonstrated using in vitro and in vivo models. In initial studies, transfection of the BCR/ABL gene fusion resulted in malignant transformation of normal fibroblasts, and induced independent survival and proliferation in growth factor-dependent cell lines. Expression of BCR/ABL was also shown to be necessary and sufficient to induce leukemogenesis in animal models (reviewed in Ref. 9 ). Expression of BCR/ABL in mice was achieved by either introduction (“knock-in”) of the fusion gene in the mouse genome or by infecting murine stem cells with BCR/ABL-containing retroviral vectors. In knock-in transgenic mice with conditionalBCR/ABL expression, a low penetrance phenotype of acute B- or T-cell leukemia was reported. In contrast, in mice sublethally radiated and transplanted with syngeneic retrovirally transfected BCR/ABL+ stem cells, a condition mimicking human myeloproliferative disorders with neutrophil increase, BM expansion, hepatosplenomegaly, extramedullary hematopoiesis, and pulmonary leukostasis was observed.

How Does BCR/ABL Transform Cells?

The fusion partner ABL is a member of the nonreceptor tyrosine kinase family (10) . This gene encodes a protein containing a tyrosine kinase activity domain (SH1) in addition to two other regulatory domains (SH2 and SH3) that mediate protein-protein interaction and modulate activation of signal transduction. A nuclear localization domain is also present, supporting a shuttling activity of the ABL protein between cytoplasm and nucleus. Genetic disruption of ABL in mice results in lymphopenia, runting, and perinatal mortality. The other fusion partner, BCR, is a protein with multiple functional domains involved in oligomerization, SH-2 binding, serine/threonine kinase activity, and activation of members of the Rho small GTP-ase family of proteins (10) . Structural analysis of this gene suggests a role as a mediator of signaling transduction. With targeted disruption of BCR, mice have increased susceptibility to septic shock, but normal hematopoiesis.

In CML, each of the two partner genes are disrupted at specific breakpoints and fuse to create the chimeric BCR/ABL gene (11) . The most common rearrangements give rise to fusion transcripts identified as b2a2 or b3a2, which, in turn, are translated into a 210 kDa protein. Alternative BCR breakpoints can be located in minor cluster (m-BCR) or micro (μ) cluster (μ-BCR) regions and result in fusion transcripts that encode smaller (190 kDa) or larger (230 kDa) products, respectively. Although usually associated with Ph′+ acute lymphoblastic PiQO leukemia, the protein can also be detected in ≥90% of the CML patients from alternative splicing of p210. p230 is instead usually associated with CML patients presenting with an unusual predominance of neutrophils, resembling chronic neutrophilic leukemia. In each of these BCR/ABL variants, the ABL tyrosine kinase domain autophosphorylates and becomes constitutionally activated. Such BCR/ABLderegulated tyrosine kinase activity is, in fact, responsible for transformation of the hematopoietic stem cell and maintenance of the leukemic phenotype by recruiting and activating transducing signal pathways (i.e., RAS, RAF, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, phosphatidylinositol 3′-kinase, cCbl, CRKL, Janus-activated kinase-signal transducers and activators of transcription, PKC and PLCγ) involved in: (a) enhanced gene transcription (i.e., c-myc, c-Jun, reviewed in Ref. 12 ); (b) altered mRNA processing, nuclear export, and translation (i.e., bcl-xL, CAAT/enhancer binding protein α, and p53; reviewed in Ref. 13 , 14 ); and (c) increased or decreased protein stability (i.e., Abi proteins; DNA-PKcs; FUS, and hnRNP A1; reviewed in Ref. 13). This, in turn, leads to enhanced proliferative potential and survival, altered motility and trafficking, and suppression of granulocytic differentiation (1 , 13 , 15 , 16) .

Mechanisms of Action of Imatinib Mesylate

BCR/ABL is an ideal target for molecular targeted therapy, because this fusion protein is present in all of the CML cells, is absent from nonmalignant cells, and is necessary and sufficient to induce leukemia. Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet derived growth factor receptor, c-kit, and Albeson-related gene (17) . The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR/ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR/ABL, thereby preventing tyrosine autophosphorylation and, in turn, phosphorylation of its substrates. This process ultimately results in “switching-off” the downstream signaling pathways that promote leukemogenesis. Preclinical in vitro and in vivo data indicated an impressive selective activity of imatinib mesylate on cells expressing BCR/ABL, and supported a rapid transition of this compound from the bench to the clinic.

