Modified R-hyperCVAD with MR showed good response rates in 22 patients with previously untreated MCL, with an ORR of 77% and CRR of 64%. Now with median follow-up of 62 months, we report a median PFS of 38 months and median OS of 70 months. These results compare favorably to other trials which have explored non-intensive immunochemotherapy approaches, where the median PFS after R-CHOP chemotherapy was typically around 18 months [7
]. Our version of modified R-hyperCVAD was actually more CHOP-like than hyperCVAD-like, leading us to speculate that the majority of the PFS prolongation we observed was due to MR rather than something unique in our induction strategy.
The role of MR in MCL has been controversial. Unlike diffuse large B-cell lymphoma, where MR for 2 years does not appear to be beneficial after R-CHOP [21
], MR has been shown to prolong PFS in incurable lymphomas [22
]. As MCL is generally an incurable B-cell lymphoma, we hypothesized that MR would have a beneficial effect in MCL. Two small randomized clinical trials in MCL have generated conflicting results. The German Low Grade Lymphoma Study Group enrolled patients with relapsed follicular lymphoma (FL) and MCL, and after induction chemotherapy with either chemotherapy or R-chemotherapy, randomized patients to MR or observation for 9 months. A statistically significant improvement in response duration was seen in the 47 patients with MCL who received MR, with a higher proportion of those patients experiencing an ongoing remission beyond 2 years (45% vs. 9%, p
= 0.049) [25
]. The Swiss Group for Clinical Cancer Research (SAKK) 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 [26
]. 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 (DSMB) recently recommended early closure of a large randomized trial which demonstrated a significant benefit for patients receiving MR after R-CHOP chemotherapy (M. Dreyling, personal communication).
The 5-year OS of 62% in our cohort is comparable to the 5-year OS of 65% reported for the conventional R-hyperCVAD regimen and 64% reported in a Cancer and Leukemia Group B (CALGB) study utilizing alternative intensive treatment strategy [27
]. We note a comparable 5-year OS despite a shorter median PFS in our trial (38 months vs. ~60 months). This observation suggests that there is a reasonable ability to administer effective salvage therapy in relapsed MCL. Unlike the experience reported by M. D. Anderson, we see no difference in outcomes when we analyze our cohort by age (using 65 years of age as the cut-off; data not shown) [27
]. So while our younger patients did somewhat worse for PFS than the M. D. Anderson cohort, our older patients did somewhat better, validating the inclusion of our regimen as a reasonable standard for older patients in the National Comprehensive Cancer Network (NCCN) guidelines [29
Finally, we were able to validate the MIPI with our patient cohort, with a particularly significant difference seen in OS between the low and high MIPI risk groups (p = 0.009).
We report the long-term follow-up from this study for three reasons: (1) to draw attention to the potential benefit for MR in MCL, (2) to emphasize the excellent OS, which is comparable to that seen in some studies using intensive strategies, and (3) to validate the inclusion of this regimen in the NCCN guidelines as an option for older patients with MCL. The US intergroup is currently designing prospective trials focusing on older patients with MCL, so that an appropriate balance between efficacy and toxicity can be evaluated in this important group of patients.