{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T17:41:20Z","timestamp":1793209280066,"version":"4.5.0"},"reference-count":40,"publisher":"American Society of Hematology","issue":"10","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,3,6]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Bruton tyrosine kinase inhibitors (BTKis) are an established standard of care in chronic lymphocytic leukemia. The covalent BTKis ibrutinib, acalabrutinib, and zanubrutinib bind to BTK C481 and are all susceptible to the C481S mutation. Noncovalent BTKi, including pirtobrutinib, overcome C481S resistance but are associated with multiple variant (non-C481) BTK mutations, including those associated with resistance to acalabrutinib and zanubrutinib (T474 codon and L528W mutations). We review the current knowledge on variant BTK mutations, discuss their clinical implications, and consider their impact on clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024026672","type":"journal-article","created":{"date-parts":[[2025,1,14]],"date-time":"2025-01-14T16:57:07Z","timestamp":1736873827000},"page":"1005-1009","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":32,"title":["Novel mechanisms of resistance in CLL: variant BTK mutations in second-generation and noncovalent BTK inhibitors"],"prefix":"10.1182","volume":"145","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9759-5017","authenticated-orcid":false,"given":"Constantine S.","family":"Tam","sequence":"first","affiliation":[{"name":"1Clinical Haematology, Alfred Hospital, Melbourne, VIC, Australia"},{"name":"2Central Clinical School, Monash University, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Balendran","sequence":"additional","affiliation":[{"name":"3Central Coast Haematology, Gosford, NSW, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piers","family":"Blombery","sequence":"additional","affiliation":[{"name":"1Clinical Haematology, Alfred Hospital, Melbourne, VIC, Australia"},{"name":"4Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia"},{"name":"5Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"3","key":"2025032119464761400_bib1","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1400376","article-title":"Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia","volume":"371","author":"Byrd","year":"2014","journal-title":"N\u00a0Engl J Med"},{"issue":"25","key":"2025032119464761400_bib2","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1056\/NEJMoa1509388","article-title":"Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia","volume":"373","author":"Burger","year":"2015","journal-title":"N\u00a0Engl J Med"},{"issue":"26","key":"2025032119464761400_bib3","doi-asserted-by":"crossref","first-page":"2517","DOI":"10.1056\/NEJMoa1812836","article-title":"Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL","volume":"379","author":"Woyach","year":"2018","journal-title":"N\u00a0Engl J Med"},{"issue":"5","key":"2025032119464761400_bib4","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1056\/NEJMoa1817073","article-title":"Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia","volume":"381","author":"Shanafelt","year":"2019","journal-title":"N\u00a0Engl J Med"},{"issue":"31","key":"2025032119464761400_bib5","doi-asserted-by":"crossref","first-page":"3441","DOI":"10.1200\/JCO.21.01210","article-title":"Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial","volume":"39","author":"Byrd","year":"2021","journal-title":"J\u00a0Clin Oncol"},{"issue":"4","key":"2025032119464761400_bib6","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa2211582","article-title":"Zanubrutinib or ibrutinib in relapsed or\u00a0refractory chronic lymphocytic leukemia","volume":"388","author":"Brown","year":"2023","journal-title":"N\u00a0Engl J Med"},{"issue":"9","key":"2025032119464761400_bib7","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1182\/bloodadvances.2023012221","article-title":"BTK inhibitors in CLL: second-generation drugs and beyond","volume":"8","author":"Tam","year":"2024","journal-title":"Blood Adv"},{"issue":"24","key":"2025032119464761400_bib8","doi-asserted-by":"crossref","first-page":"2286","DOI":"10.1056\/NEJMoa1400029","article-title":"Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib","volume":"370","author":"Woyach","year":"2014","journal-title":"N\u00a0Engl J Med"},{"issue":"1","key":"2025032119464761400_bib9","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1001\/jamaoncol.2014.218","article-title":"Etiology of ibrutinib therapy discontinuation and\u00a0outcomes in patients with chronic lymphocytic leukemia","volume":"1","author":"Maddocks","year":"2015","journal-title":"JAMA Oncol"},{"issue":"4","key":"2025032119464761400_bib10","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1002\/cncr.31831","article-title":"Targeted multigene deep sequencing of Bruton tyrosine kinase inhibitor-resistant chronic lymphocytic leukemia with disease progression and Richter transformation","volume":"125","author":"Kanagal-Shamanna","year":"2019","journal-title":"Cancer"},{"issue":"24","key":"2025032119464761400_bib11","doi-asserted-by":"crossref","first-page":"2352","DOI":"10.1056\/NEJMc1402716","article-title":"Ibrutinib