Hemophagocytic lymphohistiocytosis and disseminated intravascular coagulation are underestimated, but fatal adverse events in chimeric antigen receptor T-cell therapy

Abstract

Hematotoxicity is the most common long-term adverse event (AE) after chimeric antigen receptor T-cell (CAR-T) therapy. However, patients who receive CAR-T therapy in pivotal clinical trials are subjected to restrictive selection criteria, always causing an underestimate of rare but fatal toxicities. Here, we systematically analyzed CAR-T-associated hematologic AEs using the Food and Drug Administration Adverse Event Reporting System between January 2017 and December 2021. Disproportionality analyzes were performed using reporting odds ratios (ROR) and information component (IC), and the lower limit of the ROR and IC 95% confidence interval (CI) (ROR025 and IC025) exceeding one and zero was considered significant, respectively. Among the 105,087,611 reports in FAERS, 5112 CAR-T-related hematotoxicity reports were identified. We found 23 significant over-reporting hematologic AEs (ROR025 >1) compared to the full database, of which hemophagocytic lymphohistiocytosis (HLH, n = 136 [2.7%], ROR025 = 21.06), coagulopathy (n = 128 [2.5%], ROR025 = 10.43), bone marrow failure (n = 112 [2.2%], ROR025 = 4.88), disseminated intravascular coagulation (DIC, n = 99 [1.9%], ROR025 = 9.64), B cell aplasia (n = 98 [1.9%], ROR025 = 118.16, all IC025 > 0) were highly underreported AEs in clinical trials. Importantly, HLH and DIC led to mortality rates of 69.9% and 59.6%, respectively. Lastly, hematotoxicity-related mortality was 41.43% and 22 death-related hematologic AEs were identified using LASSO regression analysis. These findings could help clinicians early alert those rarely reported but lethal hematologic AEs, thus reducing the risk of severe toxicities for CAR-T recipients.

Endothelial activation and damage as a common pathological substrate in different pathologies and cell therapy complications

“…Coagulopathy is an underestimated adverse effect of CAR T-cell therapies ( 214 ) that usually derives from severe CRS or ICANS ( 157 , 211 ). While isolated changes in coagulation parameters, such as elevation in D-dimer, increase in fibrinogen degradation product, decrease of fibrinogen levels and prolongation of activated partial thromboplastin time (aPTT), can be observed in a high proportion of patients ( 215 , 216 ), the analytical and clinical phenotype of DIC occurs only in cases of high-grade toxicities and is related to an increase of the non-relapse mortality ( 215 ).…”

Pediatric Histiocytic Disorders: Morphology, Immunophenotype and Genetics

“…22,23 HLH can be driven by genetic abnormalities (familial) or acquired (secondary) etiologies associated with infection, autoimmune, or malignant processes. 96,97 Familial HLH is associated with genetic mutations in PRF1, UNC13D, STXBP2, and STX1. Other less frequent genetic defects affect genes involved in granule/pigment abnormalities (RAB27A, LYST, and AP3B1), X-linked lymphoproliferative disease genes (SH2D1A and XIAP), and others such as NLRC4 and CDC42.…”

Coagulation abnormalities associated with CAR‐T‐cell therapy in haematological malignancies: A review

“…17,21 When examining the data specifically for axicabtagene ciloleucel and tisagenlecleucel, the mortality rates can be as high as 59.6%. 38 Noteworthy, all patients who experienced DIC-related mortality were also affected by grade 3/4 CRS and died between days 5 and 21. 17,21 The incidence of DIC was associated with the severity of CRS.…”