Association of heparinoids exposure with cytokine release syndrome–related morbidity and mortality in patients receiving CAR-T or BITE therapies.

Abstract

e14510 Background: Chimeric antigen receptor (CAR)-T and bispecific T-cell engaging (BITE) therapies mediate cytotoxicity primarily via interferon-gamma (IFN-γ). While IFN-γ is critical in anti-cancer immunity and infection control, excessive systemic levels drive inflammation. This resembles hemophagocytic lymphohistiocytosis (HLH) IFN-γ pathophysiology. Sulfated glycosaminoglycans (sGAGs) play a critical role in locally containing IFN-γ in animal models of viral infection. We hypothesized that soluble therapeutic sGAGs such as heparinoids may interfere with native sGAG, resulting in widespread systemic cytokine storm/cytokine release syndrome (CRS) leading to adverse outcomes. Methods: A retrospective review using the Global TriNetX Research Network (18 HCO with complete data) of patients receiving the first treatment of CAR-T/BITE or HLH (index events) from 09/2017-12/2025 was carried out and divided into two cohorts based on heparinoid exposure within 30 days. Propensity matching for age at index, sex, Black race, lactate dehydrogenase levels (a surrogate for disease burden), common comorbidities and concomitant medications (37 parameters) was done. Kaplan-Meier survival curves assessed overall survival (OS). The incidence of CRS, inflammatory markers and opportunistic infections was evaluated using odds ratios (OR) with 95% confidence intervals. Results: After cohort matching, 1,001 patients per group were included for comparison (Table 1). Heparinoid exposure resulted in significantly worse OS [log-rank p=0.0026, adjusted hazard ratio (aHR) = 1.3, proportionality P=0.11 suggesting well-balanced cohorts]. These patients also showed an increased risk of CRS, opportunistic infections and elevated mean erythrocyte sedimentation rate (ESR). In secondary exploratory analyses, comparing anticoagulation with heparinoids vs direct thrombin inhibitors (DOAC) (n = 194 each), a similar trend toward worse OS and CRS was observed. Interestingly, analyses restricted to patients receiving heparin for non-therapeutic indications, had similar adverse outcomes. Finally, patients with HLH (n= 3278 each) exposed to heparinoids had increased risk of death (aHR = 1.66). Conclusions: Our findings suggest that heparinoid, but not DOAC, exposure is associated with CRS and poor OS in patients receiving CAR-T/BITE, implicating the need for confirmatory studies to establish safer anticoagulation strategies in at-risk individuals. Patient’s outcome with/without heparinoid exposure. Outcome Heparinoid n=1001 (%) NO heparinoid n=1001 (%) aHR (p-value)/OR (CI) Death 318 (32) 231 (23) 1.3 (0.0026) CRS 251 (35) 207 (25) 1.6 (1.24,1.93) ESR, mean (SD) 24.7 (25) 30.99 (28) p = 0.015 Opportunistic infection 118 (15) 88 (11) 1.5 (1.08,1.95) Heparinoid n=194 (%) DOAC n=194 (%) Death 66 (34) 41 (21) 1.37 (0.1131) CRS 33 (24) 23 (17) 1.6 (0.86,2.83)