The Bruton’s tyrosine kinase inhibitor ibrutinib is the standard of care for older patients with previously untreated chronic lymphocytic leukemia (CLL); however, it is associated with lower complete response (CR) rates and increased toxicities such as atrial fibrillation and hypertension. In the interest of developing novel strategies to address these shortcomings, the ongoing, randomized phase 3 A041702 study is comparing the combination of ibrutinib + the anti-CD20 monoclonal antibody obinutuzumab (IO) versus IO + the BCL2 inhibitor venetoclax (IVO) in older patients with previously untreated CLL using a novel response-dependent discontinuation strategy.
Eligible patients must have CLL in accordance with 2018 International Workshop on Chronic Lymphocytic Leukemia (iWCLL) criteria, be aged 70 years or older, previously untreated and in need of therapy (per 2018 iWCLL guidelines), and must have intermediate- or high-risk Rai stage, as well as Eastern Cooperative Oncology Group performance status 0 to 2. The primary objective of the study is to compare progression-free survival (PFS) between IO with ibrutinib maintenance versus IVO using a response-dependent discontinuation strategy. The secondary objectives are to compare bone marrow (BM) minimal residual disease (MRD) rates and depth of response at cycle 15 day 1 between patients treated with IO versus IVO, overall survival, 5-year PFS, and toxicity.
Preregistered patients must submit a peripheral blood sample for central fluorescence in situ hybridization analysis of del(17p) prior to being randomized 1:1 to receive IO (arm 1) or IVO (arm 2) therapy; stratification was by Rai stage and presence of del(17p). The IO regimen consists of ibrutinib daily starting on cycle 1 day 1 (420 mg orally on days 1-28 for 15 cycles), and obinutuzumab dosed as standard starting on cycle 1 day 1 and continuing to cycle 6 day 1 (100 mg intravenously on cycle 1 day 1, 900 mg on cycle 1 day 2, 1000 mg on cycle 1 day 8, cycle 1 day 15, and cycles 2-6 day 1). The IVO regimen consists of the IO dosing schedule defined in arm 1, with venetoclax starting on cycle 3 day 1 (20 mg daily orally) with standard 5-week ramp-up to a final dose of 400 mg on cycle 4 day 1 and continuing until cycle 14 day 28. At the end of 14 cycles, patients in both arms undergo response evaluation with central peripheral blood and BM MRD testing. IO-treated patients continue ibrutinib indefinitely; IVO-treated patients who achieve bone marrow MRD-CR discontinue all therapy, whereas those who do not continue ibrutinib indefinitely.
The study has 90% power to detect a hazard ratio for PFS of 0.55 (corresponding to 5-year PFS rates of 70% and 82.187% for IO and IVO, respectively), at a one-sided significance level of 0.025 by a log-rank test. This design requires 128 events and 431 total evaluable patients, assuming uniform accrual over the course of 3 years and minimum follow-up of 5 years. The study includes 2 interim analyses for superiority when 50% and 75% of the expected number of events have been observed; it also includes 3 interim analyses for futility when 25%, 50%, and 75% of the expected number of events have been observed.
As of November 20, 2019, 659 sites are open in the United States; 89 of 494 patients have been enrolled.
Woyach J, et al. ASH Abstract 1751. Session 642.