To date, imatinib mesylate has been evaluated in several Phase I and II clinical trials of patients with IFN-α-resistant chronic, accelerated, or BP CML (7 , 8 , 181920) . From the collective analysis of these studies, imatinib mesylate appears to effectively induce high CHR and cytogenetic response rates with relatively few side effects. In patients with CP CML who have failed IFN-α the CHR was 95%, MCR 60%, and complete cytogenetic remission 46%. Notably, in these patients achievement of MCR at the 3-month time point correlated with improved progression-free survival. In AP and in blast crisis, the CHRs were 34% and 8%, MCRs were 24% and 16%, and complete cytogenetic remissions were 17%, and 7%, respectively. Disease progression was 11% at 18 months for CP, 40% at 12 months for AP, and 80% at 18 months for BP. Finally, preliminary data from an interim analysis of a phase III study of untreated CML patients randomized between imatinib mesylate versus IFN-α and ARA-C indicate a significantly better CHR, complete cytogenetic remission, and progression-free survival for the imatinib mesylate group after a median follow-up of 14 months (21) . However, a longer follow-up will be necessary to assess whether this compound can also impact on the natural history of the disease and prevent or delay transformation to blast crisis.

Mechanisms of Resistance to Imatinib Mesylate

During disease progression, CML progenitor cells acquire a number of genetic alterations, most probably because of increased genomic instability, that may explain the aggressive phenotype, chemotherapeutic drug resistance, and poor prognosis of CML in BP. Despite the exciting results obtained with imatinib mesylate noted above, CML patients eventually show resistance at a rate of 80% in BP, 40–50% in AP, and 10% in CP post-IFNα failure, at 2 years (19) . Identification of the molecular basis of resistance is important, because it could provide insight into disease progression and into the design of novel therapeutic strategies to prevent and overcome treatment resistance.

CML patients with imatinib mesylate resistance can be stratified into those with primary refractory disease, most frequently in accelerated or BPs, and those who relapse after initial response, who are most frequently in CP. On the basis of the presence or absence of BCR/ABL tyrosine kinase activity in leukemia cells, it is also possible to discriminate between cases with BCR/ABL-dependent and -independent mechanisms of imatinib mesylate resistance. Notably, because the BCR/ABL enzymatic activity cannot be easily measured in blood or BM patient samples, levels of phosphorylation of the BCR/ABL substrate CRKL have been used as a surrogate end point for the tyrosine kinase activity(22) .

In patients with higher levels of CRKL phosphorylation despite treatment with imatinib mesylate, resistance has been found to result from at least three different BCR/ABL-dependent mechanisms: BCR/ABL gene amplification, BCR/ABL mutations, and high plasma levels of AGP (reviewed in Ref. 23 ).

The association of BCR/ABL gene amplification with resistance to imatinib mesylate is consistent with the reliance of CML blast crisis cells on BCR/ABL expression/activity for their proliferation and survival, and with the reported enhanced expression of BCR/ABL in these cells (24) . Indeed, high levels of BCR/ABL expression, which are detected frequently in CML-blast crisis but not CP cells, appear to be required for suppression of myeloid differentiation and increased resistance to chemotherapy-induced apoptosis ofBCR/ABL-expressing cells. Specifically, high levels of BCR/ABL kinase activity are required for hnRNP E2-dependent inhibition of CAAT/enhancer binding protein α, the major regulator of granulocytic differentiation (25) , and for the La-dependent enhancement of MDM2 expression, which, in turn, results in functional inactivation of p53(14) , also required for myeloid blastic transformation (26 , 27) Although the mechanisms underlying such an increase of BCR/ABL expression are unclear, a double Ph′ chromosome is likely to be responsible for the enhanced BCR-ABL levels in some cases.

