Safety Overview of the CLLM1 Trial: Lenalidomide Maintenance Therapy After Frontline Chemoimmunotherapy in High-Risk CLL
Patients with CLL and the persistence of MRD after frontline chemoimmunotherapy or an unfavorable genetic profile have a high risk of early relapse and inferior OS (Fink AM, et al. Leukemia. 2013;27:1949-1952). The phase 3, randomized, double-blind, placebo-controlled CLLM1 study was designed to investigate the efficacy and safety of lenalidomide maintenance therapy for high-risk CLL after first-line chemoimmunotherapy, where high risk was defined by the presence of MRD at levels ?10–2, or the combination of MRD levels ?10–4 to <10–2 with an unmutated IGVH status, or del17p or TP53 mutation. At ASH 2014, Eichhorst and colleagues reported on the preliminary safety results from the trial (Blood. 2014;124. Abstract 4699).
To date, 45 high-risk patients were randomly assigned to receive either placebo or lenalidomide 5 mg orally daily for the first 28-day cycle, 10 mg orally daily for cycles 2 to 6, and the target dose of 15 mg for cycles 7 to 12. Further escalations up to 25 mg were allowed in MRD-positive patients if the study drug was well-tolerated. First-line therapy according to the investigator’s choice included the combination of fludarabine, cyclophosphamide, and rituximab in 17 (38%) patients, bendamustine plus rituximab in 27 (60%) patients, and fludarabine plus cyclophosphamide in 1 (2%) patient.
At the time of analysis, 195 treatment cycles were documented with a median 6.5 of administered cycles. In total, 115 (59%) of 195 treatment cycles were administered without the occurrence of any AE. In 80 (41%) treatment cycles, at least 1 AE was documented, with 133 AEs of all severity grades (1-4) occurring in 19 (73%) of 26 patients. A total of 11 (42%) patients experienced at least 1 grade 3/4 AE. The most common AEs were related to hematologic parameters and infections (all grade 1/2); gastrointestinal (all grade 1/2); respiratory, thoracic, or mediastinal (all grade 1/2); and skin disorders (grade 3). AEs led to the discontinuation of the study treatment in 3 patients. A total of 13 (29%) of the 45 patients treated in both arms have discontinued the study caused by withdrawal of consent (N = 5), disease progression (N = 4), toxicity (N = 3), and technical reasons (N = 1).
To date, no treatment-related death has been reported in either treatment arm. In all, 7 serious AEs have been reported so far, 3 of which have been related to treatment (septic arthritis, autoimmune hemolytic anemia, and cholecystitis).
These results show that maintenance therapy with lenalidomide or with a placebo appears to be safe, with the majority of the AEs reported during maintenance therapy being associated with mild or moderate grade 1/2 events. Severe AEs (grade 3/4) were observed solely with skin reactions and cytopenia. The subsequent analysis of this study will outline the impact of lenalidomide maintenance on relapse-free survival in patients with high-risk CLL.