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Download of These Slides, Please Direct Your Browser to the Following Web Address Clinical Roundtable Monograph Clinical Advances in Hematology & Oncology December 2013 Integrating Emerging Treatment Options in Mantle Cell Lymphoma Moderator Brad S. Kahl, MD Skoronski Chair of Lymphoma Research Associate Professor of Medicine University of Wisconsin School of Medicine and Public Health Associate Director for Clinical Research UW Carbone Cancer Center Madison, Wisconsin Discussants Nathan H. Fowler, MD Co-Director of Clinical and Translational Research Lead, Phase I and Indolent Research Groups Department of Lymphoma/Myeloma MD Anderson Cancer Center Houston, Texas Myron S. Czuczman, MD Chief, Lymphoma/Myeloma Service Professor of Oncology Head, Lymphoma Translational Research Laboratory Departments of Medicine and Immunology Roswell Park Cancer Institute Professor of Medicine SUNY at Buffalo School of Medicine Buffalo, New York Abstract: Mantle cell lymphoma is an uncommon lymphoma subtype that is currently considered incurable and lacks a single standard of care. Choice of treatment is complicated by the disease’s clinical heterogene- ity. The course of the disease may be indolent, moderately aggressive, or aggressive. A translocation between chromosomes 11 and 14 is observed in the majority of mantle cell lymphoma patients, and the diseased cells may develop a variety of other genetic aberrations. Although the disease tends to respond well to treatment, patients almost invariably relapse, with many becoming chemotherapy refractory over time. The development of new treatment strategies has improved the prognosis for these patients. Novel approaches include intensive chemotherapy, often in combination with stem cell transplantation; maintenance therapy with extended dura- tion; and new targeted treatments such as ibrutinib, bendamustine, bortezomib, lenalidomide, and idelalisib. Many of these new agents have shown promising activity, both as single agents and in combination regimens. Supported through funding from Pharmacyclics Inc. CLINICAL ROUNDTABLE MONOGRAPH Integrating Emerging Treatment Options in Mantle Cell Lymphoma: Introduction Brad S. Kahl, MD antle cell lymphoma (MCL) is a unique p14ARF subtype of non-Hodgkin lymphoma (NHL). MCL accounts for approximately 6% of new 1 Mlymphoma cases each year. Because it is a relatively BMI-1 INK4a/ARF uncommon form of lymphoma, it is more difficult to study than other lymphoma subtypes. There are many Cyclin D1/CDK complex CDK 4 CDK 6 single-arm, phase 2 trials in the MCL literature, but there p16Ink4a Cyclin D1 is a relative paucity of large, randomized, phase 3 trials. p27Kip1 As a result, comparisons are often made across trials, and observations are based on extrapolation. P p27Kip1 Rb protein Rb protein Mantle Cell Lymphoma Biology CDK 2 G /S phase transition G /S phase transition The biology of MCL is unique. Virtually all cases of MCL Cyclin E 1 1 are characterized by a translocation between chromo- somes 11 and 14 t(11;14), which juxtaposes the BCL-1 Figure 1. In mantle cell lymphoma, overexpression of oncogene on chromosome 11 behind the immunoglobu- the protein1 cyclin D-1 leads to cell cycle deregulation 2 lin gene heavy chain promoter on chromosome 14. This and abnormal progression of these cells through normal translocation results in overexpression of the protein cyclin cell cycle0.8 checkpoints. Adapted from Benn HAN. The 8 D-1, which in turn leads to cell cycle deregulation and Molecular0.6 Oncology Report. 2006;1(1). abnormal progression of these cells through normal cell cycle checkpoints (Figure 1). It is believed that t(11;14) is late, patients0.4 tend to develop a more aggressive version of a very early event in the lymphomagenesis of MCL. MCL thatSurvival Probability 0.2 may have a higher proliferative rate and more By the time patients present for diagnosis in the generalized resistance to therapy. clinic, the biology of the disease has evolved consider- 0.0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 ably and is far more complicated than a simple t(11;14) Diagnosis and ClinicalOverall Survival Features (months) translocation. Fairly good drugs have been developed against cyclin D1 protein expression, but these drugs have The diagnosis of MCL is straightforward. The cell of shown only modest clinical activity in MCL. Therefore, origin is a pre–germinal center lymphocyte. The cell targeting cyclin D1 by itself is probably insufficient as an arises from the mantle zone just outside the germinal P Value P Value Ratio (95% CI) NI Sup antitumor strategy in MCL. As MCL progresses, some of center follicle. The1.26 immunophenotype is unique. the other genetic abnormalities that seem to be acquired PatientsEvaluable: tend IRC to be CD5-positive and 0.023CD23-negative,0.127 1.34 include mutations in genes such as ataxia telangiectasia and theyRandomized: tend IRC to have bright CD20. 