Other mechanisms of imatinib mesylate resistance involve mutations in the BCR/ABLgene itself. Several different mutations have been detected in at least 13 amino acids of the ATP-binding site or other regions of the tyrosine kinase domain, and the list is growing (23 , 28 , 29) . These mutations usually prevent imatinib mesylate from binding to BCR/ABL, thereby resulting in lack of inhibition of the tyrosine kinase activity. Among these mutations, substitution of a threonine to isoleucine at position 315 of ABL that prevents imatinib mesylate from binding to the ATP-binding domain, is the first described and one of the most frequent (22) .

A third mechanism of resistance relies on plasma levels of AGP. It has been shown that AGP binds imatinib mesylate at physiological concentrations in vitro and in vivo, and blocks the ability of imatinib mesylate to inhibit BCR/ABL kinase activity in a dose-dependent manner (reviewed in Ref. 23 ). Finally, in patients with primary refractoriness to imatinib mesylate, resistance more often occurs in absence of significant CRKL phosphorylation, suggesting activation of BCR/ABL-independent leukemogenic pathways.

In this issue, Mohamed et al. (30) hypothesized that clonal evolution, defined as acquisition of additional cytogenetic abnormalities other than t(9;22)(q34;q11), is a marker for genomic instability, and thereby, in this setting, additional “hits” can occur to activate BCR/ABL-independent leukemogenic mechanisms. Given this premise, CML patients with a more complex karyotype were expected to be more resistant to imatinib mesylate. To test their hypothesis, these authors analyzed 58 BCR/ABL-positive patients with IFN-α-resistant CP (n = 13), AP (n = 24), or BP (n = 21) CML with additional cytogenetic abnormalities who were each treated with imatinib mesylate. Of the 58 patients, 15 (CP = 46%; AP = 25%; BP = 14%) achieved a cytogenetic response, and 12 had a complete cytogenetic remission. With a follow-up of 17–30 months, 7 (12%) remained in complete remission on imatinib mesylate, supporting the notion that a subset of CML patients with t(9;22)(q34;q11) and additional cytogenetic abnormalities can achieve a sustained response. Because the molecular mechanisms of resistance in these patients were not fully evaluated, the contribution of additional cytogenetic abnormalities as an independent predictor of resistance to imatinib mesylate could not be directly addressed. Similar results were also reported in the imatinib mesylate initial studies (18 , 20) , and more recently by Schoch et al. (31) . These authors reported on 31 patients with additional chromosomal abnormalities present before the start of imatinib mesylate therapy. Additional cytogenetic abnormalities were less frequent in chronic than other phases of the disease (35.5% versus 68.8%; P = 0.0008), and when corrected for the difference in disease stage, they did not influence response to imatinib mesylate. These results have been confirmed recently by a larger study reported by Cortes et al. (32) where 498 CML patients in CP or AP were treated with imatinib mesylate. Of the 498, 121 had additional cytogenetic abnormalities. In a multivariate analysis at the 3-month time point, lack of cytogenetic response, but not presence of additional cytogenetic abnormalities, was found to be a negative prognostic factor for survival

Although a longer follow-up is necessary to draw definitive conclusions, these findings suggest that additional cytogenetic aberrations do not appear to impact on disease response, and, therefore, karyotype analysis should not be used to stratify patients for therapeutic alternatives to imatinib mesylate. Furthermore, despite clonal evolution, the oncogenic potential of BCR/ABL appears to remain the driving force for leukemogenesis, and, therefore, may continue to serve as a therapeutic target. Finally, in patients with additional cytogenetic abnormalities who are resistant to imatinib mesylate, evaluation for levels of CRKL-phosphorylation should be done to sort out the nature of the resistance to this treatment and to understand the interplay between BCR/ABL-dependent and -independent mechanisms in disease progression.

Concluding Remarks

The results obtained with imatinib mesylate to date are truly impressive, but longer follow-up will be necessary to establish whether prevention or delay of blast crisis can be achieved and whether an improved overall survival for the majority of patients with CML can be obtained. It is clear that complete cytogenetic remission is achievable in most patients with CP CML, and that those who do not achieve this important end point between 3 and 6 months are likely to have a poor outcome. However, in patients with complete cytogenetic remission, other challenges remain. In these patients, for instance, molecular remission defined as the absence of BCR/ABL fusion transcript by RT-PCR is usually not achieved. The reasons for persistent low levels of residual disease after imatinib mesylate and the prognostic significance of these findings are unknown. It is possible that small numbers of mutated and resistant BCR/ABL-positive subclones remain essentially unaffected by this treatment, and if a proliferation advantage is subsequently acquired in these cells, they may drive disease recurrence. Therefore, in patients with complete cytogenetic remission, monitoring of the BCR/ABL fusion transcript levels by quantitative RT-PCR has been suggested to predict impending relapse, and if rising levels of BCR/ABL expression are detected, consideration could be given to alternative strategies including alloBMT.

