A meta-analysis to assess the risk of bleeding and thrombosis following chimeric antigen receptor T-cell therapy: Communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy

Background Chimeric antigen receptor T cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and bleeding complications have been reported. Accurate estimates for thrombotic and bleeding outcomes are lacking. Methods We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to February 2022 for studies reporting thrombotic or bleeding outcomes in patients receiving CAR T-cell therapy. Pooled event rates were calculated using a random-effects model. We performed subgroup analyses stratified by follow up duration, CAR T-cell target antigen, and underlying hematologic malignancy. Results We included 47 studies with a total 7040 patients. High heterogeneity between studies precluded reporting of overall pooled rates of thrombotic and bleeding events. In studies with follow-up duration of ≤6 months, the pooled incidence of venous thrombotic events were 2.4% (95% CI 1.4-3.4, I2 = 0%) per patient-month whereas the rate was 0.1% (95% CI 0-0.1, I2 = 0%) per patient-month for studies with longer follow-up periods (> 6 months). The pooled incidences of any bleeding events per patient-month in studies with follow-up duration of ≤6 months and > 6 months were 1.9% (95% CI: 0.6-3.1, I2 = 78%) and 0.3% (95% CI: 0-0.8, I2 = 40%) respectively. Secondary analyses by CAR T-cell target antigen, underlying malignancy and primary outcome of the studies did not reveal significant differences in the rates of thromboembolism, any bleeding or major bleeding events. Conclusion The risk of both thrombosis and bleeding following CAR T-cell therapy appears to be highest in the initial months following infusion. Chimeric antigen receptor T cell (CAR T-cell) therapy is increasingly utilized for treatment of hematologic malignancies. Hematologic toxicities including thrombosis and bleeding complications have been reported. Accurate estimates for thrombotic and bleeding outcomes are lacking. We searched MEDLINE, EMBASE, and Cochrane CENTRAL up to February 2022 for studies reporting thrombotic or bleeding outcomes in patients receiving CAR T-cell therapy. Pooled event rates were calculated using a random-effects model. We performed subgroup analyses stratified by follow up duration, CAR T-cell target antigen, and underlying hematologic malignancy. We included 47 studies with a total 7040 patients. High heterogeneity between studies precluded reporting of overall pooled rates of thrombotic and bleeding events. In studies with follow-up duration of ≤6 months, the pooled incidence of venous thrombotic events were 2.4% (95% CI 1.4-3.4, I2 = 0%) per patient-month whereas the rate was 0.1% (95% CI 0-0.1, I2 = 0%) per patient-month for studies with longer follow-up periods (> 6 months). The pooled incidences of any bleeding events per patient-month in studies with follow-up duration of ≤6 months and > 6 months were 1.9% (95% CI: 0.6-3.1, I2 = 78%) and 0.3% (95% CI: 0-0.8, I2 = 40%) respectively. Secondary analyses by CAR T-cell target antigen, underlying malignancy and primary outcome of the studies did not reveal significant differences in the rates of thromboembolism, any bleeding or major bleeding events. The risk of both thrombosis and bleeding following CAR T-cell therapy appears to be highest in the initial months following infusion.