1218 - Lenalidomide Consolidation Improves Progression Free Survival in Patients with Chronic Lymphocytic Leukemia Following Initial FCR Chemotherapy - Final Analysis of CLL6 Residuum Study of the Australian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO)

Introduction
Eradication of residual disease after first line chemoimmunotherapy correlates with longer progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients. Lenalidomide (LEN) has antiproliferative and immunomodulatory effects in CLL and may be effective in improving response status following chemotherapy (Buhler et al 2016; Fink et al 2017). Here we report the final analysis of the phase III, randomized, CLL6 RESIDUUM trial, aiming to determine whether lenalidomide is capable of extending remission duration in patients with CLL who have detectable residual disease following induction immunochemotherapy.

Methods
The CLL6 RESIDUUM trial was a joint trial of the Australasian Leukaemia and Lymphoma Group (ALLG) and the French Innovative Leukemia Organization (FILO). CLL patients with CIRS score < 6 requiring treatment according to iwCLL criteria received 4 to 6 cycles of fludarabine cyclophosphamide rituximab combination (FCR). Following completion of treatment, patients with clinical, radiological and/or multiparameter flow cytometry evidence of residual CLL in blood or bone marrow were randomized 1:1 to receive 2 years of maintenance treatment with LEN 10 mg daily or observation (OBS). LEN treatment started at 5 mg daily, escalating by 2.5mg every 2 months until a target of 10 mg daily. The primary endpoint of this study was the time to clinical disease progression, or death, from the date of randomization. It was planned to randomize 192 patients in order for the study to be powered to detect a hazard ratio of 1.94, i.e., an increase in the percentage of patients remaining free from progression at 4 years up to 70% in the LEN arm compared with 50% in the OBS arm (two-sided log rank test at alpha = 0.05, no competing risks or loss to follow up, power = 0.86).

Results
The study closed prematurely because of an acute lymphoblastic leukemia (ALL) warning (3 of 56 patients [5.4%]) in the CLLM1 trial (Fink et al., 2017; Fürstenau et al., 2021). Between May 2011 and January 2018, 143 patients were randomized (70 in Australia and 73 in France) to the LEN (n=71) or OBS (n=72) arms. Their median age was 63 [range 41-78], and 60 [26-79] years in the LEN and OBS arms respectively and 113 patients were males. At the time of evaluation, the median follow-up was 52.56 months (range 44.9-58.97; LEN 49.84 [41.88-57.07], OBS 55.49 [43.95-61.67]). Twenty-four (34%) patients progressed in the LEN arm versus 39 (54%) in the OBS arm (Chi² p=0.01) and 8 died in each arm. Median PFS was 64.56 (95%CI 47.67-not reached [NR]) months in the LEN arm versus 42.37 (32.28-61.64) months in the OBS arm (p=0.039). Multivariate analysis did not identify any predictive factor of relapse. Median overall survival was not reached in the LEN arm and 107.66 (107.55-NR) months in the OBS arm. There were 78 adverse events (AE), 51 in the LEN and 27 in the OBS arms respectively, the main differences being more neutropenia (n=9 vs. n=1), musculoskeletal (n=4 vs. n=1), nervous system (n=5 vs. n=1), respiratory (n=5 vs. n=0) and vascular (n=3 vs. n=1) disorders in the LEN arm. Severe adverse events (SAE) were reported in 35 patients (24.5%), 24 in the LEN arm and 11 in OBS. Sixteen secondary malignancies occurred: 9 in the LEN arm; 7 in the OBS arm. Four were of hematological origin (1 Richter transformation in each arm, 1 marginal zone lymphoma in the OBS arm and 1 myelodysplastic syndrome in the LEN arm). No case of ALL occurred.

Conclusion
Overall, the CLL6 RESIDUUM study demonstrates a significant benefit of consolidation therapy with low-dose lenalidomide in CLL patients with residual disease after FCR treatment compared to simple observation. The immunomodulatory effect of lenalidomide translated into a significantly longer PFS, the median of which was not reached at more than 5 years, with no unacceptable toxicity. Specifically, no case of ALL occurred in 69 patients with a minimum 4-year follow-up. This trial was designed and conducted when FCR was gold standard and considered patients who had completed this treatment. However, even with current targeted agents, eradicating minimal residual disease may remain challenging. Some patients could still benefit from such maintenance therapy, expected to control the disease through improved anti-tumoral immune responses in poorer responders.