Intensive therapies for mantle cell lymphoma: time for a disease-specific approach?

Therapy for mantle cell lymphoma (MCL) has evolved primarily through appropriation of regimens effective in other non-Hodgkin lymphoma (NHL) subtypes. Poor outcomes following alkylator- and anthracycline-based therapies prompted subsequent investigation of rituximab, cytarabine, methotrexate, and/or autologous stem cell transplant to aggressive lymphomas, in hopes of improving survival [1–5]. In this issue ofLeukemia and Lymphoma, Lossos and colleagues [6] report results of a trial following this theme, modifying the so-called Magrath regimen (CODOX-M/IVAC: cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, mesna, etoposide, cytarabine) used in Burkitt lymphoma (BL) with the incorporation of rituximab and a thalidomide maintenance phase [7]. The authors' rationale for this intensive regimen invokes the adverse prognostic impact of a high proliferative index in MCL, drawing a parallel with BL, a highly aggressive lymphoma rendered curable by the use of intensive chemotherapy. However, the impact of intensive therapy on overall survival in MCL remains uncertain (as reviewed by Geisler et al. [8]), and a rationale for therapy based solely on the proliferation index has limitations. In particular, the median Ki67 index in MCL is generally under 30% [9–12], in stark contrast with Burkitt lymphoma, diagnosed in part by a Ki67 index nearing 100% [13]. While BL appears to be driven primarily by the MYC translocation, proliferation in MCL is related not only to cyclin overexpression from t11;14, but to a high degree of genomic instability and further lesions affecting cell cycle control, response to DNA damage, and cell survival [14,15].

The addition of rituximab to chemotherapy improves response rates and, in a meta-analysis, overall survival in mantle cell lymphoma [16]. This analysis, and studies showing a benefit when rituximab is included in the peritransplant setting, support its use in this and other first-line MCL therapies [4,17]. Like other regimens, the Lossos regimen includes high-dose cytarabine; this drug clearly improves response rates compared to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or RCHOP (plus rituximab) alone [5,18], and regimens containing cytarabine have achieved relatively favorable outcomes [1,3,4,19]. More definitive evidence regarding its role will be provided by the European MCL network, now conducting a randomized trial testing RCHOP versus RCHOP alternating with RDHAP (dexamethasone, high-dose Ara-C, cisplatin) prior to autologous stem cell transplant (ASCT) in newly diagnosed MCL [20].

The Lossos regimen is novel in using higher doses of methotrexate compared with other regimens (such as HyperCVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone] [1]), and in incorporating thalidomide maintenance. However, the activity of methotrexate in MCL is uncertain—it has been omitted from a few regimens which nonetheless achieve high rates of remission and disease control [4,19]. This report is perhaps the first publication of an immunomodulatory compound used as maintenance in MCL, and integration of these agents and proteasome inhibitors in first-line therapy for MCL is an important area of study. The rationale is drawn from a study finding that thalidomide and rituximab produced responses in 13 of 16 patients with relapsed MCL, though dose reductions under 200 mg/day were commonly required [21].

This report of Lossos' phase II study thereby offers insights into the role of methotrexate, maintenance thalidomide, and the toxicity and progression-free survival (PFS; the primary endpoint) using modified Magrath chemotherapy in MCL. Almost all patients (21 of 22) achieved a complete remission with initial therapy—despite methotrexate being omitted entirely in four patients (due to the presence of pleural effusion)—a finding which calls into question the value of methotrexate. Thalidomide was initiated at 200 mg/day in 20 patients, but required discontinuation in 10 due to toxicity, and only three remained at full dose at the time of reporting. Eight patients discontinued it after less than 4 months of use. The non-comparative design of this study, and low number of relapses despite a high rate of discontinuation, make evaluation of the role of thalidomide maintenance difficult. At most, this study suggests that careful dose determination may be necessary when incorporating novel agents into chemotherapy regimens, even when applied sequentially.

The rate of disease control is impressive—only three relapses occurred with a median follow-up of 37 months. As the authors state, longer follow-up is required to determine the durability of this finding, as most studies to date report a continual rate of relapse in MCL. The authors also point out that selection bias may affect their results; their median age is 57, and most patients belong to the low-risk group as defined by the Mantle Cell International Prognostic Index (MIPI). A major multicenter study in MCL, testing the rituximab and HyperCVAD regimen, achieved inferior outcomes compared to the initial single-center phase II study, a reminder that patient selection may be an important consideration in interpreting results [22].

Until the results of this study mature, the value of further study of the Lossos-modified Magrath regimen in MCL remains unclear. The authors' contention that myeloablative (transplant-based) therapy may not be necessary is true, but transplant-based approaches are relatively safe and effective in upfront treatment of MCL, and graft contamination with tumor cells is diminished by in vivo purging with rituximab [4,16]. The essential questions—namely, which patients benefit from intensive therapy, the optimal content of such therapy, and how to incorporate novel agents—will require prospective, collaborative studies to answer. The unique biology of MCL implies that meticulous tissue collection, correlative analyses, and trials of novel agents and schedules, rather than modification of therapies effective in other NHL subtypes, will be needed to achieve progress. The proliferation of active agents, and improving understanding of MCL's pathogenesis, have made disease-specific therapy a realistic goal of modern clinical trials.