Should There Be a Standard Therapy for Mantle Cell Lymphoma?

Mitchell R Smith

Disclosures

Future Oncol. 2011;7(2):227-237. 

In This Article

Initial Treatment Options for Mantle Cell Lymphoma

Overview & Effects of Patient Age

For B-cell lymphomas in general, including MCL, a common standard treatment is rituximab–cyclophosphamide doxorubicin vincristine prednisone (R-CHOP). As for indolent lymphomas, there is no demonstrated survival benefit for use of anthracyclines in MCL. As initial therapy for MCL, R-CHOP is active, but remissions are not durable. The Dana–Farber experience indicated a 96% response rate (RR),[25] with median progression-free survival (PFS) of 16 months. With R-CHOP followed by additional consolidation, Lenz et al. reported a similar 92% RR with a somewhat better PFS of 28 months.[26] In a randomized comparison of consolidation after a CHOP-like regimen, high-dose chemotherapy with autologous stem cell support (HDC/ASCT) yielded longer PFS (3.5 years) than interferon maintenance.[27]

The MD Anderson group initially described results with Hyper-CVAD/MA,[28] a more intensive regimen that includes hyperfractionated cyclophosphamide and alternating high-dose methotrexate–cytarabine as initial therapy for MCL, followed by HDC/ASCT. The authors later reported that, with the addition of rituximab (R-Hyper-CVAD/R-MA), the benefit of autologous stem cell transplant (SCT) was no longer apparent.[29] With R-Hyper-CVAD/R-MA, PFS appears better than R-CHOP, although patient selection may play a role as results for patients older than 65 years are not as good. Attempts to reproduce these results in cooperative settings has been problematic, with many patients unable to complete the regimen.[30,31] Thus, this regimen may be beneficial in selected young, fit patients for whom dose intensity can be preserved.

While the median age at which MCL is diagnosed is the mid-60s, the median age in many trials is 5–10 years less, and even younger in some intensive therapy trials. In MCL, as in other lymphomas, age is an important prognostic indicator, as noted in the IPI and MIPI. Age and performance status are also factors in balancing risk versus benefit of more intensive treatment. Thus, treatment strategies vary with age.

Approaches to the Young & Fit Patient

The R-Hyper-CVAD/R-MA regimen has been a standard for young, fit patients with MCL. Original data suggested that HDC/ASCT did not improve outcomes after four full cycles of R-Hyper-CVAD/R-MA; however, as previously noted, many patients cannot complete this regimen. A National Comprehensive Cancer Network retrospective review of patients treated at its centers, limited by possible selection bias, concluded that R-CHOP followed by HDC/ASCT was equivalent to R-Hyper-CVAD/R-MA in terms of PFS in younger patients.[32] Retrospective analysis suggested that patients who began HDC/ASCT following R-Hyper-CVAD/R-MA had improved outcomes compared with those who had received an R-CHOP-like regimen.[33] Thus, an approach by some centers is to give two rather than four total cycles of R-Hyper-CVAD/R-MA and to follow this with HDC/ASCT. Although no published follow-up data are available, the sense is that HDC/ASCT is actually more tolerable than an additional four cycles of R-Hyper-CVAD/R-MA. This approach will be more formally tested in an upcoming US intergroup trial.

The Nordic Lymphoma Group combined intensified induction followed by consolidation with impressive results.[34] Limited to the younger age group of 65 years or below (median age of 56 years), their treatment protocol added rituximab as an 'in vivo' purge prior to stem cell collection and high-dose cytarabine (HDAC) cycles to an already dose-intensified CHOP regimen, and then consolidated remission with HDC/SCT. Their data indicated prolonged PFS, and the authors even suggested a plateau possibly indicating 'cure', although patients with molecular relapse were treated with rituximab and longer follow-up is needed to monitor for later relapses. Since the beneficial effects of rituximab in MCL seem less pronounced than in other lymphomas,[35] the sense is that HDAC may be a particularly important component, as it is also present in the R-Hyper-CVAD/R-MA regimen. The European Mantle Cell Lymphoma Network directly tested the importance of an HDAC-containing regimen and reported preliminary results of a trial of R-CHOP versus R-CHOP alternating with rituximab–dexamethasone, cytarabine and cisplatin (R-DHAP), then consolidating with HDC/ASCT, as an initial therapy for patients 65 years or younger (median: 56 years) with MCL. The pre-SCT conditioning regimen also differed in the two arms. Patients who received the alternating R-DHAP cycles had higher clinical and molecular complete remission rates before SCT, and longer overall time to treatment failure, although no difference in overall survival has been noted yet.[36,37]

The Cancer and Leukemia Group B (CALGB) reported promising Phase II results (2-year PFS: 76%) with an R-CHOP-like regimen incorporating methotrexate (intermediate dose after significant renal toxicity issues) and higher-dose cyclophosphamide, followed by an R-HDAC-etoposide regimen and then HDC/ASCT in patients up to 69 years of age (median: 57 years), although it is difficult to differentiate the contribution of each of the many changes in this regimen.[38]

It is clear from the variety of treatment approaches that even in young and fit patients, there is no accepted standard. Of course, a clinical trial is always the best selection. Outside of an available trial, one could select R-Hyper-CVAD/R-MA given the long-term follow-up data,[39] although it involved approximately 100 patients and has been difficult to confirm in wider settings. Another reasonable choice would be the Nordic protocol,[34] as this was a group-wide effort, especially if the results are maintained with longer follow-up. The conceptually similar approach of two total cycles of R-Hyper-CVAD/R-MA followed by HDC/ASCT makes intuitive sense and is probably better tolerated than four cycles, but lacks published data and follow-up, and will be an important protocol option in the upcoming US trial. R-CHOP alternating with R-DHAP and followed by HDC/ASCT is now another reasonable option.

