학술논문
Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib.
Document Type
Academic Journal
Author
Woyach JA; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States.; Jones D; The Ohio State University Comprehensive Cancer Center; Department of Pathology, The Ohio State University, United States.; Jurczak W; Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.; Robak T Prof; Medical University of Lodz, and Copernicus Memorial Hospital, Poland.; Illes A; Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.; Kater AP; Amsterdam University Medical Centers, Cancer Center Amsterdam, University of Amsterdam, on behalf of HOVON, Netherlands.; Ghia P; Università Vita-Salute San Raffaele, Milan, Italy.; Byrd JC; The University of Cincinnati, Cincinnati, Ohio, United States.; Seymour JF; Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Australia.; Long S; Ohio State University Wexner Medical Center James Molecular Laboratory, Columbus, Ohio, United States.; Mohamed N; The Ohio State University Wexner Medical Center, Columbus, Ohio, United States.; Benrashid S; The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, United States.; Lai TH; The Ohio State University, Columbus, Ohio, United States.; De Jesus G; AstraZeneca, South San Francisco, California, United States.; Lai R; AstraZeneca, South San Francisco, California, United States.; de Bruin G; Acerta Pharma BV, a member of the AstraZeneca Group, Oss, Netherlands.; Rule S; AstraZeneca, Mississauga, Canada.; Munugalavadla V; AstraZeneca, South San Francisco, California, United States.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 7603509 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0020 (Electronic) Linking ISSN: 00064971 NLM ISO Abbreviation: Blood Subsets: MEDLINE
Subject
Language
English
Abstract
Chronic lymphocytic leukemia (CLL) progression during Bruton tyrosine kinase (BTK) inhibitor treatment is typically characterized by emergent B-cell receptor pathway mutations. Using peripheral blood samples from relapsed/refractory CLL patients in ELEVATE-RR (NCT02477696) (median 2 prior therapies), we report clonal evolution data for patients progressing on acalabrutinib or ibrutinib (median follow-up 41 months). Paired (baseline and progression) samples were available for 47 (excluding 1 Richter) acalabrutinib-treated and 30 (excluding 6 Richter) ibrutinib-treated patients. At progression, emergent BTK mutations were observed in 31 (66%) acalabrutinib-treated and 11 (37%) ibrutinib-treated patients (median variant allele fraction [VAF]: 16.1% vs 15.6%). BTK C481S mutations were most common in both groups; T474I (n = 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n = 1) occurred with acalabrutinib, while neither mutation occurred with ibrutinib. L528W and A428D co-mutations presented in one ibrutinib-treated patient. Pre-existing TP53 mutations were present in 25 (53.2%) acalabrutinib-treated and 16 (53.3%) ibrutinib-treated patients at screening. Emergent TP53 mutations occurred with acalabrutinib and ibrutinib (13% vs 7%; median VAF: 6.0% vs 37.3%, respectively). Six acalabrutinib-treated patients and one ibrutinib-treated patient had emergent TP53/BTK co-mutations. Emergent PLCG2 mutations occurred in 3 (6%) acalabrutinib-treated and 6 (20%) ibrutinib-treated patients. One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK/PLCG2 co-mutations. While common BTK C481 mutations were observed with both treatments, patterns of mutation and co-mutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W, A428D) in this patient population.
(Copyright © 2024 American Society of Hematology.)
(Copyright © 2024 American Society of Hematology.)