{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T22:42:07Z","timestamp":1775947327957,"version":"3.50.1"},"reference-count":46,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health\/National Cancer Institute Cancer Center","award":["P30 CA008748"],"award-info":[{"award-number":["P30 CA008748"]}]},{"name":"National Institutes of Health\/National Cancer Institute Cancer Center","award":["P01 CA023766"],"award-info":[{"award-number":["P01 CA023766"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Over the last 10 years, the traditional treatment paradigms for CLL have been upended as the use of traditional chemoimmunotherapy regimens has declined in favor of novel targeted therapies. Targeted therapies have become the new standard of care in CLL given their superior progression-free survival (and overall survival, in some cases) when compared with chemoimmunotherapy, as well as their improved toxicity profiles. Targeted agents are FDA approved for the treatment of CLL including ibrutinib, acalabrutinib, zanubrutinib, and venetoclax. Importantly, as opposed to traditional chemotherapy regimens, the benefits of these targeted therapies appear to be consistent regardless of high-risk mutational status. In this review, we discuss the pivotal CLL studies of the last decade and the data supporting doublet and triplet novel\u2013novel combinations. We explore the use of new surrogate end points for PFS\/OS in targeted therapies such as undetectable minimal residual disease (uMRD) and their potential role in minimizing toxicity by permitting earlier treatment discontinuation. We also highlight areas that warrant further exploration and future studies that may help address some of these key questions.<\/jats:p>","DOI":"10.3390\/cancers15041018","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T02:06:43Z","timestamp":1675649203000},"page":"1018","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A History of Targeted Therapy Development and Progress in Novel\u2013Novel Combinations for Chronic Lymphocytic Leukemia (CLL)"],"prefix":"10.3390","volume":"15","author":[{"given":"Matthew","family":"Karr","sequence":"first","affiliation":[{"name":"Heme-BMT Hospitalist Division, University of California, San Francisco, CA 94720, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lindsey","family":"Roeker","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, Division of Hematology\/Oncology, New York, NY 10065, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1097\/PPO.0000000000000416","article-title":"Targeted Therapy in Chronic Lymphocytic Leukemia","volume":"25","author":"Kipps","year":"2019","journal-title":"Cancer J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1200\/EDBK_279099","article-title":"Current Perspectives on Therapy for Chronic Lymphocytic Leukemia","volume":"40","author":"Awan","year":"2020","journal-title":"Am. 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