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

Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m² daily), rituximab (375 mg/m² cycle 1 and 500 mg/m² cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.

Figure 1.

Schedule of phase 2 of the study. *or maximum tolerated dose

Figure 2.

Flowchart of number of patients through the study protocol and off protocol, with reasons. Chlor 7: chlorambucil 7 mg/m²; Chlor 10: chlorambucil 10 mg/m²; SLL: small lymphocytic leukemia.

Figure 3.

Lenalidomide dosing: cumulative dose of lenalidomide compared to optimal dose per treatment cycle during induction-I. Lena: Lenalidomide.

Figure 4.

Responses after induction-I and -II. PD: progressive disease; SD: stable disease; PR: partial response; CR: complete response.

Figure 5.

Survival outcomes after registration. (A) Progression-free survival and (B) overall survival, with the numbers of patients at risk at 1, 2 and 3 years.