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Review
. 2025 Jul 16:S0889-8588(25)00080-2.
doi: 10.1016/j.hoc.2025.05.008. Online ahead of print.

Management of Relapsed and/or Refractory Chronic Lymphocytic Leukemia

Allison Kagerer  1 , Meghan C Thompson  2
Affiliations
Review

Management of Relapsed and/or Refractory Chronic Lymphocytic Leukemia

Allison Kagerer et al. Hematol Oncol Clin North Am. .

Abstract

Covalent Bruton's tyrosine kinase inhibitors (cBTKis), including acalabrutinib and zanubrutinib, and the BCL2 inhibitor venetoclax are currently sequenced in both front-line and relapsed and/or refractory (R/R) chronic lymphocytic leukemia (CLL). A newer challenge is the management of patients with R/R CLL after exposure to both a cBTKi and BCL2 inhibitor. Herein, we review the management of R/R CLL following prior treatment with chemoimmunotherapy, cBTKi, and venetoclax-based therapy. We review treatment options for "double exposed" CLL including venetoclax retreatment, pirtobrutinib, and CAR T-cell therapy with lisocabtagene maraleucel. Emerging treatment options include agents in clinical trials such as BTK degraders and bispecific antibodies.

Keywords: Acalabrutinib; Chronic lymphocytic leukemia (CLL); Liso-cel; Pirtobrutinib; Relapsed CLL; Venetoclax; Zanubrutinib.

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Conflict of interest statement

Disclosure A.K: No disclosures to report. M.C.T: Research support (paid to the institution): AbbVie, Adaptive Biotechnologies, AstraZeneca, BeiGene, GenMab, Nurix Therapeutics, Genentech; Honoraria from: PeerView Medical Institute, Dava Oncology, eScientiq, Mashup Media LLC, Philips Group Oncology Communications, Intellisphere LLC/MJH Life Sciences, Clinical Care Options, Presisca; Travel support: Nurix Therapeutics, Genmab, Dava Oncology; Advisory Board and/or Consulting fees paid to the individual: AbbVie, AstraZeneca, BeiGene, Jannsen, Loxo Oncology at Lilly. MCT is supported in part by National Institutes of Health, United States/National Cancer Institute Cancer Center support grant P30 CA008748.

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