R²: Preliminary Results of a Phase II Study of Lenalidomide and Rituximab in Relapsed / Refractory Indolent Non-Hodgkin's Lymphoma (NHL).

Lenalidomide (Revlimid^®) is a potent immunomodulatory agent that has recently demonstrated clinical activity in the treatment of relapsed/refractory Multiple Myeloma and low- and int-1 risk Myelodysplastic syndromes with the del (5q) mutation. Laboratory data has shown that lenalidomide enhances T- and NK-cell mediated immune synapse formation and ADCC, and it exerts antiproliferative activity. In relapsed/refractory (R/R) NHL lenalidomide treatment achieved modest responses, although duration of response was >16.5 months (Witzig et al JCO, in press). Synergistic activity between lenalidomide and rituximab has been reported in lymphoma cell and animal models. Here we assess safety and efficacy of the lenalidomide and rituximab combination (R²) in patients with R/R indolent NHL.

Eligible patients had relapsed/refractory indolent NHL with measurable disease, ≥1 prior therapy, and ECOG PS 0-2. Oral lenalidomide was administered once daily on days 1-21 of a 28-day cycle, and was continued until disease progression. Rituximab 375mg/m² IV was initiated on day 15 of cycle 1, and repeated weekly for a total of 4 doses; if after cycle 2 patient had less than a complete response (CR), 4 additional doses could be administered at discretion of the treating physician. After Gr. 3 tumor lysis syndrome (TLS) developed in 2 of the first 4 patients, the protocol was amended to reduce lenalidomide starting dose from 25 mg to 20mg daily, and TLS prophylaxis was provided with allopurinol in subsequently enrolled patients. Response and progression were evaluated according to IWG criteria (Cheson et al 1999).

Of 15 patients currently enrolled on study, 14 received >2 cycles of R², and 12 are evaluable for response. Median age for evaluable patients is 60 yrs (range: 50-91), 5 pts are female, and histologies include FL (n=9), SLL (n=1), and marginal zone lymphoma (n=2). Median time from diagnosis to treatment on study was 7.5 years (3.3-19), median number of prior therapies was 4 (range:1-11), and 9 patients were considered heavily pretreated (defined as ≥ 3 prior courses of therapy). All patients received prior rituximab, 6 patients had rituximab-resistant disease (defined as no response or relapse ' 6 months after initiating rituximab), and 5 patients had received prior radioimmunotherapy. Of 12 evaluable patients, 10 (83.3%) responded to R², including 5 patients (41%) with a CR and 4 patients (33%) with a PR. Responses occurred in 4 of 6 patients (66%) with rituximab refractory disease, and in 7 of 9 (77%) heavily pretreated patients. Of 9 patients with R/R FL, 5 (55%) achieved a CR and 3 (33%) had a PR in response to R², for an 88% ORR. At a median follow-up of 12 months, the median progression free survival has not been reached. Most common grade 3/4 adverse events were fatigue (2/12, 16%), neutropenia (3/12, 25%), lymphopenia (4/12, 33%), and hyponatremia (2/12, 16%). After prophylaxis was initiated, TLS was not observed at the 20 mg dose level.

This is the first study to demonstrate that the R² combination is generally well tolerated and active in patients with R/R indolent NHL. Clinical activity was particularly noted among patients with R/R FL, who achieved 88% OR and 55% CR rate. The tolerability profile of R² was consistent with other studies of each agent individually in the R/R setting. TLS prophylaxis and monitoring is recommended, particularly during initial cycles of treatment. These data support further evaluation of the potential clinical synergy between rituximab and lenalidomide in larger studies of FL and in earlier lines of therapy.

Off Label Use: Lenalidomide for treatment of non-hodgkin's lymphoma. Tuscano:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.