Progress in Mantle-Cell Lymphoma
Authors: Peter Martin, Morton Coleman, John P. Leonard
Journal: Journal of Clinical Oncology (2008)

Recognition of mantle-cell lymphoma (MCL) in the 1994 Revised European-American Lymphoma classification of lymphoid neoplasms as a distinct entity enabled several groups to describe their clinical experiences. The investigators found that MCL had the unfortunate characteristics of being incurable as with indolent lymphomas, yet often rapidly progressive, similar to aggressive histologies. Median overall survival (OS) cited in these early series was in the range of 2 to 4 years, prompting several groups to propose novel therapeutic approaches to improve patient outcomes. One common strategy in MCL involved intensification of therapy. Several early reports described single-center experiences with high-dose chemotherapy and autologous stem-cell transplantation (ASCT). Patient numbers were generally small, and OS rates varied considerably—from 24% at 3 years to 80% at 4 years. Since 2000, multiple phase II studies using ASCT in first or later remission reported progression-free survival (PFS) and OS rates comparing favorably with those of historical cohorts. Dreyling et al conducted an important randomized trial, which demonstrated that after initial chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisone, patients with MCL who were randomly assigned to ASCT rather than interferon, had a significant PFS—but not OS—benefit. Varying interpretations of these and other data have led many to advocate for the use of ASCT, despite its yet unproven impact on survival. Concurrently, Romaguera et al at The University of Texas M. D. Anderson Cancer Center (Houston, TX) published the results of a single-center, phase II trial of rituximab combined with alternating cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone and methotrexate/cytarabine. The response rate was 97%, with 82% 3-year OS. These data supported the idea that intensive treatment approaches might improve long-term outcomes. Since then, other investigators have published variations on the regimen, some including ASCT, with encouraging results. It is debatable, however, to what degree the data from these trials are influenced by biases based on the characteristics of patients (younger and more fit) who are candidates for such approaches. In a recent multicenter Southwest Oncology Group trial examining rituximab combined with alternating cycles of hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone and methotrexate/cytarabine, nearly half of all patients were unable to complete therapy because of toxicity. The goal of any treatment is to cure when possible, to extend survival when cure is not possible, and to improve quality of life. How do aggressive therapies fit into this schema with respect to MCL? With the debatable exception of allogeneic stem-cell transplantation, there is little evidence that cure can be achieved for most patients with MCL. Therefore, a key question is whether OS can be extended by the choice of a specific therapy. A secondary, but important, issue is whether PFS benefits, clearly achievable with more intensive treatments, translate into improved quality of life. More specifically, is the benefit of being in remission longer worth the toxicity from more aggressive treatment? Currently, this seems to be a very individualized issue based on pace of disease, MCL-related symptoms, risks of the treatment, age, comorbid illness, performance status, and patient preferences. In the near term, if approached in an evidence-based fashion, the choice of a treatment approach for a patient with MCL will remain a complex problem requiring significant discussion and consideration. In this issue of Journal of Clinical Oncology, Hermann et al provide data vital to the discussion of patient outcomes in MCL. The investigators compared the outcomes of 134 patients from two Kiel Lymphoma Study Group trials between 1975 and 1986 with those of 202 patients evaluated on two German Lymphoma Study Group trials performed since 1996. Although not a randomized comparison, OS in the latter cohort nearly doubled, from 2.7 to 4.8 years. Similar findings have been observed in follicular lymphoma. In both cases, it is of interest to postulate what changes were responsible for such a significant apparent improvement. Patients in the GLSG cohort of the current study received anthracyclineor anthracenedione-containing chemotherapy, approximately one third received rituximab, and a small number (fewer than 7%) received ASCT in first remission. Data from randomized trials, however, do not support the hypothesis that any of these differences prolong OS. Enhanced supportive care may have had a small, but significant, impact. We believe that the greatest advances in MCL outcomes are due to improved second-, third-, and fourth-line therapeutic options. This hypothesis is encouraging, because it suggests that although patients with MCL are not cured, we may be improving our ability to achieve disease control over time, even after relapse. Whether the results described by Herman et al are fully valid or could better by explained by bias must also be considered. Improved diagnostic techniques have likely changed the characteristics of the patient population over time. In addition, there may be lead time bias in the timing of initiation of therapy (study entry after observation and delayed first treatment v study entry and therapy immediately at diagnosis). As the authors point out, “patient selection is a great caveat of historical comparisons.” Using careful statistical methodology, the investigators have attempted to identify and correct JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 4 FEBRUARY 1 2009