{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:12:33Z","timestamp":1793142753130,"version":"4.5.0"},"reference-count":55,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Standard frontline treatment of chronic lymphocytic leukemia (CLL) is with fixed\u2010duration venetoclax\u2010based doublets or indefinite covalent Bruton tyrosine kinase inhibitor (BTKI). Although these approaches achieve excellent results, venetoclax doublets have diminished efficacy in high\u2010risk biological subgroups, and indefinite covalent Bruton tyrosine kinase inhibitor (cBTKI) is associated with cumulative cardiovascular and infectious toxicity. Triplet regimens for treatment of CLL involve simultaneous use of cBTKI, venetoclax, and anti\u2010CD20 monoclonal antibody. Three major frontline Phase 3 trials (CLL\u201013\/GAIA, AMPLIFY, and A041702) have demonstrated higher rates of undetectable minimal residual disease (uMRD) and longer remissions with triplets than doublets, particularly in patients with IGHV\u2010unmutated (IGHV\u2010U) disease. However, this comes at the cost of increased infectious toxicity, particularly with COVID\u201019, and thus has translated into a variable impact on progression\u2010free survival (PFS) and, to\u2010date, no overall survival (OS) benefit. Although there are promising Phase 2 data for triplets in patients with\n                    <jats:italic>TP53<\/jats:italic>\n                    aberrant or relapsed disease, the heterogeneity of treatment duration\/MRD definition, lack of control arm, and potential increased toxicity make it premature to use triplets in these groups. We recommend considering triplets in treatment na\u00efve CLL patients with IGHV\u2010U,\n                    <jats:italic>TP53<\/jats:italic>\n                    wild type, anticipated low incidence\/good tolerance of Gr\u2009\u2265\u20093 infection (&lt;70 years old, no major comorbidity and fully immunized) who are well informed and prioritize maximal time off therapy at the expense of increased short\u2010term logistical complexity. Future triplet research should focus on randomized trials in specific genomic subgroups, incorporating novel agents (e.g., non\u2010covalent BTKI, BTK degrader, and next\u2010generation BCL2 inhibitors) and new ways of adapting treatment duration to maximize efficacy and minimize toxicity.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70303","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T13:17:33Z","timestamp":1768828653000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Triplet regimens for frontline treatment of CLL\u2014Great company or just a crowd?"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3280-0120","authenticated-orcid":false,"given":"Sean","family":"McKeague","sequence":"first","affiliation":[{"name":"Department of Haematology Royal Brisbane &amp; Women's Hospital Herston Queensland Australia"},{"name":"Clinical Haematology Peter MacCallum Cancer Centre and Royal Melbourne Hospital Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John F.","family":"Seymour","sequence":"additional","affiliation":[{"name":"Clinical Haematology Peter MacCallum Cancer Centre and Royal Melbourne Hospital Melbourne Victoria Australia"},{"name":"University of Melbourne, School of Medicine Melbourne Victoria 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