Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia

Abstract

Purpose Lenalidomide is an oral immunomodulatory drug with multiple effects on the immune system and tumor cell microenvironment leading to inhibition of malignant cell growth. Based on encouraging reports of lenalidomide in relapsed and refractory chronic lymphocytic leukemia (CLL), we investigated the first-line use of single-agent lenalidomide in CLL. Patients and Methods Using a starting dose of lenalidomide 10 mg/d for 21 days of a 28-day cycle and weekly 5-mg dose escalations to a target of 25 mg, we encountered severe toxicities (tumor lysis, fatal sepsis) in the first two patients enrolled. The study was halted and the protocol amended to a more conservative regimen: starting dose of lenalidomide 2.5 mg with monthly escalations to a target dose of 10 mg, and extended tumor lysis prophylaxis and monitoring. Gene expression profiles from patient samples before and after 7 days of lenalidomide were performed. Results Twenty-five patients were enrolled on the amended protocol. No further tumor lysis events were reported. Tumor flare was common (88%) but mild. Grade 3 to 4 neutropenia occurred in 72% of patients, with only five episodes of febrile neutropenia. The overall response rate was 56% (no complete responses). Although rapid peripheral lymphocyte reductions were observed, rebound lymphocytoses during the week off-therapy were common. Lenalidomide-induced molecular changes enriched for cytoskeletal and immune-related genes were identified. Conclusion Lenalidomide is clinically active as first-line CLL therapy and is well-tolerated if a conservative approach with slow dose escalation is used. A lenalidomide-induced molecular signature provides insights into its immunomodulatory mechanisms of action in CLL.

Multiple inhibitory ligands induce impaired T-cell immunologic synapse function in chronic lymphocytic leukemia that can be blocked with lenalidomide: establishing a reversible immune evasion mechanism in human cancer

“…The immunomodulatory drug lenalidomide is clinically active in CLL and lymphoma 26,27 and repairs autologous T-cell synapse formation defects in CLL, acting on immune cells and cancer cells. 6 The results presented in Figure 4A reveal blocking the ability of tumor cells to induce T-cell tolerance as a novel activity of this drug.…”

Outcomes of first-line treatment for chronic lymphocytic leukemia with 17p deletion

“…Of note, none of the 10 patients with del(17p) included in the 2 first-line studies of the immune-modulating agent, lenalidomide, achieved CR. 28,33,34 Given the retrospective nature of our analysis and the fact that it is not a randomized evaluation of treatment regimens, it is difficult to draw firm conclusions about the most appropriate firstline therapy for these patients, although it did not appear that we could identify a regimen that seemed to stand out above the others. In our analysis, higher CR/nPR rate was associated with "low burden" del(17p) by FISH.…”

Current and Emerging Drug Therapies in Chronic Lymphocytic Leukemia

“…The 3-year PFS was 65% and OD was 85%. 55,56 Treatment with lenalidomide is associated with tumor flare in more than half of the patients and this is clinically seen as a sudden enlargement of lymph nodes accompanied by redness and tenderness. This change is benign and attributed to an "immune activation" response.…”