Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia
Authors: Nitin Jain, Michael Keating, Philip Thompson, Alessandra Ferrajoli, Jan A. Burger, Gautam Borthakur, Koichi Takahashi, Zeev Estrov, Koji Sasaki, Nathan Fowler, Tapan Kadia, Marina Konopleva, Yesid Alvarado, Musa Yilmaz, Courtney DiNardo, Prithviraj Bose, Maro Ohanian, Naveen Pemmaraju, Elias Jabbour, Rashmi Kanagal-Shamanna, Keyur Patel, Wei Wang, Jeffrey Jorgensen, Sa A. Wang, Naveen Garg, Xuemei Wang, Chongjuan Wei, Nichole Cruz, Ana Ayala, William Plunkett, Hagop Kantarjian, Varsha Gandhi, William G. Wierda
Journal: JAMA Oncology (2021)

Oral targeted therapies have advanced the treatment of chronic lymphocytic leukemia (CLL). These therapies include Bruton tyrosine kinase inhibitors, used as monotherapy, and the Bcl-2 inhibitor venetoclax, typically combined with the CD20 monoclonal antibody. Preclinical studies have shown synergy between Bruton tyrosine kinase inhibitors and the Bcl-2 inhibitor venetoclax.To examine the rate of complete remission, complete remission with incomplete count recovery, and bone marrow-undetectable measurable residual disease (U-MRD) after treatment with the combination of ibrutinib and venetoclax.A single-center, phase 2 nonrandomized trial enrolled patients from August 17, 2016, to June 5, 2018. Participants included previously untreated patients with CLL who met International Workshop on CLL 2008 criteria for treatment indication. Patients were required to have at least 1 of the following features: del(17p), TP53-mutated CLL, del(11q), unmutated immunoglobulin heavy-chain variable gene, or age 65 years or older.Therapy consisted of ibrutinib, 420 mg/d, monotherapy for 3 cycles, thereafter combined with venetoclax (standard weekly dose ramp-up to 400 mg/d) for a total of 24 cycles of combination treatment. Responses were assessed at serial points according to International Workshop on CLL 2008 criteria. Measurable residual disease (MRD) was assessed by multicolor flow cytometry with a sensitivity of 10-4.Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.Eighty patients (57 [71%] men) were treated; median age was 65 years (range, 26-83 years). The median follow-up for all 80 patients was 38.5 months (range, 5.6-51.1 months). Five patients discontinued the study during the ibrutinib monotherapy phase; the remaining 75 patients received combination therapy. On an intent-to-treat analysis of combined treatment, 45 (56%) patients achieved bone marrow U-MRD remission at 12 cycles and 53 (66%) patients achieved bone marrow U-MRD remission at 24 cycles. Overall, 60 (75%) patients achieved bone marrow U-MRD remission as their best response. Responses were seen across all high-risk subgroups, independent of the immunoglobulin heavy-chain variable gene mutation status, fluorescence in situ hybridization category, or TP53 mutation. The 3-year progression-free survival was 93%, and 3-year overall survival was 96%. No patient had CLL progression; 2 patients developed Richter transformation.The findings of this study suggest that combination therapy with ibrutinib and venetoclax might be beneficial for previously untreated patients with CLL. Remissions appeared to be durable during a follow-up of more than 3 years, with activity seen across high-risk disease subgroups, including those with del(17p)/TP53-mutated CLL.ClinicalTrials.gov Identifier: NCT02756897.