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Multiple randomized trials have documented the efficacy of oral therapy with the Bruton tyrosine kinase inhibitors ibrutinib and acalabrutinib (and zanubrutinib, pending a supplemental new drug application in CLL), as well as BCL2 inhibition using venetoclax. In this review, the authors highlight novel therapeutic strategies for using these agents in combination, either as doublet therapy or as triplet therapy, with anti\u2010CD20 antibodies. First, the current treatment landscape is outlined, and the data are reviewed for continuous and time\u2010limited therapeutic approaches, which constitute the current standard of care. Then, more recent reports are described from phase 2 and 3 studies exploring different combination strategies of Bruton tyrosine kinase and BCL2 inhibition for treatment\u2010naive patients. In addition, relevant differences are emphasized between patient characteristics (e.g., patient fitness and the presence of high\u2010risk disease features) and study methodology (e.g., dosing schedule, randomization, and assessment of measurable residual disease) across trials. Finally, the authors revisit the currently available data for these approaches in the context of ongoing studies and future planned trials, evaluating their potential impact on the frontline treatment landscape for CLL in the years to come.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cncr.34510","type":"journal-article","created":{"date-parts":[[2022,11,3]],"date-time":"2022-11-03T09:15:06Z","timestamp":1667466906000},"page":"18-31","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Novel combination approaches with targeted agents in frontline chronic lymphocytic leukemia"],"prefix":"10.1002","volume":"129","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7653-4792","authenticated-orcid":false,"given":"Andrew H.","family":"Lipsky","sequence":"first","affiliation":[{"name":"Herbert Irving Comprehensive Cancer Center Columbia University Medical Center  New York New York 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