Results of the Phase 3 Study of Lenalidomide Versus Placebo As Maintenance Therapy Following Second-Line Treatment for Patients with Chronic Lymphocytic Leukemia (the CONTINUUM Trial)

Introduction: Despite recent advances in available treatments, chronic lymphocytic leukemia (CLL) remains an incurable disease, and the vast majority of patients (pts) will relapse and require additional lines of therapy. Thus, prolonging remission is a key treatment goal in CLL. This multicenter, randomized, double-blinded phase 3 trial (NCT00774345) was designed to evaluate the efficacy and safety of lenalidomide (LEN) vs placebo (PBO) as maintenance therapy in previously treated CLL pts.

Methods: Eligible CLL pts must have had at least a partial response (PR) to second-line therapy. Pts were randomized 1:1 to receive either LEN 2.5 mg once daily on days 1-28 of the first 28-day cycle, or matching PBO. If LEN was well tolerated, escalation to 5 mg/day was permitted from cycle 2, and further escalation to 10 mg/day at cycle 7 and thereafter. Pts were stratified by their response at the end of second-line therapy (PR, nodular PR, complete response [CR], or CR with incomplete bone marrow recovery; vs minimal residual disease [MRD]-negative CR by flow cytometry); age (≤ 70 vs > 70 years); and presence of at least one of the following poor prognostic factors: del(11q), del(17p), unmutated IGHV, or b2M > 0.4 mg/L (Yes vs No vs Unknown). Co-primary endpoints were progression-free survival (PFS; IRAC assessed) and overall survival (OS). Secondary endpoints included: safety, tumor response, duration of response, second PFS (PFS2, time from randomization to second disease progression or death), and health-related quality of life (HRQoL).

Results: Overall, 314 pts were enrolled (LEN, n = 160; PBO, n = 154). Baseline characteristics were balanced between the treatment arms: median age was 63 years (range 37-82) and 63 years (range 37-84), 71.9% and 72.1% were male, 9.4% and 11.7% had MRD-negative CR to second-line treatment, and 47.5% and 47.4% had at least one poor prognostic factor, in the LEN and PBO arms, respectively.

On review of the primary analysis, 30 Sept 2015 data cutoff, the required number of progression events to complete the co-primary analysis had occurred, and the data monitoring committee recommended that the study be unblinded. Median follow-up time was 31.5 months, and the median PFS was significantly longer for LEN vs PBO: 33.9 vs 9.2 months, respectively (HR 0.40 [95% CI 0.29, 0.55]; P < 0.001).

At the time of the analysis there were 86 deaths and there was no significant difference in the OS (HR 0.96 [95% CI 0.63, 1.48]; P = 0.856). Subsequent CLL therapy was received by 35.7% of pts in the LEN arm and 58.4% of pts in the PBO arm, of these pts 16% in the LEN arm and 20% in the PBO arm were treated with a BTK or PI3K inhibitor. Median PFS2 was significantly longer for LEN vs PBO: 57.5 vs 32.7 months, respectively (HR 0.46 [95% CI 0.29, 0.70]; P <0.001).

Median number of treatment cycles received was 18 vs 9 cycles, for LEN vs PBO, respectively; a higher proportion of pts in the LEN arm started ≥25 cycles vs the PBO arm (38.9% vs 24.0%, respectively). Median dose intensity in the LEN arm was 4.2 mg/day.

The most common adverse events (AEs) of all grades were neutropenia (66.2% vs 30.5%) and diarrhea (40.8% vs 16.2%) in the LEN vs PBO arm, respectively. Febrile neutropenia occurred in 1.9% vs 0%, deep vein thrombosis in 1.9% vs 0%, and pulmonary embolism in 2.5% vs 0.6% of pts in the LEN vs PBO arm, respectively. Most common grade 3/4 AEs were neutropenia (59.9% vs 22.7%), thrombocytopenia (16.6% vs 6.5%), and diarrhea (8.3% vs 0.6%) in the LEN vs PBO arm, respectively; all other grade 3/4 AEs occurred in <5% of pts in either arm. While there was a significant difference in the incidence of neutropenia, the rate of grade 3/4 infections was 16.6% for LEN vs 10.4% for PBO-treated pts.

There were 13 (8.3%) vs 14 (9.1%) pts with at least one invasive second primary malignancy (SPM) in the LEN vs PBO arm, respectively. Hematologic invasive SPMs occurred in 7 vs 2 pts, and solid tumor invasive SPMs occurred in 7 vs 12 pts, in the LEN vs PBO arm, respectively. Overall, 44 pts in the LEN arm and 41 pts in the PBO arm died; 1 pt died on treatment in the LEN arm, and 2 pts in the PBO arm.

There was no clinically meaningful difference in HRQoL for LEN vs PBO, as measured by FACT-Leu and EQ-5D, during maintenance treatment.

Conclusions: LEN maintenance therapy significantly improved PFS from 9.2 to 33.9 months following second-line treatment in pts with CLL. The incidence of invasive SPMs was similar in both arms, and LEN maintenance treatment had an expected and acceptable safety profile.