Ibrutinib and Venetoclax for First-Line Treatment of CLL
Nitin Jain, M.D., Michael Keating, M.D., Philip Thompson, M.D., Alessandra Ferrajoli, M.D., Jan Burger, M.D., Ph.D., Gautam Borthakur, M.D., Koichi Takahashi, M.D., Zeev Estrov, M.D., Nathan Fowler, M.D., Tapan Kadia, M.D., Marina Konopleva, M.D., Ph.D., Yesid Alvarado, M.D., et al.
https://www.nejm.org/doi/full/10.1056/NEJMoa1900574?query=oncology-hematology
Abstract
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. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.)
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Supported by AbbVie, a grant from the University of Texas M.D. Anderson Cancer Center (MDACC) Chronic Lymphocytic Leukemia Moon Shot program (to Drs. Jain and Gandhi), a grant from the Andrew Sabin Family Foundation (to Drs. Jain and Gandhi), a grant from the CLL Global Research Foundation (to Dr. Gandhi), and MDACC Support Grant P30 CA016672.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Gandhi and Wierda contributed equally to this article.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who participated in this trial and their families, the MDACC Investigational New Drug office for their oversight of the study, and the referring physicians, as well as the entire clinical and research staff at the Department of Leukemia, MDACC.
Author Affiliations
From the Departments of Leukemia (N.J., M. Keating, P.T., A.F., J.B., G.B., K.T., Z.E., T.K., M. Konopleva, Y.A., M.Y., C.D., P.B., M.O., N.P., E.J., K. Sasaki, K. Sondermann, N.C., C.W., A.A., H.K., W.W.), Lymphoma and Myeloma (N.F.), Hematopathology (R.K.-S., K.P., J.J.), Diagnostic Radiology (N.G.), Biostatistics (X.W.), and Experimental Therapeutics (W.P., V.G.), University of Texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr. Jain at the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX 77030, or at njain@mdanderson.org.
Nitin Jain, M.D., Michael Keating, M.D., Philip Thompson, M.D., Alessandra Ferrajoli, M.D., Jan Burger, M.D., Ph.D., Gautam Borthakur, M.D., Koichi Takahashi, M.D., Zeev Estrov, M.D., Nathan Fowler, M.D., Tapan Kadia, M.D., Marina Konopleva, M.D., Ph.D., Yesid Alvarado, M.D., et al.
https://www.nejm.org/doi/full/10.1056/NEJMoa1900574?query=oncology-hematology
Abstract
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. (Funded by AbbVie and others; ClinicalTrials.gov number, NCT02756897.)
Digital Object Thumbnail
QUICK TAKE VIDEO SUMMARY
Combined Ibrutinib and Venetoclax for Treatment of CLL
02:02
Read this article and use 1 of your 3 remaining free subscriber-only articles.
USE 1 ARTICLE AND READ
Supported by AbbVie, a grant from the University of Texas M.D. Anderson Cancer Center (MDACC) Chronic Lymphocytic Leukemia Moon Shot program (to Drs. Jain and Gandhi), a grant from the Andrew Sabin Family Foundation (to Drs. Jain and Gandhi), a grant from the CLL Global Research Foundation (to Dr. Gandhi), and MDACC Support Grant P30 CA016672.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Gandhi and Wierda contributed equally to this article.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who participated in this trial and their families, the MDACC Investigational New Drug office for their oversight of the study, and the referring physicians, as well as the entire clinical and research staff at the Department of Leukemia, MDACC.
Author Affiliations
From the Departments of Leukemia (N.J., M. Keating, P.T., A.F., J.B., G.B., K.T., Z.E., T.K., M. Konopleva, Y.A., M.Y., C.D., P.B., M.O., N.P., E.J., K. Sasaki, K. Sondermann, N.C., C.W., A.A., H.K., W.W.), Lymphoma and Myeloma (N.F.), Hematopathology (R.K.-S., K.P., J.J.), Diagnostic Radiology (N.G.), Biostatistics (X.W.), and Experimental Therapeutics (W.P., V.G.), University of Texas M.D. Anderson Cancer Center, Houston.
Address reprint requests to Dr. Jain at the Department of Leukemia, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 428, Houston, TX 77030, or at njain@mdanderson.org.
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