Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia

Abstract

Background: Lenalidomide (Len) has been proven effective both as monotherapy and in combination with rituximab for the treatment of chronic lymphocytic leukemia (CLL). Len has shown a distinct and more difficult to manage toxicity profile in the context of CLL, potentially hampering combination treatment with this drug. Methods: In 1st-line CLL elderly and fludarabine, cyclophosphamide, rituximab (FCR) unfit patients, we conducted a phase 1-2 study to evaluate efficacy and safety of 6 cycles of chlorambucil (7mg/m2 on days 1-7), rituximab (375mg/m2 cycle 1 and 500mg/m2 cycle 2-6) and individual dosed Len (started on day 9 of cycle 1 2.5 mg, cycle 2 5 mg and cycle 3 and up 10 mg or maximum tolerated dose (MTD)) (induction-I). This was followed by 6 months of Len monotherapy at the MTD (induction-II). The primary endpoint was the overall response rate (ORR) after induction-I. Results: Of 53 evaluable patients in phase 2, 47 patients (89%) completed induction-I and 36 patients (68%) completed induction-II. In an intention-to-treat analysis, the ORR was 83%. The median progression free survival (PFS) was 49 months, after a median follow-up time of 27 months. The 2- and 3-year PFS rate was 58% (standard error [SE]=8%) and 54% (SE=8%), respectively. The corresponding rate for OS was 98% (SE=2%) and 95% (SE=3%). No tumor lysis syndrome was observed, while tumor flair reaction occurred in 5 patients (9%, 1 grade 3). Most common hematologic toxicity was grade 3-4 neutropenia in 73%. Conclusions: Addition of Len to a backbone of chlorambucil and rituximab followed by a fixed duration of Len monotherapy in 1st line elderly and FCR-unfit patients results in high remission rates and PFS rates, that seem comparable to those observed with novel combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although Len-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile.