Phase I/II Trial of Lenalidomide and Ofatumumab for the Treatment of Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL)

Introduction:

Outcomes for patients with NHL who are refractory to first line therapy as well as relapsed disease are poor. Lenalidomide, an immunomodulatory drug, stimulates T-cell proliferation, IL2, IL10 and IFN-gamma production. Ofatumumab, a monoclonal anti-CD20 antibody has shown to have activity as monotherapy in B-cell NHL. This phase I/II study evaluates the safety and clinical activity of the combination treatment of lenalidomide and ofatumumab for relapsed/refractory NHL.

Methods:

Patients with histologically confirmed diagnosis of CD20+ NHL, recurrent/ refractory to at least one prior therapy were eligible for the study. All the patients received 8 weekly infusions of ofatumumab 1000mg. Dose escalation of lenalidomide was done in three planned dose cohorts. Cohort 1 received 15mg per day, cohort 2 and 3 received 20mg and 25mg per day respectively on days 1-21 every 28 days. The study design involved a standard 3+3 approach. Dose reduction Cohort (-1) at 10mg/day was built into the protocol in the event of a dose limiting toxicity in cohort 1. Phase II evaluated lenalidomide at maximum tolerated dose (MTD) and ofatumumab in 36 patients. Flow analysis for total T-cells, sIL2r, IL12, VEGF, TNFa levels were checked at baseline, 6 months, 12 months on therapy and at the time of discontinuation of treatment.

Results:

The MTD for lenalidomide was 10mg. Six patients in phase 1 treated at the MTD and 34 patients enrolled on Phase II were eligible for evaluation. Data was analyzed for all patients treated at the MTD (n=40). Twelve (30%) patients had diffuse large B-cell lymphoma (DLBCL), 12 (30%) follicular lymphoma (FL), 6 (15%) mantle cell lymphoma (MCL), 6 (15%) chronic lymphocytic leukemia/small lymphocytic leukemia (CLL/SLL), 4(10%) other lymphomas. The median age was 64.5 years (35.5-80.7). Thirty one (78%) were male, 40 (100%) caucasians, 45% had stage IV disease. Number of lenalidomide cycles ranged from 1-63. In the phase I cohort, grade 3-4 adverse events included neutropenia (10%), thrombocytopenia (10%) and secondary malignancies (20%). Grade 3-4 adverse events on Phase II were neutropenia (42%), thrombocytopenia (8%), infusion reactions (8%) and secondary malignancies (17%). Overall response rate [stable disease (SD), partial response (PR) + complete response CR] was 67% (95% %CI:52%-80%) including 11 (92%) patients with FL, 5 (83%) MCL, 3 (25%) DLBCL and 4(66%) CLL/SLL. CR was noted in 3 patients which included DLBCL, FL and MCL. The durability of response in patients who achieved CR was 7.02 years (DLBCL), 2.89 years (FL) and 2.54 years (MCL). At 6 months, the mean change from baseline in sIL2r was 389.8 [SD=421 p=0.002], CD3+T = -0.43 [SD=0.77, p=0.04]. The median change in sIL2r and CD3+CD4+G was lower for patients with CR when compared to patients with PR or SD [sIL2r:-82.7 vs 543.5, p=0.02; CD3_CD4_G: -26.1 vs. -0.82, p=0.02]. Median progression free survival (PFS) was 6.8 months (2.3-12.1). Median overall survival (OS) was 19.8 months (7.4-42.8). Estimated 1 year PFS was 38% and 2 years was 20%. Estimated 1 year OS was 56%, 2-year survival was 49%.

Conclusion:

The combination of lenalidomide at 10 mg for 21/28 days and ofatumumab has manageable toxicities and produces some durable response in patients with relapsed/refractory indolent NHL including FL, MCL, and CLL/SLL.