Advancing through maintenance in mantle cell lymphoma

On the surface, it would seem likely that patients with mantle cell lymphoma (MCL) could gain from some form of maintenance therapy. The vast majority of patients respond to induction therapy, but relapse is inevitable and occurs more quickly than in indolent lymphomas. Unlike some other lymphoma subtypes, relapsed MCL tends to acquire chemoresistance relatively quickly, accounting for the shorter survival in these patients. Although more aggressive induction and consolidation regimens can increase the depth of response and prolong remission duration, there is limited evidence that these fairly brief interventions prolong patient survival. A prerequisite for a maintenance therapy, generally speaking, would be significant effectiveness as a stand-alone treatment and tolerability that would allow extended administration. To date, phase 3 clinical trials evaluating rituximab maintenance in MCL have produced conflicting results, perhaps related to small numbers, heterogeneous populations, and different induction regimens [1,2].

In this issue of Leukemia and Lymphoma, Kenkre, Kahl, and colleagues report their experience with rituximab maintenance with 5 years of follow-up [3]. They treated 22 patients with a modified R-Hyper-CVAD regimen (rituximab, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; essentially an intensive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]-like regimen) followed by 2 years of maintenance rituximab, and found a median progression-free survival (PFS) of 38 months. They suggest that one explanation for the apparent improvement over R-CHOP, where the median PFS is typically around 18 months [4], may be the incorporation of maintenance therapy. The results are impressive, in part due to the remission duration, but also due to the fact that the patient population consisted largely of the older, high-risk patients not typically seen in trials with more aggressive regimens.

Geisler and colleagues from the Nordic Lymphoma Group used a slightly different approach in their MCL-2 trial [5]. Following an aggressive induction/consolidation regimen, patients were followed for evidence of molecular relapse. Patients with molecular, but not clinical, evidence of progression received four weekly doses of rituximab. Since this maneuver was not continually applied on a regular schedule, it was not strictly a ‘maintenance’ strategy but was more like a ‘targeted retreatment’ approach. However, some might argue that ‘maintenance’ rituximab applied broadly to all patients may have a similar effect at least on the subset of subjects who are experiencing a similar ‘molecular-only’ recurrence, albeit undetected in the absence of polymerase chain reaction (PCR) monitoring. Roughly 20% of all patients received rituximab retreatment for molecular relapse, achieving a median remission duration of 19 months, considerably longer than typical rituximab-induced remissions when administered for clinically recurrent disease in patients with MCL.

In follicular lymphoma, rituximab maintenance therapy following single-agent rituximab, chemotherapy, or immunochemotherapy can prolong progression-free survival [6–8]. Several questions, however, remain. What is the optimal schedule and duration of maintenance? What effect does rituximab maintenance (and rituximab resistance) have on subsequent treatments? Does maintenance rituximab affect quality of life or overall survival?

The cumulative evidence in MCL suggests that we are approaching a point where we will be able to make a similar conclusion: rituximab maintenance may prolong the progression-free survival in patients with MCL. This question will be answered more definitively by the European MCL Network study of maintenance rituximab vs. interferon in older patients with MCL treated with R-CHOP or R-FC (rituximab, fludarabine, and cyclophosphamide). The remaining questions, however, will likely remain far more complicated for MCL than follicular lymphoma. Although targeting maintenance therapy to those with molecular relapse appears attractive, technical limitations are likely to limit its utility. The optimal dose and schedule of maintenance may or may not be the same as for follicular lymphoma, and may be significantly affected by the nature of the induction regimen. As Kenkre and colleagues suggest, one possible explanation for the apparent benefit in their trial is that the majority of patients were in complete remission following R-Hyper-CVAD. Several studies have noted an inverse correlation between tumor bulk and response to rituximab—it is certainly feasible that a similar relationship exists in the case of maintenance therapy. The fact that roughly one-quarter of all patients progressed during rituximab maintenance therapy suggests that rituximab maintenance is insufficient as a sole strategy to prevent relapse, and additional drugs or different drugs may be more effective (but may not be as well tolerated as rituximab). A randomized phase 2 intergroup study is being planned to evaluate the addition of lenalidomide to rituximab maintenance following bendamustine-based induction with or without bortezomib. The primary outcome will be progression-free survival. The fact that it will take approximately 6 years to obtain results is disconcerting, but then again, the fact that overall survival just one decade ago was only half that is a reflection of the significant progress taking place in MCL management. Both hypothesis-generating small studies such as that reported by Kenkre and larger randomized confirmatory studies are important in moving things forward.

Potential conflict of interest:

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