Coagulopathy Following Chimeric Antigen Receptor T Cell Therapy in R/R Adult B Cell Malignancies: A Single Center Experience
Authors: Belbachir Safia , Tudesq Jean Jacques , Lamure Sylvain , Rocanieres Pierre , Properzi Elena , Ceballos Patrice , Fegueux Nathalie , Gehlkopf Eve , Paul Franciane , Tchernonog Emmanuelle , Theron Alexandre , Teyssier Anne-Charlotte , Diaz Isabelle , Patricia Aguilar-Martinez , Herbaux Charles , Cartron Guillaume 
Published: November 2021

Abstract
Background. Immunotherapy with chimeric antigen receptor T (CAR-T cells) is a new therapeutic approach approved for patients with relapsed/refractory (R/R) B-lymphoproliferative malignancies. Specific toxicities have been described following CAR-T cells therapy, mainly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Coagulation disorders have been described in patients experiencing CRS. However, data is scarce regarding such consequences.
Methods. We retrospectively evaluated patients treated with CAR T-cells for R/R B-cell lymphoma in our tertiary hospital between 2019, January 1 st and 2021, March 1 st. Post-infusion coagulation disorders were assessed, as well as factors associated with such anomalies using a multivariate logistic regression model.
Results. During the study period, 64 patients received CAR T-cell therapy for R/R diffuse large B-cell lymphoma (n=52, 81%), transformed follicular lymphoma (n=9, 14%) and mantel cell lymphoma (n=3, 5%).The median follow-up was 7.98 months (IQR 4.24; 12.39). All patients had a normal coagulation panel at CAR-T cells infusion. The incidence of CRS was 92% (n=59; grade 3-4 n=2, 3%) and ICANS 38% (n=24; grade 3-4 n=7; 11%). We observed a decrease in fibrinogen level in all patients (grade 3-4 n=44, 69%), occurring at day 11 (median) post-infusion, prolonged prothrombin time (PT) in 27 patients (42%, grade 3-4 n=0), at day 4 (median), and thrombocytopenia in 62 patients (97%, grade 3-4 n=46, 72%) at day 1 (median).
By multivariate analysis, fibrinogen below 2 g/L after CAR-T cells infusion was independently associated with CRS grade 2 or greater (OR 58.4; 95%CI [5.8-4212.8] p = 0.009), ICANS grade 2 or greater (OR 2.36; 95%CI [2.2-80.6] p = 0.007) and day-0 lymphocyte count (OR 0.32 per 0.1 G/L; 95%CI [0.10-0.89] p = 0.037). However, it was not associated with comorbidities, disease history, tumor burden, CAR product, or outcomes.
Furthermore, by the end of the study, 5 patients (8%) did not recover a normal fibrinogen level and 41 (64%) did not recover a normal platelet count. Others recovered a normal fibrinogen level within a median of 69 days, a normal platelet count within a median of 15 days, and a normal PT within in a median of 7 days. Interestingly, no significant thrombotic or hemorrhagic events were recorded for those patients.
Conclusion. A high incidence of asymptomatic coagulation disorders was observed after CAR-T cell therapy, notably prolonged hypofibrinogenemia. Further studies should focus on the mechanisms involved in such abnormalities.

Disclosures
Lamure: Janssen: Other: miscellaneous support , Research Funding; Gilead: Other: miscellaneous support ; Roche: Other: miscellaneous support ; Abbvie: Other: miscellaneous support ; Sanofi: Other: miscellaneous support ; Novartis: Other: miscellaneous support ; Pfizer: Other: miscellaneous support ; Actelion: Other: miscellaneous support . Paul: NOVARTIS: Other: BOARD; SERVIER: Other: BOARD. Tchernonog: JANSSEN: Consultancy; ABBVIE: Consultancy; ASTRAZENECA: Consultancy. Herbaux: Takeda: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Roche: Honoraria; Janssen: Honoraria. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria.