Efficacy and Safety Of Treatments For Relapsed Or Refractory Mantle Cell Lymphoma (MCL): Results Of a Systematic Literature Review

MCL accounts for approximately 3%-10% of non-Hodgkin’s lymphoma (NHL) cases. The aggressive course of MCL includes rapid disease progression, with temporary responses to chemotherapy, and a high recurrence rate. However, the clinical course is variable with overall survival ranging from 6 months to more than 10 years. Although the median survival with MCL is 3-4 years, for those with relapsed or refractory disease, survival is much shorter. This systematic literature review (SLR) was designed to exhaustively collect and review information on the clinical efficacy and safety of the different interventions used in the treatment of refractory/relapsed MCL, and if possible to perform a meta-analysis.

Electronic databases (PubMed, Cochrane Library, Embase) were systematically searched for studies assessing the efficacy of safety of treatments for relapsed or refractory MCL published from 1997 to August 2, 2012. In addition, conference abstracts, bibliographic reference lists of included articles and recent reviews, and the Clinicaltrials.gov database were searched for phase 2, 3, or 4 studies displaying results, potentially unpublished in peer-reviewed journals. Main efficacy outcomes included objective response rate (ORR), complete response, partial response, duration of response, progression-free survival (PFS), and overall survival (OS). Safety endpoints focused on grade 3/4 toxicities and treatment withdrawals due to toxicity. Studies had to report on relapsed or refractory MCL after at least one standard treatment and patients who were not eligible to receive high-dose chemotherapy or stem cell transplant (autologous or allogeneic). Mixed type NHL studies were required to report MCL outcomes separately for inclusion.

A total of 3,308 publications were identified in the first pass of a broad SLR on NHL; of these, 67 provided relevant data for MCL representing 59 unique studies. Of the 59 studies, 6 were comparative (including 5 RCTs) and 53 were noncomparative single-arm studies; 35 evaluated single-agent regimens, and 24 evaluated combination therapies. A total of 40 different treatments were evaluated in the identified studies. Overall survival and PFS were infrequently reported. Criteria for relapsed or refractory were often not defined, with only 7 studies providing varied definitions.

The ORR of active treatments in the few comparative studies ranged from 6%-83%, with most estimates between 45% and 60%. Progression-free survival was approximately 5-7 months with the exception of bortezomib + CHOP in which a 16-month PFS was noted; median OS for these studies ranged from 11-16 months, with 36 months for the aforementioned exception. In the single-arm studies, ORR ranged from 12%-100%, with most estimates from 30%-60%. Progression-free survival was approximately 5-12 months, except for bendamustine alone or in combination (∼21 months) and bortezomib in combination (∼18 months, but with large variability). Overall survival ranged from 12-24 months, with two notable exceptions: bortezomib combination (∼38 months) and temsirolimus in combination with rituximab (∼30 months). Some increase in PFS and OS was observed over the study period. The main safety concerns were related to thrombocytopenia (11-66%), neutropenia (15-100%), anemia (4-34%), and neuropathy (9-13%). Although patients’ MIPI category was collected, outcomes were not reported by this variable.

The results of this SLR confirm that survival is still low among treatments for relapsed or refractory MCL making this a continued area of unmet need. The small number of randomized trials makes it difficult to identify a standard of care. The lack of common treatments among the randomized controlled trials for MCL and the variability in the populations studied did not allow for a valid meta-analysis. Small sample size, infrequent reporting of OS/PFS, limited information on prior treatments/responses, and patient characteristics also make comparison of results difficult. Comparative studies demonstrating relative survival advantages of various therapies in relapsed or refractory MCL are needed, as is more information on the relation between MIPI scores and outcomes. In the absence of such evidence, management of relapsed or refractory disease should be based on individual patient characteristics and concerns regarding tolerability.

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