Page 274 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR
fusion mutation at both baseline and disease progression; CCND1-IGH fusions have been reported to be associated with ibrutinib resistance in MCL patients.13 Four other patients with CLL harbored mutations in genes associated with poor prognosis, including TP53, ATM, and SF3B1 (Online Supple- mentary Table S2).9,10
Here we show that the gene mutational profile of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib is comparable to that of patients with relapsed or refractory disease. For example, patients with mutations in TP53, SF3B1, or ATM genes had a less favorable prognosis in this study and similar to that previously observed in patients treated with BTK inhibitors.9,10 Furthermore, pro- gression-free survival was comparable between zanubru- tinib-treated patients with or without NOTCH1 mutations. Lastly, four of seven intolerant patients who progressed on zanubrutinib acquired new BTK mutations and/or had an increase in the frequency of BTK mutations. Although there are limitations to this study (e.g., small sample size, short follow-up times, and a lack of direct comparison to non-intolerant patients), this is the first study to describe the genomic landscape of patients with B-cell malignancies who were intolerant to ibrutinib and/or acalabrutinib and were switched to treatment with zanubrutinib.
Authors
Linlin Xu,1 Mazyar Shadman,2 Ian W. Flinn,3 Moshe Y. Levy,4 Ryan Porter,5 John M. Burke,6 Syed F. Zafar,7 Jennifer L. Cultrera,8 Jamal Misleh,9 Edwin C. Kingsley,10 Habte A. Yimer,11 Benjamin Freeman,12 Arvind Chaudhry,13 Praveen K. Tumula,14 Mitul D. Gandhi,15 Rocco Crescenzo,1 Kunthel By,1 Aileen Cohen,1 Dih Yih Chen,1 Adam Idoine,1 Sudhir Manda,16 Jeff P. Sharman17 and Vanitha Ramakrishnan1
1BeiGene (Beijing) Co., Ltd., Beijing, China and BeiGene USA, Inc., San Mateo, CA, USA; 2Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA, USA; 3Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 4Texas Oncology Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA; 5SSM Health Dean Medical Group, Madison, WI, USA; 6Rocky Mountain Cancer Centers, Aurora, CO, USA; 7Florida Cancer Specialists & Research Institute, Fort Myers, FL, USA; 8Florida Cancer Specialists & Research Institute, Leesburg, FL, USA; 9Medical Oncology Hematology Consultants PA, Newark, DE, USA; 10Comprehensive Cancer Centers of Nevada, Las Vegas, NV, USA; 11Texas Oncology, Tyler, TX, USA; 12Summit Medical Group, Florham Park, NJ, USA; 13Summit Cancer Centers, Spokane, WA, USA; 14Texas Oncology, Amarillo, TX, USA; 15Virginia Cancer Specialists, Gainesville, VA, USA; 16Arizona Oncology/US Oncology Research, Tucson, AZ, USA and 17Willamette Valley Cancer Institute and Research Center, Eugene, OR, USA
Correspondence:
L. XU - Linlin.Xu@beigene.com
https://doi.org/10.3324/haematol.2023.283861
Received: July 10, 2023. Accepted: January 18, 2024. Early view: January 25, 2024.
©2024 Ferrata Storti Foundation Published under a CC BY-NC license
Disclosures
The study protocol was developed by BeiGene, Ltd. in collaboration with the study investigators. BeiGene was also involved in data collection, analysis, and interpretation of results. Statistical analyses were performed by statisticians at BeiGene. LX, RC, KB, AC, AI, and VR are employees of and hold stock/shares in BeiGene Co. MS is a consultant for AbbVie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, BeiGene, Bristol Myers Squibb, Morphosys/Incyte, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune, Mustang Bio, Regeneron, Merck, Fate Therapeutics, MEI Pharma, and Atara Biotherapeutics, and receives research funding from Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, AbbVie, TG Therapeutics, BeiGene, AstraZeneca, Sunesis, Atara Biotherapeutics, Genmab, and Morphosys/Incyte. IF is a member of a board of directors or advisory committees at Vincerx. ML receives consulting fees from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Genmab, GSK, Incyte, Janssen, Karyopharm, Kite, Lilly, Sanofi, Seagen, and Takeda, payment or honoraria from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Genmab, GSK, Incyte, Janssen, Karyopharm, Kite, Lilly, Sanofi, Seagen, and Takeda, travel support from AbbVie, Amgen, AstraZeneca, BeiGene, Bristol Myers Squibb, Genmab, GSK, Incyte, Janssen, Karyopharm, Kite, Lilly, Sanofi, Seagen, and Takeda, and has a leadership or fiduciary role from Sellas. JMB receives consulting fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, Bristol Myers Squibb, Constellation, Eli Lilly, Epizyme, Foresight, Genentech, Genmab, Kura, Kymera, Morphosys, Novartis, Nurix, TG Therapeutics, Verastem, and X4 Pharmaceuticals and receives payments/honoraria from Seagen and BeiGene. SFZ receives honorarium from Bristol Myers Squibb, Immunosome, and AbbVie. MDG receives honoraria from Karyopharm, TG Therapeutics, Janssen, and GSK. RC has equity with Pfizer and GSK and individual stocks in SAGA Diagnostics. D-YC has equity with BeiGene. JPS receives consulting fees from TG Therapeutics, Genentech, AbbVie, AstraZeneca, BeiGene, Bristol Myers Squibb, and Merck, and research funds from Genentech, Celgene, Gilead Sciences, TG Therapeutics, Merck, and Takeda.
Contributions
MS, IWF, MYL, RP, JMB, SFZ, JLC, JM, ECK, HAY, BF, AC, PKT, MDG, SM, and JPS enrolled patients and collected clinical data. LX, RC, KB, AC, D-YC, AI, and VR contributed to the intellectual content, conception, and design of the study. LX and KB processed data, analyzed statistics, generated figures, and wrote the manuscript. All authors contributed to data interpretation and revised the manuscript.
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