The Combination of Lenalidomide and Rituximab Induces Complete and Partial Responses In Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.

Lenalidomide is an immunomodulatory drug with single-agent activity in untreated and relapsed patients (pts) with chronic lymphocytic leukemia (CLL). Lenalidomide may potentiate the activity of rituximab through enhancement of NK and cytotoxic T-cell activity and antibody-dependent cytotoxicity. As lenalidomide is active as single-agent in relapsed/refractory CLL, we designed a trial to evaluate the combination of lenalidomide and rituximab in pts with previously treated CLL. Between 09/2008 and 10/2009, 59 pts with relapsed or treatment-refractory CLL were enrolled in this Phase II trial. Pts were eligible if they had relapsed disease requiring treatment and had received prior fludarabine-based therapy. Pts were required to have adequate performance status (WHO <3) and adequate renal and liver function (serum Cr or bilirubin <2mg/dl). Pts with an unrelated malignancy or with HIV, hepatitis B or C infection were excluded. Rituximab 375 mg/m² was given intravenously weekly × 4 from Day 1 in Cycle 1 then every 4 weeks during cycles 3 – 12. Oral lenalidomide 10 mg/day was started on Day 9 of cycle 1 on a continuous dosing schedule. Cycles were 28 days with intention to continue therapy for 12 cycles or longer if the patient experienced a clinical response. Dose reductions were made following grade 3 or 4 lenalidomide-related toxicity. Allopurinol 300mg daily was prescribed during the first 2 weeks as tumor lysis prophylaxis. Response evaluation was performed with after cycles 3, 6 and every 6 cycles thereafter using 2008 IWCLL response assessment guidelines. Toxicity was graded according to CTC-v3.0 criteria. All 59 pts are evaluable for response and clinical outcome. Patient pre-treatment characteristics are shown in Table 1. All pts had prior rituximab therapy and 52 (88%) pts had prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). The overall response rate was 64% with 5 complete responses (CR, 8%), 3 CR with incomplete hematological recovery (CRi, 5%), 7 nodular partial remissions (nPR, 12%) and 23 PR (39%). Most response (32/38, 84%) occurred by 3 cycles of therapy, but the majority of CR/CRi (7 of 8, 88%) occurred after 6 cycles of therapy. At a median follow-up of 14 months, the estimated treatment failure rate was 42% and estimated overall survival (OS) was 90%. There was no significant difference in responses or TTF for pts with deletion 17p when compared to other FISH subgroups. Two deaths occurred while on study therapy, one due to ischemic stroke and one to infectious exacerbation of chronic obstructive pulmonary disease. Six deaths occurred after progression of disease during subsequent therapies. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 40 (68%), 13 (22%) and 6 (10%) pts, respectively. Grade 3/4 infections occurred in 18 pts (31%), mostly lower respiratory tract. Seventy-three % of pts required a dose reduction of lenalidomide with a median tolerated daily dose of 5mg (2.5mg – 10mg). One patient experienced a grade 3 tumor lysis syndrome and 22 pts had grade 1–2 tumor flare reactions. In conclusion, combination therapy with lenalidomide and rituximab induces both complete and partial responses as salvage therapy in CLL. The addition of rituximab to lenalidomide appears to improve responses relative to single agent lenalidomide (Ferrajoli 2008, Chanan-Khan 2006) despite all pts having received prior rituximab-based therapies. This treatment was well tolerated with the most common toxicity being myelosuppression.

Ferrajoli:Celgene: Research Funding; Genentech: Research Funding. Off Label Use: The use of lenalidomide in the treatment of chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy.