{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T19:21:23Z","timestamp":1793733683878,"version":"4.6.1"},"reference-count":35,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,1,1]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed\/refractory (R\/R) patients with CLL pretreated with cBTKi enrolled in the phase 1\/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired \u22651 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I\/F\/S\/Y\/L, 26%), kinase-impaired L528W (16%), C481S\/R\/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate\u2013binding pocket, D539A\/G\/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18\/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R\/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024027009","type":"journal-article","created":{"date-parts":[[2025,10,7]],"date-time":"2025-10-07T15:12:15Z","timestamp":1759849935000},"page":"24-34","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Genomic determinants of response and resistance to pirtobrutinib in relapsed\/refractory chronic lymphocytic leukemia"],"prefix":"10.1182","volume":"147","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2040-4961","authenticated-orcid":false,"given":"Jennifer R.","family":"Brown","sequence":"first","affiliation":[{"name":"1Chronic Lymphocytic Leukemia Center, Division of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6166-4746","authenticated-orcid":false,"given":"Bastien","family":"Nguyen","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1157-6489","authenticated-orcid":false,"given":"Sai Prasad","family":"Desikan","sequence":"additional","affiliation":[{"name":"3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Won","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8732-562X","authenticated-orcid":false,"given":"Shady I.","family":"Tantawy","sequence":"additional","affiliation":[{"name":"4Faculty of Medicine, Suez Canal University, Ismailia, Egypt"},{"name":"16Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel C.","family":"McNeely","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narasimha","family":"Marella","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hetal S.","family":"Randeria","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren M.","family":"Hanson","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, 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WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Constantine S.","family":"Tam","sequence":"additional","affiliation":[{"name":"7Department of Hematology, Alfred Health and Monash University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6631-9749","authenticated-orcid":false,"given":"Toby A.","family":"Eyre","sequence":"additional","affiliation":[{"name":"8Department of Hematology, Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7988-1565","authenticated-orcid":false,"given":"Chan Y.","family":"Cheah","sequence":"additional","affiliation":[{"name":"9Department of Hematology, Linear Clinical Research, Perth, WA, Australia"},{"name":"10Department of Hematology, Sir Charles Gairdner Hospital Perth, Perth, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4336-1071","authenticated-orcid":false,"given":"Nirav N.","family":"Shah","sequence":"additional","affiliation":[{"name":"11Division of Hematology and Oncology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-7342","authenticated-orcid":false,"given":"Paolo","family":"Ghia","sequence":"additional","affiliation":[{"name":"12Strategic Research Program on Chronic Lymphocytic Leukemia, Division of Experimental Oncology, Universit\u00e0 Vita-Salute San Raffaele, Milan, Italy"},{"name":"13Strategic Research Program on Chronic Lymphocytic Leukemia, Division of Experimental Oncology, IRCCS Ospedale San Raffaele, Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1879-8084","authenticated-orcid":false,"given":"Wojciech","family":"Jurczak","sequence":"additional","affiliation":[{"name":"14Department of Clinical Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minna","family":"Balbas","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binoj","family":"Nair","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, IN"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Abada","sequence":"additional","affiliation":[{"name":"2Eli Lilly and Company, Indianapolis, 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