TY - JOUR
T1 - Ibrutinib plus Venetoclax for First-line Treatment of Chronic Lymphocytic Leukemia
T2 - A Nonrandomized Phase 2 Trial
AU - Jain, Nitin
AU - Keating, Michael
AU - Thompson, Philip
AU - Ferrajoli, Alessandra
AU - Burger, Jan A.
AU - Borthakur, Gautam
AU - Takahashi, Koichi
AU - Estrov, Zeev
AU - Sasaki, Koji
AU - Fowler, Nathan
AU - Kadia, Tapan
AU - Konopleva, Marina
AU - Alvarado, Yesid
AU - Yilmaz, Musa
AU - Dinardo, Courtney
AU - Bose, Prithviraj
AU - Ohanian, Maro
AU - Pemmaraju, Naveen
AU - Jabbour, Elias
AU - Kanagal-Shamanna, Rashmi
AU - Patel, Keyur
AU - Wang, Wei
AU - Jorgensen, Jeffrey
AU - Wang, Sa A.
AU - Garg, Naveen
AU - Wang, Xuemei
AU - Wei, Chongjuan
AU - Cruz, Nichole
AU - Ayala, Ana
AU - Plunkett, William
AU - Kantarjian, Hagop
AU - Gandhi, Varsha
AU - Wierda, William G.
N1 - Publisher Copyright:
© 2021 American Medical Association. All rights reserved.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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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U2 - 10.1001/jamaoncol.2021.1649
DO - 10.1001/jamaoncol.2021.1649
M3 - Article
C2 - 34110383
AN - SCOPUS:85108074594
SN - 2374-2437
VL - 7
SP - 1213
EP - 1219
JO - JAMA Oncology
JF - JAMA Oncology
IS - 8
ER -