{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T10:45:33Z","timestamp":1789469133312,"version":"build-2803163510"},"reference-count":12,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Ann Hematol"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The phase III BRUIN CLL-313 and CLL-314 trials have established pirtobrutinib, a noncovalent Bruton tyrosine kinase (BTK) inhibitor, as a candidate for first-line therapy in chronic lymphocytic leukemia (CLL), and all-lines regulatory approval has now been granted in the European Union. We highlight an untested asymmetry: after failure of covalent BTK inhibitors, pirtobrutinib retains phase III\u2013validated activity, whereas resistance to first-line pirtobrutinib can arise through kinase-domain mutations (e.g., A428D, L528W) that confer in vitro cross-resistance to covalent agents, the class that currently anchors relapse management. No clinical data exist on covalent BTK inhibitors after pirtobrutinib failure. We argue that, until reverse-sequence data emerge, a cautious approach that retains the clinically validated covalent-first sequence is reasonable for patients expected to need multiple lines of therapy, and we suggest mutation testing at progression, registry tracking of post-pirtobrutinib outcomes, and explicit discussion of sequencing in forthcoming guideline updates.<\/jats:p>","DOI":"10.1007\/s00277-026-07264-x","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:50:33Z","timestamp":1788270633000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sequencing asymmetry: the case for caution before first-line pirtobrutinib in chronic lymphocytic leukemia"],"prefix":"10.1007","volume":"105","author":[{"given":"Boyi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6844-7277","authenticated-orcid":false,"given":"Shenxian","family":"Qian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"7264_CR1","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1200\/JCO-25-02380","volume":"44","author":"W Jurczak","year":"2026","unstructured":"Jurczak W, Kwiatek M, Czyz J et al (2026) BRUIN CLL-313: randomized phase III trial of pirtobrutinib versus bendamustine plus rituximab in untreated patients with chronic lymphocytic leukemia\/small lymphocytic lymphoma. J Clin Oncol 44:466\u2013475. https:\/\/doi.org\/10.1200\/JCO-25-02380","journal-title":"J Clin Oncol"},{"key":"7264_CR2","doi-asserted-by":"publisher","first-page":"476","DOI":"10.1200\/JCO-25-02477","volume":"44","author":"JA Woyach","year":"2026","unstructured":"Woyach JA, Qiu L, Grosicki S et al (2026) Pirtobrutinib versus ibrutinib in treatment-na\u00efve and relapsed\/refractory chronic lymphocytic leukemia\/small lymphocytic lymphoma. J Clin Oncol 44:476\u2013485. https:\/\/doi.org\/10.1200\/JCO-25-02477","journal-title":"J Clin Oncol"},{"key":"7264_CR3","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1200\/JCO-25-02691","volume":"44","author":"MS Davids","year":"2026","unstructured":"Davids MS (2026) The BRUIN 313 and 314 trials open the door for noncovalent Bruton tyrosine kinase inhibition as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 44:435\u2013439. https:\/\/doi.org\/10.1200\/JCO-25-02691","journal-title":"J Clin Oncol"},{"key":"7264_CR4","unstructured":"European Medicines Agency (2026) Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 22\u201325 June 2026. https:\/\/www.ema.europa.eu\/en\/news\/meeting-highlights-committee-medicinal-products-human-use-chmp-22-25-june-2026 ; European Commission approval of the all-lines indication disclosed in Eli Lilly and Company\u2019s Q2 2026 results, 5 August 2026. Accessed 23 Aug 2026"},{"key":"7264_CR5","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1056\/NEJMoa2300696","volume":"389","author":"AR Mato","year":"2023","unstructured":"Mato AR, Woyach JA, Brown JR et al (2023) Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. N Engl J Med 389:33\u201344. https:\/\/doi.org\/10.1056\/NEJMoa2300696","journal-title":"N Engl J Med"},{"key":"7264_CR6","doi-asserted-by":"publisher","first-page":"2538","DOI":"10.1200\/JCO-25-00166","volume":"43","author":"JP