Hypertension in Patients Treated With Ibrutinib for Chronic Lymphocytic Leukemia

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Abstract

This cohort study describes patterns of development, management strategies, and long-term vascular consequences of hypertension associated with ibrutinib in the non–clinical trial setting.

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Ibrutinib increases the risk of hypertension and atrial fibrillation: Systematic review and meta-analysis

Daniel Caldeira, Daniela Alves, João T. Costa … (2019)

Introduction Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm’s macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction. Methods We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach. Results There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52–5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17–7.64) with high quality evidence. Conclusions Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.

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Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies

Steven E Coutre, John C. Byrd, Peter Hillmen … (2019)

Ibrutinib, a first-in-class once-daily oral Bruton tyrosine kinase inhibitor indicated for chronic lymphocytic leukemia (CLL), is continued until progressive disease or unacceptable toxicity. We conducted an integrated safety analysis of single-agent ibrutinib from randomized phase 3 studies PCYC-1112 (RESONATE, n = 195) and PCYC-1115/1116 (RESONATE-2, n = 135), and examined longer-term safety separately in the phase 1b/2 PCYC-1102/1103 study (n = 94, 420 mg/d). In the integrated analysis (ibrutinib treatment up to 43 months), the most common adverse events (AEs) were primarily grade 1/2; diarrhea (n = 173, 52% any-grade; n = 15, 5% grade 3) and fatigue (n = 119, 36% any-grade; n = 10, 3% grade 3). The most common grade 3/4 AEs were neutropenia (n = 60, 18%) and pneumonia (n = 38, 12%). Over time, prevalence of AEs of interest (diarrhea, fatigue, grade ≥3 infection, bleeding, and neutropenia) trended down; prevalence of hypertension increased, but incidence decreased after year 1. AEs led to dose reductions in 42 (13%) patients and permanent discontinuations in 37 (11%); dose modifications due to AEs were most common during year 1 and decreased in frequency thereafter. The most common AEs (preferred term) contributing to discontinuation included pneumonia (n = 4), anemia (n = 3), and atrial fibrillation (n = 3). With long-term follow-up on PCYC-1102/1103 (ibrutinib treatment up to 67 months), grade 3/4 AEs were generally similar to those in the integrated analysis. Overall, AEs were primarily grade 1/2 and manageable during prolonged ibrutinib treatment in patients with CLL. These trials were registered at www.clinicaltrials.gov as #NCT01578707, #NCT01722487, #NCT01724346, #NCT01105247, and #NCT01109069.

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Long-term effects of ibrutinib on blood pressure in patients with chronic lymphocytic leukemia (CLL)

J. JONES, B George, C.B. Peterson … (2019)

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Author and article information

Journal

Journal ID (nlm-ta): JAMA Netw Open

Journal ID (iso-abbrev): JAMA Netw Open

Journal ID (pmc): JAMA Netw Open

Title: JAMA Network Open

Publisher: American Medical Association

ISSN (Electronic): 2574-3805

Publication date (Electronic): 2 December 2019

Publication date Collection: December 2019

Publication date PMC-release: 2 December 2019

Volume: 2

Issue: 12

Electronic Location Identifier: e1916326

Affiliations

[1 ]Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

[2 ]Division of Hematology and Oncology, Department of Medicine, Georgetown University Hospital Lombardi Comprehensive Cancer Center, Washington, DC

[3 ]Department of Hematology and Oncology, Northwell Health Cancer Institute, New Hyde Park, New York

[4 ]Division of Hematology and Oncology, Department of Medicine, University of Alabama, Birmingham

[5 ]Cardiovascular Division, Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia

[6 ]Division of Hematologic Malignancies, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Author notes

Article Information

Accepted for Publication: September 23, 2019.

Published: December 2, 2019. doi:10.1001/jamanetworkopen.2019.16326

Corresponding Author: Lindsey E. Roeker, MD, Memorial Sloan Kettering Cancer Center, 530 E 74th St, 22nd Floor, New York, NY 10065 ( roekerl@ 123456mskcc.org ).

Author Contributions: Drs Roeker and Mato had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Roeker, Mato.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Roeker, Sarraf Yazdy, Mato.

Critical revision of the manuscript for important intellectual content: Roeker, Rhodes, Goodfriend, Narkhede, Carver, Mato.

Statistical analysis: Roeker, Narkhede, Mato.

Administrative, technical, or material support: Sarraf Yazdy, Goodfriend.

Supervision: Sarraf Yazdy, Narkhede, Carver.

Conflict of Interest Disclosures: Dr Roeker reported having a spouse with a minority ownership interest in AbbVie and Abbott Laboratories; receiving a travel grant from AbbVie; and receiving a grant from the American Society of Hematology outside the submitted work. Dr Sarraf Yazdy reported receiving grants from Genentech; serving as a consultant for AbbVie and Octapharma; and speaking at Bayer Pharmaceuticals outside the submitted work. Dr Rhodes reported serving as a medical reviewer for Medscape; serving as a consultant for DAVA Oncology and AstraZeneca; and receiving grants from Conquer Cancer Foundation outside the submitted work. Dr Mato reported receiving grants and personal fees from Pharmacyclics, Johnson and Johnson, AbbVie, Loxo Oncology, Sunesis Pharmaceuticals, Genetech, and Adaptive Biotechnologies; receiving grants and personal fees from and serving on the data and safety monitoring board of TG Therapeutics; serving on the data and safety monitoring board of Celgene; and receiving grants from Regeneron Pharmaceuticals outside the submitted work. No other disclosures were reported.

Article

Publisher ID: zld190033

DOI: 10.1001/jamanetworkopen.2019.16326

PMC ID: 6902749

PubMed ID: 31790561

SO-VID: 3f102266-926e-40ab-8d39-4901a113376b

License:

This is an open access article distributed under the terms of the CC-BY License.

History

Date received : 15 July 2019

Date accepted : 23 September 2019

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