Combination Biologic Therapy Without Chemotherapy As Initial Treatment For Mantle Cell Lymphoma: Multi-Center Phase II Study Of Lenalidomide Plus Rituximab

Initial treatment for mantle cell lymphoma (MCL) is not standardized. Current conventional upfront chemoimmunotherapies are generally not curative and can be deferred in some patients. This presents an opportunity to evaluate novel therapeutic approaches in the first line setting. 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 findings of the first study of a chemotherapy-free approach as initial treatment for MCL, using lenalidomide and rituximab as a combination biologic doublet.

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. Based on a Simon two-stage design comparing an ORR of ≥60% with treatment to an unacceptable ORR of ≤40% (alpha=10%, power=80%), 15 or more overall responses out of 28 enrolled patients were required to declare the treatment effective and worthy of further testing.

From 7/2011 to 2/2013, 31 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 3:1. All patients had stage III/IV disease, 12 (39%) had elevated LDH, and 27 (87%) had bone marrow involvement. MIPI scores were evenly distributed between low-, intermediate-, and high-risk (36%, 32%, and 32% respectively). Ki67 index was <30% in 23 (74%) subjects. Treatment was generally well tolerated with expected side effects. Grade 3-4 hematologic toxicities included neutropenia (39%), thrombocytopenia (13%) and anemia (7%). Grade 3-4 non-hematologic toxicities included rash (23%), tumor flare (7%) and serum sickness associated with rituximab (7%). Grade 1-2 infections included URI (29%), UTI (10%), pneumonia (10%) and sinusitis (7%). One incidence each of DVT and PE were observed and resolved with treatment. As of July 2013 at a median follow-up of 12 months (range 5-23 months), 27 (87%) patients remain on study without evidence of disease progression, including 18 who have completed induction and now in the maintenance phase. Four patients went off study – one withdrew consent, two had progression of disease, and one could not tolerate tumor flare associated side effects. Thirty patients are evaluable for efficacy with at least one response assessment. The preliminary ORR for evaluable patients is 77% (95% CI = 57% to 89%) with 40% CR/CRu (95% CI = 23% to 59%), and may further improve with additional follow-up on continued treatment. Median time to objective response was 2.8 months, with CR typically confirmed between 6-12 months. Four patients (13%) have stable disease with ongoing clinical benefit at 5+, 6+, 12+ and 13+ months. Median progression-free survival and duration of response have not been reached. Neither MIPI score nor Ki67 index correlated with response. All patients have maintained or improved quality of life parameters during treatment by FACT-Lym analysis.

This study provides the first demonstration that a chemotherapy-free, combination biologic approach is feasible as initial therapy for mantle cell lymphoma. Lenalidomide up to 25 mg daily given 21 out of 28 days can be safely combined with rituximab as frontline therapy for MCL. Preliminary efficacy data on response rates are encouraging. More precise assessment of response rate and durability will require more follow-up with additional subjects. However, 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 both in the upfront and relapsed settings.

Ruan:Celgene: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Lenalidomide in the frontline treatment of mantle cell lymphoma. Martin:Seattle Genetics: Consultancy, Speakers Bureau; Millennium: Research Funding; Genentech: Speakers Bureau; Celgene: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Shah:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Schuster:Celgene: Research Funding. Smith:Micromet: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Allos: Consultancy; Genentech: Consultancy; Onyx: Consultancy. Furman:Celgene: Research Funding. Coleman:Celgene: Consultancy. Leonard:Celgene: Consultancy; Genentech: Consultancy.