TY - JOUR
T1 - Ibrutinib and venetoclax for first-line treatment of CLL
AU - Jain, Nitin
AU - Keating, Michael
AU - Thompson, Philip
AU - Ferrajoli, Alessandra
AU - Burger, Jan
AU - Borthakur, Gautam
AU - Takahashi, Koichi
AU - Estrov, Zeev
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 - Sasaki, Koji
AU - Kanagal-Shamanna, Rashmi
AU - Patel, Keyur
AU - Jorgensen, Jeffrey
AU - Garg, Naveen
AU - Wang, Xuemei
AU - Sondermann, Katrina
AU - Cruz, Nichole
AU - Wei, Chongjuan
AU - Ayala, Ana
AU - Plunkett, William
AU - Kantarjian, Hagop
AU - Gandhi, Varsha
AU - Wierda, William
N1 - Publisher Copyright:
© 2019 Massachusetts Medical Society.
PY - 2019/5/30
Y1 - 2019/5/30
N2 - BACKGROUND Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10−4). RESULTS A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL.
AB - BACKGROUND Ibrutinib, an inhibitor of Bruton’s tyrosine kinase, and venetoclax, an inhibitor of B-cell lymphoma 2 protein, have been approved for patients with chronic lymphocytic leukemia (CLL). Preclinical investigations have indicated potential synergistic interaction of their combination. METHODS We conducted an investigator-initiated phase 2 study of combined ibrutinib and venetoclax involving previously untreated high-risk and older patients with CLL. All patients had at least one of the following features: chromosome 17p deletion, mutated TP53, chromosome 11q deletion, unmutated IGHV, or an age of 65 years or older. Patients received ibrutinib monotherapy (420 mg once daily) for 3 cycles, followed by the addition of venetoclax (weekly dose escalation to 400 mg once daily). Combined therapy was administered for 24 cycles. Response assessments were performed according to International Workshop on Chronic Lymphocytic Leukemia 2008 criteria. Minimal residual disease was assessed by means of multicolor flow cytometry in bone marrow (sensitivity, 10−4). RESULTS A total of 80 patients were treated. The median age was 65 years (range, 26 to 83). A total of 30% of the patients were 70 years of age or older. Overall, 92% of the patients had unmutated IGHV, TP53 aberration, or chromosome 11q deletion. With combined treatment, the proportions of patients who had complete remission (with or without normal blood count recovery) and remission with undetectable minimal residual disease increased over time. After 12 cycles of combined treatment, 88% of the patients had complete remission or complete remission with incomplete count recovery, and 61% had remission with undetectable minimal residual disease. Responses were noted in older adults and across all high-risk subgroups. Three patients had laboratory evidence of tumor lysis syndrome. The adverse-event profile was similar to what has been reported with ibrutinib and venetoclax. CONCLUSIONS In this study, combined venetoclax and ibrutinib was an effective oral regimen for high-risk and older patients with CLL.
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U2 - 10.1056/NEJMoa1900574
DO - 10.1056/NEJMoa1900574
M3 - Article
C2 - 31141631
AN - SCOPUS:85066459165
SN - 0028-4793
VL - 380
SP - 2095
EP - 2103
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 22
ER -