Lenalidomide consolidation benefits patients with CLL receiving chemoimmunotherapy: results for CALGB 10404 (Alliance)

Abstract

Prior to novel targeted agents for chronic lymphocytic leukemia (CLL), the best chemoimmunotherapy regimen in patients with non-del(11q) disease was unclear. The role of lenalidomide was also not defined. This phase 2 study randomized 342 untreated patients with non-del(11q) CLL requiring therapy to fludarabine plus rituximab (FR; n = 123), FR plus lenalidomide consolidation (FR+L; n = 109), or FR plus cyclophosphamide (FCR; n = 110) and compared 2-year progression-free survival (PFS) rates of each to the historical control rate with FC (60%). Patients with del(11q) in at least 20% of pretreatment cells continued with FCR (n = 27) or were reassigned to FCR+L (n = 31) and excluded from the primary analysis. Among non-del(11q) patients, 2-year PFS rates were 64% (90% confidence interval [CI], 57-71; FR), 72% (90% CI, 65-79; FR+L), and 74% (90% CI, 66-80; FCR); FR+L and FCR had rates significantly greater than historical control. Median PFS was significantly shorter with FR compared with FR+L ( = .04) and FCR ( < .001): 43 (95% CI, 33-50), 61 (95% CI, 45-71), and 97 (95% CI, 61 to not reached) months, respectively. Median follow-up was 73 months and median overall survival (OS) was only reached with FCR (101 months; 95% CI, 96 to not reached). With FR+L, the risk of death decreased over time and was lower than with FR at later time points ( = .01), but not significantly different from FCR ( = .21). Future studies incorporating short courses of lenalidomide into other novel treatment regimens are justified.

Harnessing the Effects of BTKi on T Cells for Effective Immunotherapy against CLL

“…To limit toxicity, lenalidomide was evaluated as maintenance therapy after chemoimmunotherapy. Two randomized clinical trials (CLL M1 and CALGB10404) showed that lenalidomide maintenance reduced disease progression [83,84]. However, three unexpected cases of B-ALL in the lenalidomide maintenance arm resulted in the termination of the CLL M1 study [83].…”

Role of Non-Coding RNAs in the Development of Targeted Therapy and Immunotherapy Approaches for Chronic Lymphocytic Leukemia

“…In a clinical trial for patients with symptomatic CLL (NCT00602459), lenalidomide was combined with fludarabine and rituximab. Results showed that a lenalidomide consolidation after chemoimmunotherapy is tolerated and extends progression-free survival and overall survival [192]. Thus, clinical trials are ongoing to test the safety of lenalidomide as maintenance therapy for CLL patients after chemotherapy (NCT00774345), and its use as first-line treatment in combinations with bendamustine and rituximab (NCT01400685).…”

Intrinsic Resistance of Chronic Lymphocytic Leukemia Cells to NK Cell-Mediated Lysis Can Be Overcome In Vitro by Pharmacological Inhibition of Cdc42-Induced Actin Cytoskeleton Remodeling

“…Interestingly, it has been shown that immune escape of CLL can be achieved by various means, notably by those interfering with the formation or the function of the lytic IS (25)(26)(27)(28)(29). Lytic IS formation of CD8 + T cells and NK cells with CLL cells can be rescued in part by drug treatments, such as lenalidomide or blocking antibodies, or can even be bypassed by infusion of genetically modified cytotoxic lymphocytes which do not rely on MHC-mediated antigen presentation as they form a non-classical IS (30)(31)(32)(33)(34)(35)(36). Nevertheless, toxic side effects or acquired resistance against these new therapeutic options have been reported and result in disease progression (37,38).…”