resistance in chronic lymphocytic leukemia","volume":"370","author":"Furman","year":"2014","journal-title":"N\u00a0Engl J Med"},{"issue":"4","key":"2025032119464761400_bib12","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1038\/leu.2014.263","article-title":"Functional characterization of BTK(C481S) mutation that confers ibrutinib\u00a0resistance: exploration of alternative kinase inhibitors","volume":"29","author":"Cheng","year":"2015","journal-title":"Leukemia"},{"issue":"12","key":"2025032119464761400_bib13","doi-asserted-by":"crossref","first-page":"2794","DOI":"10.1182\/bloodadvances.2022008821","article-title":"BTK and PLCG2 remain unmutated in one-third of patients with CLL relapsing on\u00a0ibrutinib","volume":"7","author":"Bonfiglio","year":"2023","journal-title":"Blood Adv"},{"issue":"16","key":"2025032119464761400_bib14","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1158\/1078-0432.CCR-22-3887","article-title":"B-cell receptor pathway mutations are infrequent in patients with chronic lymphocytic leukemia on continuous ibrutinib therapy","volume":"29","author":"Woyach","year":"2023","journal-title":"Clin Cancer Res"},{"issue":"10","key":"2025032119464761400_bib15","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1182\/blood.2023023659","article-title":"Mutational profile of previously treated chronic lymphocytic leukemia patients progressing on acalabrutinib or ibrutinib","volume":"144","author":"Woyach","year":"2024","journal-title":"Blood"},{"issue":"20","key":"2025032119464761400_bib16","doi-asserted-by":"crossref","first-page":"5589","DOI":"10.1182\/bloodadvances.2022008325","article-title":"Enrichment of BTK Leu528Trp mutations in patients with CLL on zanubrutinib: potential for pirtobrutinib cross-resistance","volume":"6","author":"Blombery","year":"2022","journal-title":"Blood Adv"},{"issue":"9","key":"2025032119464761400_bib17","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.3324\/haematol.2020.272500","article-title":"Phase II study of acalabrutinib in ibrutinib-intolerant patients with relapsed\/refractory chronic lymphocytic leukemia","volume":"106","author":"Rogers","year":"2021","journal-title":"Haematologica"},{"issue":"1","key":"2025032119464761400_bib18","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1158\/1535-7163.MCT-22-0642","article-title":"Bruton's tyrosine kinase inhibitors with distinct binding modes reveal differential functional impact on B-cell receptor signaling","volume":"23","author":"Li","year":"2024","journal-title":"Mol Cancer Ther"},{"issue":"26","key":"2025032119464761400_bib19","first-page":"3137","article-title":"Pirtobrutinib: a new hope for patients with BTK inhibitor\u2013refractory lymphoproliferative disorders","volume":"141","author":"Thompson","year":"2023","journal-title":"Blood"},{"issue":"10277","key":"2025032119464761400_bib20","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/S0140-6736(21)00224-5","article-title":"Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1\/2 study","volume":"397","author":"Mato","year":"2021","journal-title":"Lancet"},{"issue":"1","key":"2025032119464761400_bib21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2300696","article-title":"Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia","volume":"389","author":"Mato","year":"2023","journal-title":"N\u00a0Engl J Med"},{"issue":"1","key":"2025032119464761400_bib22","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1158\/2159-8290.CD-23-0670","article-title":"First-in-human study of the reversible BTK inhibitor nemtabrutinib in patients with relapsed\/refractory chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma","volume":"14","author":"Woyach","year":"2024","journal-title":"Cancer Discov"},{"issue":"8","key":"2025032119464761400_bib23","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1056\/NEJMoa2114110","article-title":"Mechanisms of resistance to noncovalent Bruton\u2019s tyrosine kinase inhibitors","volume":"386","author":"Wang","year":"2022","journal-title":"N\u00a0Engl J Med"},{"issue":"suppl 1","key":"2025032119464761400_bib24","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1182\/blood-2023-180143","article-title":"Genomic evolution and resistance during pirtobrutinib therapy in covalent BTK-inhibitor (cBTKi) pre-treated chronic lymphocytic leukemia patients: updated analysis from the BRUIN study [abstract]","volume":"142","author":"Brown","year":"2023","journal-title":"Blood"},{"issue":"12","key":"2025032119464761400_bib25","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1182\/bloodadvances.2016003632","article-title":"Clonal evolution underlying leukemia progression and Richter transformation in patients with ibrutinib-relapsed CLL","volume":"1","author":"Kadri","year":"2017","journal-title":"Blood Adv"},{"issue":"1","key":"2025032119464761400_bib26","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/leu.2016.153","article-title":"Substitution scanning identifies a novel, catalytically active ibrutinib-resistant BTK cysteine 481 to threonine (C481T) variant","volume":"31","author":"Hamasy","year":"2017","journal-title":"Leukemia"},{"issue":"6682","key":"2025032119464761400_bib27","doi-asserted-by":"crossref","first-page":"eadi5798","DOI":"10.1126\/science.adi5798","article-title":"Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1\/3 degrader NX-2127","volume":"383","author":"Montoya","year":"2024","journal-title":"Science"},{"issue":"suppl 1","key":"2025032119464761400_bib28","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1182\/blood-2019-125488","article-title":"BTK Leu528Trp - a potential secondary resistance mechanism specific for patients with chronic lymphocytic leukemia treated with the next generation BTK inhibitor zanubrutinib [abstract]","volume":"134","author":"Handunnetti","year":"2019","journal-title":"Blood"},{"issue":"1","key":"2025032119464761400_bib29","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/bjh.18162","article-title":"A\u00a0two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed\/refractory B-cell malignancies","volume":"198","author":"Song","year":"2022","journal-title":"Br J Haematol"},{"issue":"14","key":"2025032119464761400_bib30","doi-asserted-by":"crossref","first-page":"3378","DOI":"10.1182\/bloodadvances.2022009366","article-title":"BTK\u00a0mutations in patients with chronic lymphocytic leukemia receiving tirabrutinib","volume":"7","author":"Jackson","year":"2023","journal-title":"Blood Adv"},{"issue":"19","key":"2025032119464761400_bib31","doi-asserted-by":"crossref","first-page":"5698","DOI":"10.1182\/bloodadvances.2022008955","article-title":"Acquired BTK mutations associated with resistance to noncovalent BTK inhibitors","volume":"7","author":"Qi","year":"2023","journal-title":"Blood Adv"},{"issue":"736","key":"2025032119464761400_bib32","doi-asserted-by":"crossref","first-page":"eabg5216","DOI":"10.1126\/scisignal.abg5216","article-title":"Kinase-deficient BTK mutants confer ibrutinib resistance through activation of the kinase HCK","volume":"15","author":"Dhami","year":"2022","journal-title":"Sci Signal"},{"issue":"25","key":"2025032119464761400_bib33","doi-asserted-by":"crossref","first-page":"3237","DOI":"10.1182\/blood-2016-01-695098","article-title":"HCK is a survival determinant transactivated by mutated MYD88, and a direct target of\u00a0ibrutinib","volume":"127","author":"Yang","year":"2016","journal-title":"Blood"},{"issue":"suppl 1","key":"2025032119464761400_bib34","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1182\/blood-2019-127674","article-title":"Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations [abstract]","volume":"134","author":"Woyach","year":"2019","journal-title":"Blood"},{"issue":"5","key":"2025032119464761400_bib35","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/s41375-021-01123-6","article-title":"BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib","volume":"35","author":"Estupinan","year":"2021","journal-title":"Leukemia"},{"issue":"suppl 1","key":"2025032119464761400_bib36","doi-asserted-by":"crossref","first-page":"1890","DOI":"10.1182\/blood-2023-173547","article-title":"Acquired mutations in patients (pts) with relapsed\/refractory (R\/R) chronic lymphocytic leukemia (CLL) that progressed in the ALPINE study [abstract]","volume":"142","author":"Brown","year":"2023","journal-title":"Blood"},{"issue":"4","key":"2025032119464761400_bib37","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1182\/bloodadvances.2023011574","article-title":"Five-year follow-up of a phase 2 study of ibrutinib plus fludarabine, cyclophosphamide, and rituximab as initial therapy in CLL","volume":"8","author":"Ahn","year":"2024","journal-title":"Blood Adv"},{"issue":"9","key":"2025032119464761400_bib38","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1182\/bloodadvances.2022008447","article-title":"Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL but second-site BTK mutations lead to\u00a0resistance","volume":"7","author":"Naeem","year":"2023","journal-title":"Blood Adv"},{"issue":"13","key":"2025032119464761400_bib39","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1182\/blood.2023022993","article-title":"Degraders upgraded: the rise of PROTACs in hematological malignancies","volume":"143","author":"Casan","year":"2024","journal-title":"Blood"},{"issue":"7762","key":"2025032119464761400_bib40","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1038\/s41586-019-1252-x","article-title":"Growth dynamics in naturally progressing chronic lymphocytic leukaemia","volume":"570","author":"Gruber","year":"2019","journal-title":"Nature"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/145\/10\/1005\/2357360\/blood_bld-2024-026672-main.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/145\/10\/1005\/2357360\/blood_bld-2024-026672-main.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T16:49:33Z","timestamp":1742575773000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/145\/10\/1005\/535067\/Novel-mechanisms-of-resistance-in-CLL-variant-BTK"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,6]]},"references-count":40,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,3,6]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2024026672","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,6]]}}}