What we will probably see becoming a de facto standard for the young, fit patient will be a treatment plan that incorporates R-CHOP-like and high-dose cytarabine-based regimens followed by HDC/ASCT consolidation. Subsequent trials should build on this by incorporating additional agents (e.g., bortezomib, referred to later) into the induction regimen and then investigating the role of maintenance therapies (e.g., lenalidomide and rituximab, discussed later).

Approach to the Older, Less Fit Patient

What is the Best Chemoimmunotherapy Backbone? Approaches more generally applicable to the majority of patients with MCL will need to be less intensive. As previously discussed, R-CHOP has remained, at least until recently, the basic regimen for MCL. As for indolent lymphoma, the benefit of anthracycline is not entirely clear.[40] Rituximab is not as active in MCL as in follicular lymphoma, but is generally included in treatment regimens given its relatively low toxicity. A meta-analysis suggested modest benefit from its use in combination with chemotherapy in MCL.[35] One question is whether we can improve induction, either by incorporating newer agents into R-CHOP or perhaps even dispensing with the R-CHOP backbone. Another concept, since remissions are already obtainable in many patients with MCL, is to try to consolidate remission to eradicate the residual MCL cells that lead to the inevitable relapse. As an example, Eastern Cooperative Oncology Group (ECOG) has approached each of these questions in recent trials. Radioimmunotherapy (RIT) following four cycles of R-CHOP was well tolerated, increased response rates and yielded promising PFS, even in patients over 60 years of age, although no plateau in PFS was apparent.[41] More recently, ECOG completed a trial of initial therapy for MCL combining R-Hyper-CVAD (without MA) with bortezomib, with dose modifications for neuropathy due to concomitant vincristine, expanding on encouraging pilot data.[42] This was feasible in the cooperative group setting and yielded a high complete remssion rate,[43] although outcome results require further follow-up.

Bendamustine, an alkylating agent that also contains a purine-like benzimidazole ring, is active in MCL. Based on in vitro data suggesting synergy between rituximab and bendamustine (R–B), much of the data on the efficacy of bendamustine in MCL comes from combination studies of R–B. Some MCL patients were included in Phase II trials of R–B in relapsed/refractory lymphoma, with impressive response rates of 12 out of 16 (75%)[44] and 11 out of 12 (92%).[45] MCL patients were included in the German randomized trial comparing R-CHOP with R–B as initial therapy for indolent lymphoma. Almost 100 patients with MCL were randomized and significantly longer PFS was seen in MCL patients who received R–B.[46] Given that R–B was also less toxic than R-CHOP, without the risk of cardiac toxicity, whether this single study is adequate to make R–B the new standard of care for MCL, at least in the older, less fit group, remains somewhat controversial. Some would like to see longer follow-up, particularly for the results of additional therapy in terms of efficacy and toxicity after bendamustine, given potential concerns regarding the marrow toxicity of bendamustine. Nonetheless, R–B appears to be worthy of further exploration as initial therapy in MCL, perhaps as a platform to achieve high response rates with less toxicity. This would allow additional agents to be added, either concurrently or as consolidation.

What Can We Add to R-CHOP or Rituximab–Bendamustine? Bortezomib, a selective and reversible proteasome inhibitor, is active in relapsed MCL, with a 47% RR (8% complete remission).[11] The bortezomib plus rituximab combination is also active and well tolerated, with no unexpected toxicities. Bortezomib combinations with other chemotherapy regimens, such as R-CHOP,[47] are under investigation. As bortezomib is active in relapsed MCL and can be combined with standard chemotherapy and rituximab without undue toxicity, bortezomib is being further investigated in combination therapy for MCL. Based on the aforementioned discussion, R–B may be a base upon which to build improved treatment regimens in MCL. Bortezomib has a largely nonoverlapping toxicity profile with R–B. R–B plus bortezomib has been investigated in a Phase I/II trial in lymphoma, including a few patients with MCL.[48] With bortezomib as the standard twice-weekly myeloma dose and schedule, this combination was tolerable. The major toxicities were thrombocytopenia and neuropathy. Another trial using bortezomib administered weekly for 4 weeks of a 5-week cycle also demonstrated tolerability with similar toxicity.[49] Studies investigating R–B with or without bortezomib as initial therapy for MCL are planned. Similarly, bortezomib can be added to R-CHOP, and studies of this combination are also underway.

Biologically targeted agents with nonoverlapping toxicity, particularly lacking myelosuppression and neuropathy, can be more easily added to R-CHOP or R–B. In general, in lymphoma, the immunomodulatory agent lenalidomide has been combined with R-CHOP with promising results, while R-CHOP combined with the antiangiogenic antibody bevacizumab has been less successful.[50] Various newer anti-CD20 antibodies in development have been engineered as humanized or fully human, with Fc portions that enhance antibody-dependent cytotoxic cell (ADCC) or complement activation, that target different epitopes on CD20 or do not require translocation into lipid rafts. Other agents under consideration include monoclonal antibodies targeting the pan-B-cell marker CD22, including unlabeled anti-CD22 (epratuzumab), chalicheamycin-linked anti-CD22 immunoconjugate inotuzumab ozogamicin (formerly CMC-544) and radiolabelled anti-CD22. Furthermore, apoptosis-promoting agents, such as obatoclax and navitoclax (ABT-263), which target the BCL2 family of proteins via the BH3 domain responsible for many protein–protein interactions, are also under investigation with immunochemotherapy combinations.

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