{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:28:30Z","timestamp":1792517310500,"version":"4.5.0"},"reference-count":32,"publisher":"American Society of Hematology","issue":"10","license":[{"start":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T00:00:00Z","timestamp":1715817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,9,5]]},"abstract":"<jats:sec>\n                  <jats:title>Abstract<\/jats:title>\n                  <jats:p>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 patients with relapsed\/refractory CLL 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 acalabrutinib-treated (66%) and 11 ibrutinib-treated patients (37%; median variant allele fraction [VAF], 16.1% vs 15.6%, respectively). BTK C481S mutations were most common in both groups; T474I (n\u00a0= 9; 8 co-occurring with C481) and the novel E41V mutation within the pleckstrin homology domain of BTK (n\u00a0= 1) occurred with acalabrutinib, whereas neither mutation occurred with ibrutinib. L528W and A428D comutations presented in 1 ibrutinib-treated patient. Preexisting TP53 mutations were present in 25 acalabrutinib-treated (53.2%) and 16 ibrutinib-treated patients (53.3%) 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 1 ibrutinib-treated patient had emergent TP53\/BTK comutations. Emergent PLCG2 mutations occurred in 3\u00a0acalabrutinib-treated (6%) and 6 ibrutinib-treated patients (20%). One acalabrutinib-treated patient and 4 ibrutinib-treated patients had emergent BTK\/PLCG2 comutations. Although common BTK C481 mutations were observed with both treatments, patterns of mutation and comutation frequency, mutation VAF, and uncommon BTK variants varied with acalabrutinib (T474I and E41V) and ibrutinib (L528W and A428D) in this patient population. The trial was registered at www.clinicaltrials.gov as #NCT02477696.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1182\/blood.2023023659","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T20:01:40Z","timestamp":1715889700000},"page":"1061-1068","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":56,"title":["Mutational profile in previously treated patients with chronic lymphocytic leukemia progression on acalabrutinib or ibrutinib"],"prefix":"10.1182","volume":"144","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3403-9144","authenticated-orcid":false,"given":"Jennifer A.","family":"Woyach","sequence":"first","affiliation":[{"name":"1The Ohio State University Comprehensive Cancer Center, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Jones","sequence":"additional","affiliation":[{"name":"1The Ohio State University Comprehensive Cancer Center, Columbus, OH"},{"name":"2Department of Pathology, The Ohio State University, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1879-8084","authenticated-orcid":false,"given":"Wojciech","family":"Jurczak","sequence":"additional","affiliation":[{"name":"3Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3411-6357","authenticated-orcid":false,"given":"Tadeusz","family":"Robak","sequence":"additional","affiliation":[{"name":"4Medical University of Lodz, and Copernicus Memorial Hospital, Lodz, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c1rp\u00e1d","family":"Ill\u00e9s","sequence":"additional","affiliation":[{"name":"5Division of Hematology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3190-1891","authenticated-orcid":false,"given":"Arnon P.","family":"Kater","sequence":"additional","affiliation":[{"name":"6Amsterdam University Medical Centers, Cancer Center Amsterdam, University of Amsterdam, on behalf of HOVON, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-7342","authenticated-orcid":false,"given":"Paolo","family":"Ghia","sequence":"additional","affiliation":[{"name":"7Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy"},{"name":"8Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John C.","family":"Byrd","sequence":"additional","affiliation":[{"name":"9Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2188-6835","authenticated-orcid":false,"given":"John F.","family":"Seymour","sequence":"additional","affiliation":[{"name":"10Peter MacCallum Cancer Centre, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Long","sequence":"additional","affiliation":[{"name":"11The Ohio State University Wexner Medical Center James Molecular Laboratory, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehad","family":"Mohamed","sequence":"additional","affiliation":[{"name":"2Department of Pathology, The Ohio State University, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0465-0231","authenticated-orcid":false,"given":"Samon","family":"Benrashid","sequence":"additional","affiliation":[{"name":"1The Ohio State University Comprehensive Cancer Center, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzung-Huei","family":"Lai","sequence":"additional","affiliation":[{"name":"1The Ohio State University Comprehensive Cancer Center, Columbus, OH"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"De Jesus","sequence":"additional","affiliation":[{"name":"12AstraZeneca, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lai","sequence":"additional","affiliation":[{"name":"12AstraZeneca, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerjan","family":"de Bruin","sequence":"additional","affiliation":[{"name":"13Acerta Pharma BV, a member of the AstraZeneca group, Oss, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Rule","sequence":"additional","affiliation":[{"name":"14AstraZeneca, Mississauga, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerendra","family":"Munugalavadla","sequence":"additional","affiliation":[{"name":"12AstraZeneca, South San Francisco, CA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2024090515204624600_bib1","doi-asserted-by":"crossref","first-page":"20406207221116577","DOI":"10.1177\/20406207221116577","article-title":"Selecting the optimal BTK inhibitor therapy in CLL: rationale and practical considerations","volume":"13","author":"Lovell","year":"2022","journal-title":"Ther Adv Hematol"},{"issue":"11","key":"2024090515204624600_bib2","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1182\/blood-2016-06-719294","article-title":"Clonal evolution leading to ibrutinib resistance in chronic lymphocytic 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