{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T14:42:12Z","timestamp":1778337732601,"version":"3.51.4"},"reference-count":126,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2024,1,27]],"date-time":"2024-01-27T00:00:00Z","timestamp":1706313600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recent years have seen significant improvement in chronic lymphocytic leukemia (CLL) management. Targeting B-cell lymphoma (BCL-2) and Bruton\u2019s kinase (BTK) have become the main strategies to restrain CLL activity. These agents are generally well tolerated, but the discontinuation of these therapies happens due to resistance, adverse effects, and Richter\u2019s transformation. A growing population of patients who have previously used both BTK inhibitors and BCL2 suffer from the constriction of the following regimens. This review explores the resistance mechanisms for both ibrutinib and venetoclax. Moreover, we present innovative approaches evaluated for treating double-refractory CLL.<\/jats:p>","DOI":"10.3390\/ijms25031589","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T04:57:07Z","timestamp":1706504227000},"page":"1589","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Treatment of Double-Refractory Chronic Lymphocytic Leukemia\u2014An Unmet Clinical Need"],"prefix":"10.3390","volume":"25","author":[{"given":"Przemys\u0142aw","family":"Zygmunciak","sequence":"first","affiliation":[{"name":"Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3411-6357","authenticated-orcid":false,"given":"Tadeusz","family":"Robak","sequence":"additional","affiliation":[{"name":"Department of Hematology, Medical University of Lodz, 93-510 Lodz, Poland"},{"name":"Department of General Hematology, Copernicus Memorial Hospital, 93-510 Lodz, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0116-5002","authenticated-orcid":false,"given":"Bartosz","family":"Pu\u0142a","sequence":"additional","affiliation":[{"name":"Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/cyto.b.21595","article-title":"Reproducible diagnosis of chronic lymphocytic leukemia by flow cytometry: An European Research Initiative on CLL (ERIC) & European Society for Clinical Cell Analysis (ESCCA) Harmonisation project","volume":"94","author":"Rawstron","year":"2018","journal-title":"Cytom. 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