Incidence of thrombosis and bleeding in patients receiving CAR-T cell therapy: A multicentric retrospective analysis of the Canadian experience Free

Introduction: Autologous genetically modified T cells armed with CD19-targeting chimeric antigen receptors (CARs) have revolutionized treatment strategies and significantly modified the outcomes of patients with hematologic malignancies. However, this therapeutic modality comes at the expense of significant treatment-related complications, such as cytokine release syndrome (CRS), immune effector-associated neurotoxicity (ICANS), and prolonged cytopenias. Most patients who receive CAR-T cell infusions develop CRS, characterized by a storm of cytokines that leads to a systemic inflammatory response manifested by fever, hypoxemia, and organ dysfunction. This inflammatory milieu has been variably associated with thrombotic and hemorrhagic complications. Besides, due to the significant comorbid complications developed by the individuals receiving CAR-T therapies, most centers offer only in-hospital CAR-T infusions, incrementing the risk of thrombotic complications. However, the risk-benefit ratio of thromboprophylaxis in this patient population remains unclear.

In this multicentric retrospective study, we aim to determine the incidence of thrombosis and bleeding in patients receiving CAR-T cell therapy for the treatment of lymphoid malignancies in Canada.

Methods: We conducted a retrospective chart review of adult individuals with CD19-positive lymphomas or acute lymphoblastic leukemias who received CAR-T cell therapy at eight participating Canadian centres from September 2018 to December 2023. Data on patient demographics (including cardiovascular risk factors and malignancy-related variables) and clinical outcomes up to 90 days following the CAR-T infusion were collected. The outcomes of interest included the development of major venous thromboembolism (VTE), defined as proximal lower or upper extremity deep vein thrombosis and pulmonary embolism; clinically relevant bleeding (CRB), defined as the composite of major bleeding and clinically relevant non-major bleeding events per the International Society on Thrombosis and Haemostasis; and death. The incidence of VTE and CRB during the follow-up period were estimated using the cumulative incidence function, treating death as a competing event.

Results: Our patient population consisted of 561 individuals who had undergone CAR-T therapy. Three hundred and thirty-two patients (59.2%) received axicabtagene ciloleucel, 210 (37.4%) received tisagenlecleucel, and 19 (3.4%) received brexucabtagene autoleucel. Five hundred and fifty-one (98.2%) had undergone this treatment for CD19-positive lymphomas. 37.8% were female, and the median age was 61 (interquartile range [IQR] 16). 33.2% had a diagnosis of hypertension, 17.1% had diabetes, 10.7% had a renal function of less than 60 mL/min, and the median body mass index was 26.5 (IQR 7.5). 31.2% of patients had a prior diagnosis of VTE, and 6.4% had a prior diagnosis of arterial thromboembolism. 32.9% of patients received anticoagulation therapy before or during the CAR-T treatment, while 9.3% received an antiplatelet agent. Thromboprophylaxis was given to 54.3% of patients, most commonly in the form of low-molecular-weight heparin. Following CAR-T therapy, 87.0% of patients developed CRS and 37.5% developed ICANS. During the 90-day follow-up period, 8.7% of patients died. The cause of death was attributed to disease progression in 65.3% of cases, sepsis in 12.2%, treatment toxicities in 8.2%, cardiovascular cause in 6.1%, bleeding in 4.0% and unknown in 4.0%. At 90 days post-CAR-T, the cumulative incidence of VTE was 6.7% (95% confidence interval [CI] 4.8-9.0). No fatal pulmonary embolism was documented. The cumulative incidence of CRB was 6.5% (95% CI 4.7-8.8). There were two fatal bleeding events, both intracranial hemorrhages in patients not receiving thromboprophylaxis but with thrombocytopenia (platelets less than 100).

Conclusion: Patients receiving CAR-T therapy for CD19-positive lymphomas or acute lymphoblastic leukemias are at elevated risks of both major VTE and CRB during the 90-day period following CAR-T infusion. Although both thrombotic and bleeding events occurred at similar rates, bleeding was fatal in two cases. Identifying which CAR-T patients should receive thromboprophylaxis during the CAR-T treatment remains a significant challenge. Additional analyses on risk factors for the development of thrombotic and bleeding complications are underway.