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Original Investigation
June 10, 2021

Ibrutinib Plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia: A Nonrandomized Phase 2 Trial

Author Affiliations
  • 1Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston
  • 2Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston
  • 3Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston
  • 4Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston
  • 5Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston
  • 6Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston
JAMA Oncol. Published online June 10, 2021. doi:10.1001/jamaoncol.2021.1649
Key Points

Question  What are the long-term responses with combined ibrutinib and venetoclax first-line therapy in patients with chronic lymphocytic leukemia?

Findings  In this phase 2 nonrandomized trial, 80 previously untreated patients with chronic lymphocytic leukemia received combined ibrutinib and venetoclax for 24 cycles; on an intent-to-treat analysis, bone marrow–undetectable measurable residual disease remission was achieved by 56% of the patients at 12 cycles and 66% of the patients at 24 cycles of combined treatment. Overall, 75% of the patients achieved bone marrow–undetectable measurable residual disease remission as best response, with 3-year progression-free survival noted in 93% of the patients.

Meaning  The findings of this study suggest that combination therapy with ibrutinib and venetoclax may be a useful regimen for previously untreated patients with chronic lymphocytic leukemia.

Abstract

Importance  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.

Objective  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.

Design, Setting, and Participants  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.

Interventions  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.

Main Outcomes and Measures  Outcomes included complete remission, complete remission with incomplete count recovery, and bone marrow U-MRD rate.

Results  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.

Conclusions and Relevance  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.

Trial Registration  ClinicalTrials.gov Identifier: NCT02756897

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