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Ibrutinib Plus Venetoclax Achieve Deep Responses and High uMRD Rates in CLL
Two-year post-randomization results of the phase 2 CAPTIVATE study were presented at the 2021 American Society of Hematology (ASH) Annual Meeting to demonstrate the admirable safety profile of ibrutinib plus venetoclax and achievement of high undetectable minimal residual disease (uMRD) rates in chronic lymphocytic leukemia (CLL).
“Ibrutinib and venetoclax, with distinct and complementary mechanisms of action, work synergistically to mobilize CLL cells from lymph nodes and lymphoid niches, enhance cell killing, and eliminate distinct CLL cell populations,” explained Paola Ghia, MD, PhD, Università Vita-Salute San Raffaele, Italy, and co-investigators.
A total of 164 patients were enrolled under the age of 70 years old with previously untreated CLL. The regimen involved 3 cycles of ibrutinib lead-in then 12 cycles of combined ibrutinib and venetoclax (oral ibrutinib 420 mg/day; oral venetoclax ramp-up to 400 mg/day). During cycle 16, patients with confirmed uMRD were randomized 1:1 to receive double-blind treatment with placebo or single-agent ibrutinib.
The primary endpoint was 2-year disease-free survival (DFS) in patients with confirmed uMRD randomized to placebo versus ibrutinib. Secondary endpoints were investigator-assessed best response, progression-free survival (PFS), and adverse events (AEs).
The median follow-up time was 38.2 months (range, 15.0-47.9), and the median post-randomization follow-up was 24 months (range, 5.8-33.1). Patients with confirmed uMRD randomized to placebo versus ibrutinib did not experience new DFS events since primary analysis.
“2-year DFS rates post-randomization remained unchanged at 95% (placebo) vs 100% ibrutinib, for a 4.7% difference (95 CI, 1.6-10.9; P=0.1573). In both arms post-randomization, modest improvements were observed in complete response (CR) rates, including CR with incomplete bone marrow recovery (CRi),” continued Dr Ghia and co-authors.
Further, the estimated 36-month PFS rates were 95% with placebo and 100% with ibrutinib.
Notably, in patients without confirmed uMRD randomized to ibrutinib versus ibrutinib plus venetoclax, greater improvements in best uMRD rates and CR/CRi rates were observed in the combination treatment arm than with ibrutinib alone.
Grade 3 and 4 AEs were observed across both arms, the most being neutropenia (36%), hypertension (10%), hypertension (10%), thrombocytopenia (5%), and diarrhea (5%). With up to 48 months of treatment, AEs led to discontinuation of ibrutinib plus venetoclax in 13% of patients.
These findings in patients with confirmed uMRD support the potential for treatment-free remission with fixed-duration treatment, including patients with high-risk factors.
“First-line ibrutinib plus venetoclax is an all-oral, once-daily, chemotherapy-free regimen that provides deep responses in patients with CLL. With an additional year of follow-up and no new MRD relapses, progressive disease or deaths in patients with confirmed uMRD, the 2-year DFS rate in the MRD-guided placebo arm remained high at 95% while 3-year PFS rates were ≥95% across all randomized treatment arms,” concluded Dr Ghia, et al.—Alexa Stoia
