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Management of haemostatic complications of chimaeric antigen receptor T‐cell therapy

D. Swan,J. Thachil

Published 2022 in British Journal of Haematology

ABSTRACT

The link between thrombosis, inflammation and the immune system is well established, with numerous cytokines and chemokines affecting pathways associated with thrombosis.1 Novel immunotherapies may have unintended prothrombotic consequences related to these effects, particularly when used in the treatment of conditions with high thrombotic potential such as haematological malignancies. CAR (chimaeric antigen receptor)Tcell therapy has shown remarkable efficacy particularly in the treatment of Bcell malignancies. CARTs are engineered T cells expressing a modified Tcell receptor (TCR) designed to recognize a tumour epitope. A hinge region connects the TCR to a costimulatory molecule which enhances CARTcell persistence and proliferation in vivo.2,3 CARTs directed against the CD19 antigen are approved for the treatment of relapsed refractory Bacute lymphoblastic leukaemia (BALL) and nonHodgkin lymphoma (NHL), based on results from the ELIANA (BALL), JULIET (diffuse large Bcell lymphoma [DLBCL]), ZUMA1 (DLBCL and primary mediastinal Bcell lymphoma [PMBCL], ZUMA2 (mantle cell lymphoma [MCL]), and ZUMA5 (follicular lymphoma) studies.49 Approval has also recently been granted by the European Medicines Agency for antiBcell maturation antigen (BCMA) CARTcell therapy in relapsed refractory multiple myeloma (MM).10 There have been several reports of thrombotic events occurring in patients following CARTcell therapy.11,12 There is some evidence to suggest that these complications may be associated with the development of cytokine release syndrome (CRS) following CARTcell infusion. CRS is a consequence of CARTcell proliferation, target cell lysis and cytokine production, characterized by fever, hypotension, capillary leak, multiorgan failure, neurological impairment, coagulopathy and sometimes death.13 Severe CRS is associated with worsened coagulopathy with features of disseminated intravascular coagulation (prolonged prothrombin time [PT], activated partial thromboplastin time [APTT], reduced fibrinogen, thrombocytopenia and increasing DDimers) alongside an increased risk of bleeding and thrombosis.

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