TP53 Mutation or Deletion and Efficacy with Single-Agent Lenalidomide in Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Abstract Introduction Relapsed and refractory (rel/ref) CLL patients have a poor prognosis and limited therapeutic options. The oral immunomodulatory agent lenalidomide has shown single-agent activity in untreated and rel/ref CLL patients, including patients with TP53 deleted/mutated CLL, which is associated with poor outcomes in response to chemotherapy. Lenalidomide targets the microenvironment to restore functional immunity to drive the elimination of leukemic cells. Here we report the efficacy of lenalidomide monotherapy in high-risk rel/ref CLL patients. Methods This phase 2, multicenter, double-blind, parallel-group, adaptive-design study evaluated the safety and efficacy of lenalidomide in rel/ref CLL. Patients had active disease per iwCLL guidelines and received ≥1 prior line of therapy, including purine-analogs or bendamustine. Patients were randomized 1:1:1 to receive oral lenalidomide at a starting dose of 5, 10, or 15 mg daily at their initial 28-day cycle, followed by intra-patient dose escalation in 5-mg increments every 28 days, up to 25 mg/day as tolerated. Samples to determine genetic status were collected at entry and analyzed centrally at Ulm University. Results A total of 104 patients were enrolled; 103 patients were dosed and median age was 64.0 (32-81). Del(17p) and TP53 mutation were found in 23/93 (25%) and 36/96 (38%) patients, respectively; 20 patients with TP53 mutation did not have del(17p). Del(17p) patients were more likely to have TP53 mutation (77% vs. 26%), age >65 years (64% vs. 43%), high risk/Binet C (64% vs. 33%), and platelet count <150,000/mm3 (77% vs. 50%); del(17p) patients were less likely to have del(11q) (14% vs. 36%). TP53 mutation was significantly associated with del(17p) (47% vs. 8%), age >65 years (67% vs. 38%), high risk/Binet C (53% vs. 33%), and platelet count <150,000/mm3(75% vs. 45%). The median number of treatment cycles was 6.6 vs. 11.1 for patients with and without del(17p), and 8.7 vs. 10.2 for patients with and without TP53 mutations. At a median follow-up of 47.6 weeks, the overall response rate (ORR) was 44% for all patients. There was a trend toward significance for ORR in patients with vs. without del(17p) (22% vs. 46%; p = 0.051). The ORR was 36% vs. 42% for patients with and without TP53 mutation (p = 0.669). A multivariate analysis for overall response in all evaluable patients was completed on the baseline characteristics of del(11q), del(17p), TP53 mutation, unmutated IGHV, high-risk disease (Binet C or Rai high-risk), B2M (≤4 vs. >4 mg/dL), age (<65 vs. ≥65 years), number of prior treatments (<3 vs. ≥3), bulky disease, and refractory to purine-analogues in a previous regimen. None of the baseline characteristics showed statistically significant impact on response. Median progression-free survival (PFS) was 45.1 weeks (95% CI 24.1-89.3) in all patients, 21.4 weeks (95% CI 12.4-117.6) in patients with del(17p), and 66.3 weeks (95% CI 31.4-98.4) in patients without del(17p) (p = 0.157). Median PFS in patients with and without TP53 mutation was 47.6 weeks (95% CI 20.6-117.6) vs. 41.1 weeks (95% CI 21.4-85.1) (p = 0.584). Median overall survival (OS) was 151.6 weeks (95% CI 90.3-not reached [NR])in the overall population, 80.9 weeks (95% CI 66.6-NR) in patients with del(17p), and 151.6 weeks (95% CI 90.7-NR) in patients without del(17p) (p = 0.464). Median OS in patients with and without TP53 mutation was 90.3 weeks (95% CI 68.1-NR) vs. 151.6 (95% CI 92.1-NR) (p = 0. 274). A multivariate analysis for PFS and OS was performed, including number of prior treatments. Median PFS was 89.3 weeks (95% CI 31.4-117.6) for patients with <3 prior therapies, and 31.9 weeks (95% CI 20.6-77.6) for patients with ≥3 prior therapies (p = 0.116). OS was NR for patients with <3 prior therapies, and 92.1 weeks (95% CI 68.1-151.6) for patients with ≥3 prior therapies (p = 0.012). No other variable showed statistically significant impact on PFS or OS. Conclusion Single-agent lenalidomide treatment led to similar responses, PFS, and OS in rel/ref CLL patients with or without TP53 mutations, indicating that lenalidomide activity in rel/ref CLL patients is not affected by loss of functional TP53. Despite differences in baseline characteristics (more high-risk features in the TP53-mutated subgroup), outcomes with lenalidomide treatment were comparable, and the ORR of 44% is a promising result for this heavily pretreated rel/ref CLL population with poor prognosis. Disclosures: Wendtner: Celgene: Consultancy, Honoraria, Research Funding. Hallek:Celgene: Consultancy, Honoraria, Research Funding. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hillmen:Celgene: Honoraria. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Mei:Celgene: Employment, Equity Ownership. Stilgenbauer:Celgene: Honoraria, Research Funding.

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