Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management.

Genetically engineered chimeric antigen receptor (CAR) T cells have become an effective treatment option for several advanced B-cell malignancies. Haematological side-effects, classified in 2023 as immune effector cell-associated haematotoxicity (ICAHT), are very common and can predispose for clinically relevant infections. As haematopoietic reconstitution after CAR T-cell therapy differs from chemotherapy-associated myelosuppression, a novel classification system for early and late ICAHT has been introduced. Furthermore, a risk stratification score named CAR-HEMATOTOX has been developed to identify candidates at high risk of ICAHT, thereby enabling risk-based interventional strategies. Therapeutically, growth factor support with granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, with haematopoietic stem cell (HSC) boosts available for patients who are refractory to G-CSF (if available). Although the underlying pathophysiology remains poorly understood, translational studies from the past 3 years suggest that CAR T-cell-induced inflammation and baseline haematopoietic function are key contributors to prolonged cytopenia. In this Review, we provide an overview of the spectrum of haematological toxicities after CAR T-cell therapy and offer perspectives on future translational and clinical developments.

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Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

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Declaration of interests KR reports research funding from Kite/Gilead; consultancy fees from Kite/Gilead and Bristol-Myers Squibb/Celgene; honoraria from Kite/Gilead, Novartis, and Bristol-Myers Squibb/Celgene; and travel support from Kite/Gilead and Pierre-Fabre. MDJ reports research funding from Kite/Gilead, Loxo@Lilly, and Incyte and consultancy fees from Kite/Gilead, Novartis, and Myeloid Therapeutics. NNS reports research funding from Lentigen, VOR Bio, and CARGO therapeutics and has participated in Advisory Boards (no honoraria) for Sobi, Allogene, invoX, ImmunoACT, and VOR. M-AP reports honoraria from Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharmal; serves on data safety and monitoring boards for Cidara Therapeutics, Medigene, and Sellas Life Sciences; serves on the scientific advisory board of NexImmune; has ownership interests in NexImmune, Omeros, and OrcaBio; and has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. MS reports research funding from Morphosys, Novartis, Seattle Genetics, AMGEN, Kite/Gilead, and Roche AG; consultancy fees from Novartis, Janssen, AMGEN, Celgene, Kite/Gilead, and Roche AG; and honoraria from AMGEN, Celgene, and Kite/Gilead.