Sharman","year":"2025","unstructured":"Sharman JP, Munir T, Grosicki S et al (2025) Phase III trial of pirtobrutinib versus idelalisib\/rituximab or bendamustine\/rituximab in covalent Bruton tyrosine kinase inhibitor\u2013pretreated chronic lymphocytic leukemia\/small lymphocytic lymphoma (BRUIN CLL-321). J Clin Oncol 43:2538\u20132549. https:\/\/doi.org\/10.1200\/JCO-25-00166","journal-title":"J Clin Oncol"},{"key":"7264_CR7","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1056\/NEJMoa2114110","volume":"386","author":"E Wang","year":"2022","unstructured":"Wang E, Mi X, Thompson MC et al (2022) Mechanisms of resistance to noncovalent Bruton\u2019s tyrosine kinase inhibitors. N Engl J Med 386:735\u2013743. https:\/\/doi.org\/10.1056\/NEJMoa2114110","journal-title":"N Engl J Med"},{"key":"7264_CR8","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1056\/NEJMoa2211582","volume":"388","author":"JR Brown","year":"2023","unstructured":"Brown JR, Eichhorst B, Hillmen P et al (2023) Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med 388:319\u2013332. https:\/\/doi.org\/10.1056\/NEJMoa2211582","journal-title":"N Engl J Med"},{"key":"7264_CR9","doi-asserted-by":"publisher","first-page":"3441","DOI":"10.1200\/JCO.21.01210","volume":"39","author":"JC Byrd","year":"2021","unstructured":"Byrd JC, Hillmen P, Ghia P et al (2021) Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: results of the first randomized phase III trial. J Clin Oncol 39:3441\u20133452. https:\/\/doi.org\/10.1200\/JCO.21.01210","journal-title":"J Clin Oncol"},{"key":"7264_CR10","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/S0140-6736(26)01204-3","volume":"408","author":"MS Davids","year":"2026","unstructured":"Davids MS, Eyre TA, Woyach JA et al (2026) Fixed-duration pirtobrutinib plus venetoclax\u2013rituximab versus venetoclax\u2013rituximab for patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (BRUIN CLL-322): an open-label, multicentre, randomised, controlled, phase 3 trial. Lancet 408:453\u2013470. https:\/\/doi.org\/10.1016\/S0140-6736(26)01204-3","journal-title":"Lancet"},{"key":"7264_CR11","doi-asserted-by":"publisher","first-page":"eadi5798","DOI":"10.1126\/science.adi5798","volume":"383","author":"S Montoya","year":"2024","unstructured":"Montoya S, Bourcier J, Noviski M et al (2024) Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1\/3 degrader NX-2127. Science 383:eadi5798. https:\/\/doi.org\/10.1126\/science.adi5798","journal-title":"Science"},{"key":"7264_CR12","doi-asserted-by":"publisher","first-page":"1818","DOI":"10.1038\/s41375-024-02317-4","volume":"38","author":"RL Wong","year":"2024","unstructured":"Wong RL, Choi MY, Wang H-Y, Kipps TJ (2024) Mutation in Bruton tyrosine kinase (BTK) A428D confers resistance to BTK-degrader therapy in chronic lymphocytic leukemia. Leukemia 38:1818\u20131821. https:\/\/doi.org\/10.1038\/s41375-024-02317-4","journal-title":"Leukemia"}],"container-title":["Annals of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07264-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00277-026-07264-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00277-026-07264-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:43:00Z","timestamp":1789465380000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00277-026-07264-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":12,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["7264"],"URL":"https:\/\/doi.org\/10.1007\/s00277-026-07264-x","relation":{},"ISSN":["1432-0584"],"issn-type":[{"value":"1432-0584","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"assertion":[{"value":"20 August 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"During the preparation of this work, AI-based tools were used for literature retrieval only; the authors reviewed and verified all content and take full responsibility for the integrity of the manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval is not applicable to this correspondence.","order":2,"name":"Ethics","label":"Ethics approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"404"}}