Phase II Trial of Lenalidomide - Rituximab +/− Dexamethasone in Relapsed or Refractory Indolent B-Cell or Mantle Cell Lymphomas Resistant to Rituximab

Lenalidomide is an immunomodulatory drug with effects on the innate immune system that may enhance antibody-dependent cell mediated cytotoxicity as well as the development of specific anti-tumor immune responses. These immunologic effects may synergize with the action of rituximab. To test the efficacy of lenalidomide combined with rituximab, we are conducting a single center, open label phase II clinical trial in patients (pts) with indolent B-cell or mantle cell lymphomas previously resistant to rituximab. Patients and Methods: Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond or has progressed within six months of a standard course of rituximab monotherapy (375 mg/m² weekly for at least four weeks) or a prior rituximab-containing chemotherapy regimen. Thus, all pts enrolled are considered rituximab refractory. Patients were enrolled sequentially into two treatment cohorts. In Cohort 1, pts received two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly (Part I: lenalidomide + dexamethasone). After assessment of response to Part I, all pts received a single course of rituximab 375 mg/m², consisting of four weekly doses during cycle 3 (Part II: lenalidomide + dexamethasone + rituximab). Treatment with lenalidomide + dexamethasone continued during and subsequent to rituximab; stable and responding pts continued on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II was performed three months after the first dose of rituximab. In Cohort 2, dexamethasone was eliminated; otherwise, eligibility and treatment were the same. Results: As of August 9, 2011, 45 pts have started therapy (Cohort 1, n = 27; Cohort 2, n = 18); diagnoses include: follicular (n = 28), mantle cell (n = 11), small lymphocytic (n = 4), and marginal zone (n = 2) lymphomas; median age is 58 years (range: 35–85); male: female ratio is 31:14; median number of prior therapies is 3 (range: 1 – 7); LDH is increased in 18%. For Cohort 1, 24 pts completed Part II and are evaluable for response; 3 pts are not evaluable, 1 due to death (myocarditis) and 2 due to removal from study (1 thrombocytopenia attributed to myelodysplasia; 1 rash attributed to lenalidomide). For Cohort 2, 11 pts are evaluable for response assessment after Part II; 2 pts are not evaluable due to discontinuation of protocol therapy (1 rash attributed to lenalidomide; 1 with early symptomatic progression of lymphoma); 5 pts have not completed Part II. For 35 pts completing Parts I and II, at a median follow-up of 11.8 months, PFS is 73% (95%CI: 53 – 86%). Overall response rate (ORR) after Part I is 37% (6 CR; 7 PR); ORR after Part II is 60% (12 CR; 9 PR). Overall response rates after Part II do not differ between Cohort 1 (with dexamethasone) and Cohort 2 (without dexamethasone) [58% vs. 64%, respectively; p = 0.5]. There were fewer dose interruptions during Part I in Cohort 1 (15%) versus Cohort 2 (50%) [p = 0.02], reflecting reduced episodes of tumor flare and rash in Cohort 1. Conclusions: For rituximab-resistant pts with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide and a single four week course of rituximab, with or without low-dose weekly dexamethasone, achieves a high overall response rate with relatively durable responses. The addition of low-dose weekly dexamethasone may improve tolerance without decreasing the efficacy of the lenalidomide-rituximab combination.

No relevant conflicts of interest to declare.