0.008They0.055 should be mutated (ATM), TEK2, INK4, retinoblastoma, MDM2, nuclear cyclin D-1 positive1.51 by immunohistochemistry. Evaluable: Investigator 0.002 0.005 and p53. As more of these genetic abnormalities accumu- They should be FMC-7 positive as well, although not 1.16 Randomized: IRC 0.129 – Indolent NHL Randomized: IRC 1.95 0.017 0.018 Disclaimer MCL Funding for this clinical roundtable monograph has been provided by Pharmacyclics Inc. Support0 0.5 of1 this1.5 monograph2 2.5 does3 not3.5 imply4 the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and otherRate Ratioinformation are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2013 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form. 1.0 0.9 0.8 0.7 2 Clinical Advances in Hematology & Oncology Volume 11, Issue 12, Supplement 19 December 2013 Rituximab (median, 75 months) 0.6 0.5 Interferon alfa 0.4 Probability (median, 27 months) 0.3 0.2 Median follow-up, 36 months 0.1 P<.001 0.0 0 12 24 36 48 60 72 84 96 Months Since Second Randomization CLINICAL ROUNDTABLE MONOGRAPH all institutions stain for this marker. Genetic testing (OS) improved from 3 years to 5 years.5 Prognosis for should show a t(11;14) detectable by fluorescence in individual patients can be based on biologic and clinical situ hybridization. The morphology of MCL cells can factors. Rosenwald and coauthors used gene expression vary. The cells are typically small-to-medium–sized profiling and the resultant proliferation index to divide with irregular nuclei. Sometimes the nuclei are round, an MCL population into 4 quartiles.6 They found that mimicking small lymphocytic lymphoma. Occasion- 25% of patients had a very high proliferation index and ally, the cells are larger and can be confused with large a poor prognosis, with a median survival of less than 18 cell lymphoma. There is also a blastic variant of MCL, months. Approximately half of the patients had a median in which the disease may initially resemble acute lym- survival of 3 to 4 years. The remaining 25% of patients phoblastic leukemia. had a median survival of 7 to 8 years. Unfortunately, Within the lymph node, the growth pattern can gene expression profiling cannot currently be used in the show a somewhat vague nodular pattern that is usually clinic. Ki-67 staining can be used as a surrogate but is less diffuse but can also resemble follicular lymphoma. Occa- reliable and provides less discriminatory power. Prolifera- sionally, patients have a mantle zone growth pattern in tion index cut points—of less than 10%, 10% to 30%, which the mantle outside the follicle is expanded. There and greater than 30%—can provide an estimate of the is some evidence that these patients have a slightly more patient’s risk. Patients with a high proliferation rate tend indolent course. to have a worse prognosis. The clinical features for MCL are also unique com- The MCL International Prognostic Index (MIPI) pared with other types of NHL.3 For example, MCL is can be used to help estimate prognosis based on clinical much more common in men than in women, with a ratio features. The following factors have a negative impact of approximately 4:1. The median age for MCL patients on prognosis: age older than 60 years; poor performance is 64 years, which is older than for other NHL subtypes. status; high lactate dehydrogenase; and high white blood Most patients present at an advanced stage, and 30% of cell count. A web-based tool incorporates a logarithm to patients will present in a leukemic phase. Bone marrow calculate a patient’s MIPI.7 The MIPI separates newly involvement is also common. As shown by researchers at diagnosed MCL patients into 3 risk categories. Approxi- MD Anderson, involvement of the gastrointestinal tract is mately 40% to 50% of new patients are low risk, 35% common.4 Biopsies of normal-appearing mucosa indicate of patients are intermediate risk, and 20% of patients that 80% of patients have gastrointestinal involvement. are high risk. This knowledge can be useful at diagnosis, Some patients will present with lymphomatous polypo- when estimating a patient’s prognosis and considering sis, such that the colon with MCL may contain dozens therapeutic options. of small polyps. Elevated lactate dehydrogenase occurs in approximately a quarter of patients, and elevated Acknowledgment β2-microglobulin is observed in a majority. Dr Kahl is a consultant for Genentech, Celgene, Millennium, Infinity, and Gilead.
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