MCL represents 6% of all adult NHL, has an aggressive clinical course, and is incurable with standard treatment regimens. CALGB 59909 was designed to be feasible, intense, and brief for untreated patients with MCL, incorporating HDCT and ASCT with rituximab immunotherapy. CALGB 59909 was successful because the 2-year PFS was greater than 50% (observed, 76%), and the probability of an event by day +100 of ASCT was under 20% (observed, 5.1%). The final 58 patients receiving lower-dose methotrexate had a 2-year PFS of 73%, reconfirming the success of this treatment regimen. There is no clear plateau in the PFS curve, so it remains to be seen if any patients are cured with this treatment. The only proven potential cure for MCL at this time remains allogeneic hematopoietic stem-cell transplantation.36
CALGB 59909 produced a high PFS rate. Although relapses continued to occur between 2 and 5 years following treatment, late relapses appeared to be less frequent than those seen with most other treatment approaches, but further follow-up will be necessary to determine the long-term impact of this treatment. The reason for a high PFS is likely a combination of intensified induction chemotherapy, in vivo purging of the autologous PBSC grafts, the use of HDCT and ASCT, and the incorporation of rituximab. Our outcomes are similar to those produced by the M. D. Anderson Cancer Center for MCL with rituximab added to the Hyper-CVAD regimen (R-Hyper-CVAD), which did not incorporate ASCT.13,37
Of note, a Southwest Oncology Group study of R-Hyper-CVAD in MCL patients showed a CR rate of 58%, a 2-year PFS of 64%, and a continuous pattern of relapse, results inferior to those of the M. D. Anderson Cancer Center study.38
Another trial that used R-Hyper-CVAD (without methotrexate/cytarabine) followed by rituximab maintenance produced a 2-year PFS of 60%.39
Thus, the optimal overall treatment strategy for MCL remains undefined.
HDCT and ASCT are important components of curing patients with aggressive NHL after relapse.40
ASCT may be important in the management of patients with MCL as well. Phase II trials involving ASCT for newly diagnosed MCL patients have shown 3-year PFS or EFS rates of 54% or greater, which appear better than most MCL programs not using ASCT.16–20,22,41,42
These data are biased by selecting patients who are candidates for HDCT and ASCT. The Nordic MCL protocol had a treatment design similar to ours.43
With the Nordic MCL protocol, the 4-year PFS and OS were 73% and 81%, respectively, with an apparent plateau to the survival curve beyond 5 years. This study, short of allogeneic stem-cell transplantation, is the only one to demonstrate a plateau in the survival curve, and it led the authors to speculate about cure. However, preemptive rituximab was given for molecular evidence of MCL relapse, not scored as a progression, thus dampening conclusions of curability from the study. Another study prospectively randomly assigned first-remission MCL patients to ASCT or to alpha-interferon.20,21
ASCT resulted in a better median PFS (39 v
17 months), and after a median 6 years of follow-up, improved median OS (7.5 v
5.3 years), but there was no plateau to the OS curve, suggesting a limited benefit from ASCT.21
Our regimen demonstrates results consistent with these other phase II-III trials involving ASCT and supports the use of ASCT in the initial treatment plan of patients under age 70 years with MCL.
The contribution of purging MCL cells from the PBSC graft to improving outcomes in MCL is not certain. At the time of CALGB 59909 design, there were data showing success in purging contaminating NHL cells from autologous PBSC grafts by the in vivo administration of rituximab with chemotherapy in individuals with informative reverse transcriptase polymerase chain reaction for the rearranged bcl-1/IgH
We therefore adopted the emerging concept of in vivo purging and using EAR for MCL.23
We are analyzing the effectiveness of in vivo purging with EAR, and preliminary information suggests that in vivo purging is effective and that the degree of in vivo purging is predictive of relapse.44
Rituximab has shown substantial benefit in patients with low-grade and aggressive NHL.9,10
Rituximab has a modest response rate in patients with relapsed MCL as a single agent.11,12
The contribution of rituximab to our favorable outcomes in untreated MCL cannot be dissected. The German Lymphoma Study Group found that the addition of rituximab to CHOP in untreated MCL improved the CR rate but did not improve either the PFS or the OS.7
Perhaps adding rituximab to HDCT/ASCT is the key to improving outcomes in MCL. It can be argued that more rituximab is needed in treatment regimens like ours, not less, as the Nordic trial suggests. The magnitude of the contribution of rituximab to survival outcomes in CALGB 59909 remains unknown, and the optimal number of rituximab doses is open for debate.
CALGB 59909 is currently one of several effective treatment strategies for MCL. Despite its intensity, it was associated with acceptable morbidity and low NRM. But how do we make further advancement? Bortezomib has activity as a single agent in MCL.45
CALGB 50403 is designed to add maintenance bortezomib for patients with MCL otherwise receiving the backbone treatment of CALGB 59909. The addition of post-ASCT bortezomib might improve survival outcomes compared with those in CALGB 59909, with or without the expectation of cure. With new approaches and novel agents, progress in the management of MCL is being made.