Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study

The optimal management of patients (pts) with untreated, advanced stage indolent non-Hodgkins lymphoma (NHL) is evolving. Although several traditional chemo-immunotherapy regimens achieve high overall response (OR) rates, toxicity is common and nearly all patients relapse. Lenalidomide has single-agent activity in relapsed indolent NHL, and rituximab is effective alone and in combination with chemotherapy in untreated pts. Preclinical studies suggest that lenalidomide may augment immune effector cell function and ADCC in the presence of rituximab. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, advanced stage, indolent NHL.

Pts with advanced stage untreated indolent NHL and measurable disease (>1.5cm) were eligible for study entry. Pts received 20 mg/day of lenalidomide on days 1–21 and rituximab 375 mg/m² on day 1 of each 28 day cycle for 6 cycles. Patients with evidence of tumor response could continue up to 12 cycles. To reduce the incidence of tumor flare, pts with small lymphocytic lymphoma (SLL) started at 10mg, with monthly dose escalation. Pts were evaluable for response if they had at least 1 response assessment. Prophylactic growth factors were not used. Response was assessed every 3 cycles using the 1999 International Working Group Response Criteria.

The study enrolled 110 pts; all have completed treatment or are off-study, and 103 pts are evaluable for response. Histologies included: SLL n=30, follicular lymphoma (FL) n=50, and marginal zone lymphoma (MZL) n=30. The median age was 58 (34-84) years, and 53% were male. Of the 46 evaluable pts with FL,78% had a FLIPI score of ≥ 2, and 52% met GELF criteria for high tumor burden. The best response for the 103 evaluable pts is listed in Table 1.

Among the FL pts, responses were high regardless of FLIPI score, tumor bulk, or GELF criteria at study entry. At the completion of therapy nearly all FL pts demonstrated molecular response with the absence of detectable BCL-2 by PCR. Forty five evaluable pts with FL had a positive PET scan prior to therapy and 42 (93%) attained a complete metabolic response following treatment. At a median follow up of 22 months, the estimated 2 year progression free survival (PFS) is 83% for all pts and 89% in pts with FL.

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Among all pts, grade ≥3 neutropenia occurred in 40% (13% of total cycles) and thrombocytopenia occurred in 4% of pts. The most common grade ≥ 3 non-hematologic toxicities included rash (8 pts), muscle pain (7 pts), fatigue (3 pts), thrombosis (3 pts). Two episodes of neutropenic fever occurred. Six pts stopped treatment due to adverse events.

The combination of lenalidomide and rituximab is active and tolerable in pts with untreated indolent lymphoma. High complete response rates with durable remissions were observed in patients with follicular lymphoma. Randomized studies comparing this regimen versus traditional combination chemotherapy regimens are underway.

Fowler:Celgene: Research Funding; Roche: Research Funding. Off Label Use: lenalidomide. Neelapu:Celgene: Research Funding. McLaughlin:Celgene: Data Monitoring Committee for another study Other. Fanale:Celgene: Honoraria, Research Funding. Wang:Pharmacyclic: Research Funding. Lacerte:Celgene: Honoraria. Samaniego:Celgene: Research Funding.