The VcR-CVAD induction regimen produced a high CR rate (77%) and high OR rate (90%) in a representative MCL patient population (median age 61 years, 60% intermediate/high risk MIPI). When compared to our previous trial (Kahl et al 2006
) using a similar induction, without bortezomib, we observed a higher CR rate (77% vs. 64%) and higher OR rate (90% vs. 77%). If these differences are “real”, we cannot be certain bortezomib is solely responsible, as the VcR-CVAD induction was administered on slightly more intensive schedule than the modified hyper-RCVAD regimen (21 vs. 28 days). Despite the uncertainties, the data are not inconsistent with the hypothesis that bortezomib potentiates cytotoxic chemotherapy in MCL.
The major toxicities from VcR-CVAD were myelosuppression and PPN. The severity of myelosuppression did not appear to be altered by the addition of bortezomib. However, there is clearly an increased risk for PPN when combining bortezomib and vincristine, and our data suggest the risk can be ameliorated with alternative dosing. The approved dose of bortezomib is 1.3 mg/m2
on days 1, 4, 8, and 11, repeated in 21 day cycles. In an effort to make the treatment schedule more patient-friendly and to maximize overlap with cytotoxic chemotherapy, we opted for two bortezomib doses (days 1 and 4) with each chemotherapy cycle. We initially selected a dose of 1.5 mg/m2
, as existing data suggested superiority for this dose in MCL.(Goy, et al 2005
, O’Connor, et al 2005
) Once apparent that severe PPN was occurring at an unacceptable frequency, the protocol was modified (twice) resulting in our final dosing of bortezomib 1.3 mg/m2
days 1 and 4 and vincristine 1 mg each cycle. Using this strategy, only one of the last 16 patients enrolled experienced significant PPN, which developed after cycle 6. One of the interesting observations from the study was the onset of the PPN. For all patients affected by severe PPN, it developed quite suddenly after cycle 4, 5, or 6 and there was little opportunity for pre-emptive dose modifications.
We are aware of two other published studies that have combined bortezomib with vincristine (as part of the R-CHOP regimen) in B cell lymphomas. The French adult lymphoma study group (Groupe d’ Etude des Lymphomes de l’ Adulte) has published results from a randomized Phase 2 trial where bortezomib was added to R-CHOP using escalating doses and bi-weekly vs. weekly schedules.(Ribrag, et al 2009
) These investigators also advise caution when combining both neurotoxic agents. The PPN was clearly increased when using higher doses (1.6 mg/m2
) and when using the bi-weekly schedule. However, a report from a multicentre trial conducted in the U.S. did not find excessive neurotoxicity when combining bortezomib 1.3 mg/m2
days 1 and 4 with R-CHOP 21, using full-dose vincristine (2 mg).(Furman, et al, 2010
With a median follow up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. These results compare favourably to the parent study (no bortezomib) in which the 3-year PFS and OS were 50% and 75%, respectively (Kahl et al 2006
). Again, if these differences are real, we cannot say whether they are due to the incorporation of bortezomib, intensification of the induction regimen from 28 to 21 days, or prolongation of the MR from 2 to 5 years.
The inclusion of MR for MCL has been controversial. Maintenance rituximab for 2 years was proven to be of no clinical benefit in a curable lymphoma (DLBCL).(Habermann, et al 2006
) Maintenance rituximab for 2 years has prolonged PFS in incurable lymphomas, including follicular and other indolent histologies.(Hochster, et al 2004
, Salles, et al 2011
, van Oers, et al 2006
). Similar to other incurable B cell lymphomas, we hypothesized MR would have a beneficial effect in MCL. Two small, randomized controlled trials have generated conflicting results. The German Low Grade Lymphoma Study Group enrolled patients with relapsed MCL, re-established remission with chemotherapy, with or without rituximab and then randomized to MR for 9 months or observation.(Forstpointner, et al 2006
) Only 47 patients were analysed in the MCL cohort, but a statistically significant improvement in response duration was observed in favour of MR (remission beyond 2 years 45% vs. 9%, p = 0.049). The Swiss Group for Clinical Cancer Research (Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung) enrolled 104 patients with a mixture of untreated and relapsed MCL and randomized them to a single 4-week rituximab treatment or a prolonged rituximab schedule of a 4-week treatment followed by a single dose every 8 weeks × 4 doses.(Ghielmini, et al 2005
) The extended schedule did not improve response rates, response duration, or event-free survival. The reasons for these discrepant results are unclear, but we speculate that the quality of the response to induction therapy may affect the likelihood of MR benefit. The question may soon be put to rest in MCL, as an independent Data and Safety Monitoring Board recently recommended early closure of a large randomized trial that demonstrates a significant benefit for patients receiving MR after R-CHOP chemotherapy (Martin Dreyling, University of Munich-Grosshadern, Germany, personal communication).
The duration of MR is another question in need of further study in B cell lymphomas. Most published studies in FL and MCL have utilized a 1 or 2 year maintenance strategy.(Ghielmini, et al 2005
, Hochster, et al 2004
, Salles, et al 2011
, van Oers, et al 2006
) In this study, we sought to determine the safety and efficacy of a longer duration of MR. Infections, seemingly related to hypogammaglobulinaemia, caused premature discontinuation of MR in six patients. Two infections were severe (sepsis and intractable clostridium difficile
colitis), and four patients have gone on to gamma globulin replacement therapy. Although the majority of patients have tolerated the prolonged MR without difficulty, the intolerance rate of 22% leads us to recommend that 2 years of MR remain the standard until randomized controlled trials comparing 2 years against more prolonged schedules are completed.
The 3-year PFS of 63% and OS of 86% observed in this trial are comparable to other studies that used more intensive regimens. For example, with nearly identical follow up time, Romaguera et al (2005)
reported a 3-year PFS of 64% and 3-year OS of 82% for the conventional R-hyperCVAD regimen. The Cancer and Leukemia Group B has published the results of an intensive immunochemotherapy induction regimen followed by autologous stem cell transplantation (ASCT), producing a 3-year PFS of 63% and 3-year OS of 83%.(Damon, et al 2009
) Two multicentre European studies, utilizing high dose cytarabine in the induction and consolidative ASCT have generated slightly superior PFS results, but both were limited to patients aged 65 years and younger, making comparison with the present trial difficult.(Delarue, et al 2008
, Geisler, et al 2008
To determine if these promising results could be replicated in a cooperative setting, ECOG protocol E1405 was initiated and utilized the same VcR-CVAD induction therapy followed by MR for 2 years. Enrollment completed in November 2008 and the OR (96%) and CR (75%) rates were similar to those observed in the present study.(Kahl, et al 2009
) More follow up time is needed before we can report on the 3-year PFS and OS from E1405.
Further progress in the treatment of MCL will require larger trials capable of generating robust, comparative data. The U.S. cooperative groups have agreed in principle to an intergroup trial for the older MCL patients, which will test the contribution of bortezomib in a randomized fashion. The chemotherapy backbone for this trial will be bendamustine plus rituximab (BR), a logical choice given the promising activity and toxicity profile of the BR regimen.(Robinson, et al 2008
, Rummel, et al 2005
) The role of MR will also be evaluated in this trial. In a separate intergroup trial, younger patients will be randomized to receive either BR or conventional R-hyperCVAD, with all patients receiving ASCT as part of an intensive therapy strategy. These intergroup efforts represent a genuine opportunity to move the MCL field forward by establishing standard regimens upon which novel agents can be systematically evaluated.