{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T11:30:17Z","timestamp":1792668617722,"version":"4.5.0"},"reference-count":84,"publisher":"American Society of Hematology","issue":"2","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,7,10]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Targeted therapy with covalent Bruton tyrosine kinase inhibitors (cBTKis) and\/or the B-cell lymphoma 2 inhibitor (BCL-2i) venetoclax is now well established in the first-line management of chronic lymphocytic leukemia (CLL). However, patients with \u201cdouble-refractory\u201d disease due to the acquired resistance to both drug classes represent an increasing clinical challenge for whom few well-tolerated and effective treatment options currently exist. The highly selective, noncovalent BTKi pirtobrutinib and CD19-directed chimeric antigen receptor T-cell therapy lisocabtagene maraleucel have both recently gained US Food and Drug Administation approval for use in patients with CLL, which has progressed following \u22652 prior lines, including a cBTKi and a BCL-2i. Additionally, novel BTK-directed therapies and T-cell\u2013engaging bispecific antibodies have achieved promising responses in pretreated CLL in early-phase clinical trials. Here, we review the mechanisms responsible for resistance to cBTKi and venetoclax in CLL, appraise recent evidence supporting the use of each of the novel and emerging agent classes, and then suggest innovative treatment strategies incorporating these in patients with double-refractory disease, remaining cognizant of the variability of access to novel therapies and clinical trials.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2024024893","type":"journal-article","created":{"date-parts":[[2025,4,10]],"date-time":"2025-04-10T15:06:51Z","timestamp":1744297611000},"page":"145-154","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":5,"title":["Doubling down: the new deal in the clinical management of double-refractory chronic lymphocytic leukemia"],"prefix":"10.1182","volume":"146","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1067-9315","authenticated-orcid":false,"given":"Brian T.","family":"Grainger","sequence":"first","affiliation":[{"name":"1Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2086-6031","authenticated-orcid":false,"given":"Philip A.","family":"Thompson","sequence":"additional","affiliation":[{"name":"2Department of Clinical Haematology, Peter MacCallum Cancer Centre and the Royal Melbourne Hospital, Parkville, VIC, Australia"},{"name":"3The Sir Peter MacCallum Department of Clinical Oncology, University of Melbourne, Melbourne, VIC, Australia"}],"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":"1Department of Haematology, Sir Charles Gairdner Hospital, Nedlands, WA, Australia"},{"name":"4Linear Clinical Research, Nedlands, WA, Australia"},{"name":"5University of Western Australia, Nedlands, WA, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"issue":"1","key":"2025071011261312700_bib1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41408-024-01001-1","article-title":"Update on the management of relapsed\/refractory chronic lymphocytic leukemia","volume":"14","author":"Bennett","year":"2024","journal-title":"Blood Cancer J"},{"issue":"6","key":"2025071011261312700_bib2","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1182\/bloodadvances.2023011327","article-title":"Venetoclax-rituximab is active in patients with BTKi-exposed CLL, but durable treatment-free remissions are uncommon","volume":"8","author":"Lew","year":"2024","journal-title":"Blood Adv"},{"issue":"25","key":"2025071011261312700_bib3","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1182\/blood.2020004782","article-title":"BTK inhibitor therapy is effective in 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Haematol"},{"issue":"20","key":"2025071011261312700_bib12","doi-asserted-by":"crossref","first-page":"4054","DOI":"10.1182\/bloodadvances.2021005083","article-title":"Outcomes of patients with CLL sequentially resistant to both BCL2 and BTK inhibition","volume":"5","author":"Lew","year":"2021","journal-title":"Blood Adv"},{"issue":"suppl 1","key":"2025071011261312700_bib13","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1182\/blood-2024-198147","article-title":"BRUIN CLL-321: randomized phase III trial of pirtobrutinib versus idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR) in BTK inhibitor pretreated chronic lymphocytic leukemia\/small lymphocytic lymphoma [abstract]","volume":"144","author":"Sharman","year":"2024","journal-title":"Blood"},{"issue":"10402","key":"2025071011261312700_bib14","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1016\/S0140-6736(23)01052-8","article-title":"Lisocabtagene maraleucel in chronic lymphocytic leukaemia and 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