However, emerging data support the notion that hematologic or cytogenenetic remission can be achieved in imatinib-relapsed CP CML patients with higher doses of this agent. Kantarjian et al. reported on 54 patients with CML in CP who were initially treated with 400 mg of imatinib mesylate and, subsequently, with a higher dose (i.e., 800 mg) when hematologic or cytogenetic resistance or relapse developed (33) . Among 20 patients treated for hematologic resistance or relapse, 13 (65%) achieved CHR without complete cytogenetic remission, and among 34 patients treated for cytogenetic resistance or relapse, 19 (56%) achieved a complete cytogenetic remission or MCR. However, the mechanisms of resistance to standard dose were not evaluated in these patients and, therefore, correlation of these mechanisms with clinical response to the higher doses was not possible. Nevertheless, these data are intriguing and pose the question of whether a higher dose of imatinib mesylate could be used at the time of the initial diagnosis or during molecular relapse to prevent overt leukemia recurrence or blast transformation. Future studies will no doubt address these important issues. Regardless, it is undeniable that imatinib mesylate has changed our approach to CML and paved the way for additional molecular targeted strategies in leukemia.

Footnotes

  • 1 Supported in part by P30-CA16058, and K08-CA90469 Grants from the National Cancer Institute, Bethesda, MD, The Elsa U. Pardee Cancer Research Foundation, and The Coleman Leukemia Research Foundation.

  • 2 To whom requests for reprints should be addressed, at The Ohio State University, 458A Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: (614) 293-7597; Fax: (614) 293-7527; E-mail: marcucci-1@medctr.osu.edu.

  • 3 The abbreviations used are: CML, chronic myelogenous leukemia; Ph′, Philadelphia; ABL, Abelson; RT-PCR, reverse transcription-PCR; BM, bone marrow; CHR, complete hematologic remission; MCR, major cytogenetic response; alloBMT, allogeneic bone marrow transplantation; AGP, α1 glycoprotein; CP, chronic phase; AP, accelerated phase; BP, blastic phase.

  • Received March 3, 2003.
  • Accepted March 3, 2003.

Imatinib May Help Treat Aggressive Lymphoma

Based on the results of a new study, researchers are developing a clinical trial to test imatinib (Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

The authors decided to investigate the effect of imatinib after finding a link between PDGFRB and a genetic abnormality that is found in many patients with ALCL. Previous work had shown that this genetic change—a translocation that leads to the production of an abnormal fusion protein called NPM-ALK—stimulates the production of two proteins, transcription factors called JUN and JUNB.

In the new study, experiments in mice revealed that these proteins promote lymphoma development by increasing the levels of PDGFRB.

Because imatinib inhibits PDGFRB, the authors tested the effect of the drug in mice with the NPM-ALK change and found that it improved their survival. They also found that imatinib given together with the ALK inhibitor crizotinib (Xalkori) greatly reduced the growth of NPM-ALK-positive lymphoma cells in mice.

To test the treatment strategy in people, they identified a terminally ill patient with NPM-ALK-positive ALCL who had no other treatment options and agreed to try imatinib. The patient began to improve within 10 days of starting the therapy and has been free of the disease for 22 months, the authors reported.

The observation that inhibiting both ALK and PDGFRB “reduces lymphoma growth and alleviates relapse rates” led the authors to suggest that the findings might be relevant to lymphomas with PDGFRB but without the NPM-ALK protein. “Our findings suggest that imatinib is a potential therapeutic option for patients with crizotinib-resistant lymphomas.”

A planned clinical trial will be based on the expression of PDGFRB in tumors.

SOURCE:

http://www.cancer.gov/ncicancerbulletin/103012/page3#b

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