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BTKi\/venetoclax\u2010treated patients with exposure to both novel agents (regardless of the reason for discontinuation) are classified as \u201cdouble\u2010exposed,\u201d and often have poor prognoses. This study aims to assess the efficacy and effectiveness of treatments in double\u2010exposed CLL patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>PubMed, Embase, and Web of Science databases were searched until December 2023.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We retrieved 3948 articles for screening and included 13 publications covering nine distinct studies. Three clinical trials reported a median PFS of 16.8\u2009months with pirtobrutinib, 13\u2009months with lisocabtagene maraleucel, and 10.1\u2009months with nemtabrutnib. ORR ranged from 58% with nemtabrutinib and 80% with lisocabtagene maraleucel. In observational studies, PFS ranged from 3\u2009months with chemoimmunotherapy to 12\u2009months with BTKi, and ORR ranged from 31.8% with chemoimmunotherapy to 85.7% with chimeric antigen receptors (CAR)\u00a0T\u2010cell therapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This study highlights the limited clinical data on efficacy outcomes for double\u2010exposed CLL\/SLL patients. Pirtobrutinib, lisocabtagene maraleucel, and a combination of ibrutinib and venetoclax have shown promising effects. However, the scarcity of treatment options and efficacy data for patients who have failed BTKi and venetoclax underscores a significant unmet medical need.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.70258","type":"journal-article","created":{"date-parts":[[2024,9,30]],"date-time":"2024-09-30T09:24:49Z","timestamp":1727688289000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Efficacy and Effectiveness Outcomes of Treatments for\u00a0Double\u2010Exposed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma Patients: A Systematic Literature Review"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4842-7551","authenticated-orcid":false,"given":"Mohammed","family":"Zuber","sequence":"first","affiliation":[{"name":"Clinical and Administrative Pharmacy, College of Pharmacy University of Georgia  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4061-9839","authenticated-orcid":false,"given":"Sreelatha","family":"Akkala","sequence":"additional","affiliation":[{"name":"School of Public Health The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1412-9783","authenticated-orcid":false,"given":"Niying","family":"Li","sequence":"additional","affiliation":[{"name":"Clinical and Administrative Pharmacy, College of Pharmacy University of Georgia  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7009-7907","authenticated-orcid":false,"given":"Sajesh\u00a0K.","family":"Veettil","sequence":"additional","affiliation":[{"name":"Department of Pharmacy Practice, School of Pharmacy IMU University  Kuala Lumpur Malaysia"},{"name":"School of Medicine Taylor's University  Subang Jaya Selangor Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2452-0556","authenticated-orcid":false,"given":"Chia\u00a0Jie","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Pharmacotherapy, College of Pharmacy University of Utah  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3821-4595","authenticated-orcid":false,"given":"Lorenzo","family":"Villa\u00a0Zapata","sequence":"additional","affiliation":[{"name":"Clinical and Administrative Pharmacy, College of Pharmacy University of Georgia  Athens Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,30]]},"reference":[{"key":"e_1_2_10_2_1","volume-title":"StatPearls","author":"Mukkamalla S. 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