Pooled safety analysis of zanubrutinib monotherapy in patients with B-cell malignancies.

Abstract

Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (5%), URI, UTI, sepsis, diarrhea, and musculoskeletal pain (2% each). Atrial fibrillation and major hemorrhage occurred in 3% and 4% of patients, respectively. Atrial fibrillation, hypertension, and diarrhea occurred at lower rates than those reported historically for ibrutinib. Grade ≥3 adverse events included neutropenia (23%), thrombocytopenia (8%), and anemia (8%). Serious TEAEs included pneumonia (11%), sepsis (2%), and pyrexia (2%).Treatment discontinuations and dose reductions for adverse events occurred in 10% and 8% of patients, respectively. Thirty-nine patients (4%) had fatal TEAEs, including pneumonia (n = 9), sepsis (n = 4), unspecified cause (n = 4), and multiple organ dysfunction syndrome (n = 5). This analysis demonstrates that zanubrutinib is generally well tolerated with a safety profile consistent with known BTK inhibitor toxicities; these were manageable and mostly reversible.

• Authors: Constantine S Tam, Meletios Dimopoulos, Ramon Garcia-Sanz, Judith Trotman, Stephen Opat, Andrew W Roberts, Roger Owen, Yuqin Song, Wei Xu, Jun Zhu, Jianyong Li, Lugui Qiu, Shirley D'Sa, Wojciech Jurczak, Gavin Cull, Paula Marlton, David Gottlieb, Javier Munoz, Tycel Phillips, Chenmu Du, Meng Ji, Lei Zhou, Haiyi Guo, Hongjie Zhu, Wai Y Chan, Aileen Cohen, William Novotny, Jane Huang, Alessandra Tedeschi
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 4 Pg. 1296-1308 (02 22 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 34724705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Piperidines
• Pyrazoles
• Pyrimidines
• zanubrutinib

Topics

• Adult
• Aged
• Atrial Fibrillation
• Diarrhea (chemically induced)
• Humans
• Hypertension
• Leukemia, Lymphocytic, Chronic, B-Cell (drug therapy)
• Lymphoma, B-Cell
• Lymphoma, Follicular
• Musculoskeletal Pain
• Piperidines
• Pneumonia
• Pyrazoles
• Pyrimidines
• Sepsis