Good Tolerance of Lenalidomide Maintenance Therapy in Patients with High Risk Profile Chronic Lymphocytic Leukemia (CLL) after Frontline Chemoimmunotherapy: Preliminary Safety Overview of the CLLM1 Trial of the German CLL Study Group (GCLLSG)

Introduction: CLL patients (pts) with persistence of minimal residual disease (MRD) after frontline chemoimmunotherapy or an unfavourable genetic profile have a high risk of early relapse and a short survival (Fink et al., Leukemia 2013). Therefore, the GCLLSG designed the CLLM1 trial, a phase 3, randomized, double-blinded, placebo-controlled study to investigate the efficacy and safety of lenalidomide maintenance therapy for high–risk (HR) CLL following first-line chemoimmunotherapy. HR is defined by the presence of MRD at levels of ≥10^-2 or the combination of MRD levels of ≥10^-4 to <10^-2 with an unmutated IGHV status, or del(17p) or TP53 mutations.

Methods and patients: Prior to randomization pts underwent central screening procedures including the assessment of all risk factors and eligibility in particular response to first-line therapy. MRD levels were centrally analyzed. Pts were randomly assigned to receive either placebo or lenalidomide 5 mg p.o. daily for the first 28-day cycle, 10 mg p.o. daily for cycle 2-6, and the target dose of 15 mg for cycle 7-12. Further escalations up to 25 mg were allowed in MRD-positive pts if the study drug was well tolerated. Pts were treated until progression. Between July 2012 and June 2014 535 pts were registered from 130 sites in five countries (Austria, Germany, Italy, Netherlands and Spain). 126 (23.6%) of the pts were excluded before proceeding to MRD-analysis after first-line therapy due to misdiagnosis of other B-cell lymphoma (N=18), withdrawal of consent (N=44), comorbidities (N=5), hepatitis B infections (N=2) or other reasons (N=57). A total of 239 pts completed the screening. 186 (77.8%) achieved MRD negativity and were therefore ineligible for the study, and 8 (3.3%) pts are awaiting randomization. Pts remained blinded for this analysis.

Results: To date, 45 HR pts were randomized. First-line therapy according to investigator’s choice included FCR in 17 (37.8%), BR in 27 (60.0%) and FC in 1 (2.2%) of 45 pts. Before first-line therapy, 9 of 45 (20.0%) pts had Binet A, 19 (43.2%) Binet B and 16 (36.4%) Binet C stage of disease, respectively. The median age was 66 years (range 44-80), median CIRS score was 2 (range 0-6). 33 of 45 pts (73.3%) showed MRD levels between ≥10^-4 to <10^-2 combined with by high risk genetics, and 12 (26.7%) showed MRD levels ≥10^-2. 43 (95.1%) pts had unmutated IGVH genes. Del(17p) was detected in 4 (8.9%) and TP53 mutation in 6 (13.3%) pts, while 2 (4.4%) pts carried both abnormalities.

At the time point of analysis 195 treatment cycles [60.2% of 324 expected cycles] were documented in 26 of 45 (57.8%) randomized pts. The median number of administered cycles was 6.5 (range 1-20). 115 of 195 treatment cycles (59.0%) were administered without the occurrence of any adverse event (AE). In 80 treatment cycles (41.0%) at least one AE was documented. 133 adverse events (AEs) of all CTC grades (1 to 4) occurred in 19 of 26 pts (73.1%). Eleven pts (42.3%) experienced at least one AE of CTC grade 3 or 4. The most common AEs were related to haematological parameters [9 (34.6%) pts, 7 (26.9%) with CTC grade 3/4], infections [8 (30.7%), all CTC grade 1/2], gastrointestinal [9 (34.6%), all CTC grade 1/2], respiratory/thoracic/mediastinal [4 (15.4%), all CTC grade 1/2] and skin disorders [9 (34.6%), 2 (7.6%) with CTC grade 3]. AEs led to the discontinuation of study treatment in 3 pts (11.5%) including fatigue [N=1, CTC grade 3] and allergic dermatitis [N=2, both CTC grade 3]. In total 13 of 45 pts (28.9%) 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 both treatment arms. Seven SAEs have been reported so far, three of them related to treatment including septic arthritis due to staphylococcal infection, autoimmune haemolytic anemia and cholecystitis, the latter resulted in study discontinuation.

Conclusion: So far, maintenance therapy with lenalidomide or placebo appears to be a safe treatment option as the majority of adverse events reported during the maintenance therapy were mild or moderate (CTC grade 1/2). Severe adverse events (CTC grade 3/4) were observed solely with skin reactions and cytopenia. Reasons for discontinuation were mostly non-serious events including skin reactions and fatigue. Later analyses will clarify the impact of lenalidomide maintenance on relapse-free survival in high-risk CLL.