Sustained Remission with the Combination Biologic Doublet of Lenalidomide Plus Rituximab As Initial Treatment for Mantle Cell Lymphoma: A Multi-Center Phase II Study Report

BACKGROUND: Initial treatment for mantle cell lymphoma (MCL) is not standardized. Current conventional upfront chemoimmunotherapies are generally not curative. Lenalidomide, an immunomodulatory compound which targets both the tumor cells directly and the tumor microenvironment, has shown clinical efficacy either alone or in combination with rituximab in relapsed MCL. We report the mature findings of the first study of a chemotherapy-free approach as initial treatment for MCL, using lenalidomide and rituximab as a combination biologic doublet.

METHODS: The study protocol includes both an induction phase and a maintenance phase. During the induction phase, lenalidomide is administered at 20 mg daily on days 1-21 of a 28-day cycle for a total of 12 cycles, with dose escalation to 25 mg daily if tolerated. Standard dose rituximab is administered weekly x 4 during cycle 1, then once every other cycle, for a total of 9 doses. During the maintenance phase which starts with cycle 13, lenalidomide is administered at 15 mg daily on days 1-21 of a 28-day cycle, with rituximab maintenance once every other cycle until progression of disease. The primary objective was to evaluate overall response rate (ORR). Secondary objectives included safety analysis, progression-free survival, overall survival, and QOL assessment.

RESULTS: From 7/2011 to 4/2014, 38 subjects with previously untreated MCL were enrolled at 4 centers, and the study met its accrual. At study entry, median age was 65 years (range 42-86), and the M:F ratio was 2.5:1. All patients had stage III/IV disease, 14 (37%) had elevated LDH, and 34 (89%) had bone marrow involvement. MIPI scores were evenly distributed between low-, intermediate-, and high-risk (34%, 34%, and 32% respectively). Ki67 index was <30% in 26 (68%) subjects. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (47% in total, 42% with induction, 24% with maintenance), thrombocytopenia (13%) and anemia (8%). Grade 3-4 non-hematologic toxicities including rash (26%), tumor flare (11%), serum sickness associated with rituximab (8%) and fatigue (8%), were reported during induction phase only. Grade 1-2 infections including URI (34%), UTI (16%), sinusitis (11%) and bronchitis (8%) were reported during both induction and maintenance. One patient developed grade 3 cholangitis from cholecystitis requiring cholecystectomy. Secondary malignancy was reported in an 86 yo patient who developed melanoma in-situ and Merkel cell carcinoma following 18 month of therapy. As of July 2014 at a median follow-up of 24 months (range 3-35 months), 37 patients are alive, and 36 patients are evaluable for efficacy with at least one response assessment. Two patients were inevaluable – one withdrew consent, and one was intolerant of tumor flare. The ORR for all patients is 84.2% (95% CI = 68.7% to 94%) with 52.6% CR (95% CI = 35.8% to 69%). Median time to objective response was 2.8 months, with median time to CR achieved at 11 months. Thirty (79%) patients remain on study without evidence of disease progression, including 24 who have completed induction and are now in maintenance. During induction, 29% of patients tolerated dose escalation of lenalidomide to 25 mg from 20 mg, while 39% required dose reduction to 15 mg or less. Six evaluable patients had disease progression – 3 with primary refractory disease, 3 progressed following initial responses (1 CR with PFS of 18 months, 2 PRs with PFS at 14 and 25 months, respectively). Median progression-free survival and duration of response have not been reached. The 2-yr PFS rate is estimated at 83.9% (95% CI = 65.2% to 93.1%). Neither MIPI score nor Ki67 index correlated with response. Quality of life parameters were maintained or improved during treatment by FACT-Lym analysis.

CONCLUSIONS: This study provides the first demonstration that a chemotherapy-free, combination biologic approach is feasible and active as initial therapy for mantle cell lymphoma. A high proportion of MCL patients can achieve durable remissions while maintaining quality of life with the frontline therapy of lenalidomide up to 25 mg daily given 21 out of 28 days combined with rituximab. These data justify further evaluation of the lenalidomide + rituximab regimen both alone and as a platform for the integration of novel agents in combination approaches in MCL, particularly in the upfront setting. (ClinicalTrials.gov - NCT01472562.)