Chimeric antigen receptor T-cell (CAR T) therapy has revolutionized the field of malignant hematology. CD19-targeted CAR T-cell therapy has resulted in effective, often durable, responses for chemotherapy-refractory B-cell lymphoma and B-acute lymphoblastic leukemia (B-ALL) in prospective clinical trials.

CAR T cells against B-cell maturation antigen have also shown overall response rates in the range of 70% to 80% and very good partial response or better in 50% to 60% of heavily pretreated patients with multiple myeloma. As the CAR T experience matures, so does our recognition of emerging toxicities that may contribute to the morbidity of our patients. Among these, distinct hematologic disorders including impaired hematopoietic reconstitution, hemostatic defects and a tendency toward thrombosis may be acquired after CAR T therapy. 

Whereas it is known that prolonged cytopenias can lead to prolonged transfusion dependency and infectious complications, less is understood about the consequences of abnormal hemostasis after CAR T therapy that could promote bleeding or thrombotic complications. Such coagulation abnormalities, specifically diffuse intravascular coagulation (DIC) are frequently attributed to cytokine release syndrome (CRS), although the mechanism and true relationship of such findings remains poorly understood. Ongoing exploration of the incidence and characteristics of bleeding and thrombosis after CAR T therapy is therefore necessary to elucidate such mechanisms and for the development of optimal management strategies.

This retrospective study recordS bleeding episodes and thrombotic complications and their associated clinical and laboratory characteristics in a cohort of 127 consecutive patients with diffuse large B-cell lymphoma (DLBCL) or ALL who were treated with CD19-directed CAR T therapy at Stanford University institution.

Twelve (9.4%) and 8 (6.3%) patients developed bleeding and thrombosis within the first 3 months, respectively. In the axi-cel subgroup, these occurred in 11.2% and 6.7%, respectively. Bleedingoccurred between days 8 and 30 (median, 17.5) and thrombosis between days 2 and 91 (median, 29).

Bleeding sites included genitourinary, soft tissue, intracranial, gastrointestinal, and pulmonary and were associated with features of consumptive coagulopathy. On univariate analysis, patients with bleeding were older, had lower baseline platelets, lower platelet and fibrinogen nadirs , and elevated lactate dehydrogenase.

Immune effector cell (IEC)–associated neurotoxicity syndrome (ICANS) grade >3 was associated with increased bleeding, prothrombin time prolongation, hypofibrinogenemia, and elevated D-dimer. Low pretreatment platelet counts were associated with bleeding in a multivariate logistic regression model.

Patients with thrombocytopenia or severe ICANS are at increased risk of bleeding and should be closely monitored, particularly within the first month after CAR therapy.

Future studies in larger cohorts should assess risk factors for systemiccoagulopathies in CAR T therapy, including their association with neurotoxicity.

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