Phase II Trial of Lenalidomide - Dexamethasone - Rituximab 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.

Eligible pts must have relapsed/refractory indolent B-cell or mantle cell lymphoma with measurable disease that has failed to respond to 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-resistant. In Part I (lenalidomide + dexamethasone), pts receive two 28-day treatment cycles of lenalidomide 10 mg every day and dexamethasone 8 mg once weekly. After assessment of response to Part I, all pts receive 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 continue during and subsequent to rituximab; stable and responding pts continue on lenalidomide + dexamethasone until disease progression or development of clinically unacceptable toxicity. Response assessment after Part II is performed three months after the first dose of rituximab.

To date, 22 pts have started therapy; diagnoses included: follicular (n = 17), mantle cell (n = 2), small lymphocytic (n = 2), and marginal zone (n = 1) lymphomas; median age was 59 years (range: 35 - 72); male: female ratio was 5:6; median number of prior therapies was 3 (range: 1 - 7); LDH was increased in 23%. For 21 pts with at least one follow-up visit, there were 2 deaths and 2 episodes of disease progression. One death due to myocarditis occurred during Part I treatment; one death due to lymphoma occurred in a patient removed from study due to grade 3 rash, which subsequently resolved. Both episodes of disease progression occurred in pts with follicular lymphoma, one of whom had been removed from study during Part 1 because of thrombocytopenia attributed to myelodysplasia. For all patients, at a median follow-up of 5.0 months (range: 0.3 - 12.3), progression-free survival (PFS) is 81% (95% CI: 51-94). For 10 pts with response assessments after Parts I and II, overall response rate (ORR) after Part I was 30% (3 CR; 6 SD; 1 PD) and ORR after Part II was 70% (5 CR; 2 PR; 2 SD; 1 PD). At a median follow-up of 7.8 months (range: 5.0 - 11.9), PFS is 89% (95% CI: 43-98) for these 10 pts. For pts who completed Parts I and II, grade 3 or 4 non-hematologic toxicities included hypokalemia (2/10 pts), hypophosphatemia (1/10 pts), and hypocalcemia (1/10 pts); grade 1 tumor flare occurred in one pt with follicular lymphoma.

Based on these preliminary data in rituximab-resistant patients with indolent B-cell or mantle cell lymphomas, the combination of continuous daily lenalidomide, low-dose weekly dexamethasone, and a single four week course of rituximab during cycle 3, achieves a high overall response rate with relatively durable responses. Additional follow-up and correlative studies will be presented.

Off Label Use: Lenalidomide is used in this trial for treatment of lymphoma.. Downs:Genentech: Honoraria; Celgene: Honoraria. Nasta:Genentech: Speakers Bureau. Schuster:Celgene: Consultancy, Research Funding.