One Size Does Not Fit All in Follicular Lymphoma

The treatment paradigm for follicular lymphoma (FL) has changed dramatically during the past decade. Despite many attempts to increase the overall survival (OS) for patients with FL, only since the introduction of rituximab has it shown improvement. This improvement has been largely through the use of combination chemoimmunotherapy. More recently, several studies have investigated the use of maintenance rituximab therapy for patients who have experienced response to various first-line chemoimmunotherapy regimens. Although no difference in OS has yet been observed, the addition of rituximab maintenance to induction therapy with single-agent rituximab, CVP (cyclophosphamide, vincristine, prednisone) with or without rituximab, and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) has resulted in improvements in progression-free survival (PFS). Given the long natural history of this disease, the relative similarity in survival of different treatment approaches, and the emerging evidence in support of maintenance strategies, two therapeutic questions emerge: how can we maximize efficacy while minimizing toxicity, and for whom do maintenance strategies deliver benefit? In the article that accompanies this editorial, Vitolo et al present the results of a randomized phase III study that addresses both of these questions. They investigate an abbreviated course of chemoimmunotherapy, namely R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone), for four cycles followed by four weekly courses of rituximab, followed by either rituximab maintenance or observation. All patients participating in this study were older than age 60 years (median age, 65-66 years), and had untreated disease. After induction therapy, the overall response rate (ORR) was 86%. Whereas 3-year PFS for all patients was 66%, 2-year PFS for patients receiving rituximab maintenance was 81% compared with 69% in the observation group; this difference in PFS between groups, however, was not statistically significant. This regimen was well tolerated, with neutropenia being the most common grade 3/4 toxicity, occurring approximately one quarter of the time. Grade 3/4 neutropenia was more common in the maintenance compared with the observation group. This study is one of the first to not show a PFS benefit of maintenance rituximab after induction chemotherapy in the first-line treatment of FL. The PRIMA (Primary Rituximab and Maintenance) study allowed for three different induction chemoimmunotherapy regimens (R-CHOP, R-CVP, and R-FCM [rituximab, fludarabine, cyclophosphamide, mitoxantrone]); although the number of patients who received R-FCM was small (45 compared with 272 for R-CVP and 885 for R-CHOP), this group was the only group that did not seem to benefit from maintenance rituximab. Vitolo et al offer a number of reasonable explanations for why they did not observe a significant improvement in PFS with the addition of maintenance rituximab: the use of an abbreviated maintenance schedule of only 8 months, a better-than-expected PFS for the observation group, and the relatively short follow-up of just 2 years. However, the lack of significant PFS benefit of this regimen speaks to the lack of universality of maintenance immunotherapy strategies after induction chemoimmunotherapy for this disease. The extrapolation of data regarding the efficacy of rituximab maintenance after regimens other than singleagent rituximab, CVP with or without rituximab, and R-CHOP, and outside of the front-line setting, as is becoming increasingly prevalent, is unfounded and may not only be without benefit, but also may carry increased risk of toxicity and cost. This concern is exemplified in the increasing use of maintenance rituximab after the recently resurrected drug bendamustine in combination with rituximab (BR) for the first-line treatment of FL. In a recently reported randomized study, BR was associated with a significant improvement in PFS compared with R-CHOP chemotherapy for the treatment of indolent B-cell non–Hodgkin’s lymphoma and mantle-cell lymphoma; specifically, the estimated 3-year PFS for BR versus R-CHOP in FL was 70% versus 50%. These results are similar to the 3-year PFS benefit seen with the addition of rituximab maintenance in the PRIMA study (74.9 v 57.6%; P .001). However, despite the absence of data to support a benefit of maintenance rituximab after BR, many physicians adopt this practice, assuming that it will yield results superior to those generated by BR alone. Unfortunately, the MAINTAIN trial of two different maintenance rituximab regimens after BR will not answer the principal question of whether maintenance rituximab after BR is better than observation or R-CHOP with rituximab maintenance. i This issue aside, the efficacy of BR in indolent lymphoma, and specifically FL, does raise the question of the relevance of the regimen of R-FND with rituximab consolidation presented by Vitolo et al. Although abbreviated and well tolerated in an older population of patients, the results are not dissimilar from those seen after BR (estimated 2-year PFS 75%). In this study, BR was similarly well tolerated, with an incidence of grade 3/4 neutropenia of 29%. Whereas only 35% to 40% of patients were older than age 60 years in the studies investigating R-CHOP and R-CVP, 65% of patients in the Rummel et al study were older than age 60 years, suggesting that BR is a highly efficacious and tolerable regimen even in older patients. Furthermore, although the effect of bendamustine on stem cell mobilization for autologous stem-cell transplantation remains to be fully elucidated, there are data that FND, and fludarabine specifically, does JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 27 SEPTEMBER 2