Pre-infusion risk factors predict severe infectious complications of CAR T-cell therapy in pediatric and adult patients with B-ALL.

Despite the curative potential for chimeric antigen receptor (CAR) T-cells in B-cell acute lymphoblastic leukemia (B-ALL), efficacy can be limited by life-threatening adverse events such as severe infections. As immune effector cell-associated hematotoxicity and secondary immunodeficiency may be particularly profound in B-ALL, understanding pre-infusion risk of severe infection is imperative. The ALL-HEMATOTOX (ALL-HT) score is a recently validated tool designed to predict CAR-associated hematotoxicity in B-ALL, but the relationship between ALL-HT and severe infections post-infusion has not yet been comprehensively assessed. In this multicenter, retrospective analysis, we evaluated ALL-HT and other pre-infusion variables for an association with severe infection through day+60 (D+60) in patients with B-ALL treated with CD19 and CD22-based CAR T-cell constructs across three institutions. Infections were identified by microbiology, histopathology, or as a clinical syndrome and graded by CTCAE (Common Terminology Criteria for Adverse Events) V.5.0. Severe infections were defined as grade≥3. Multivariable logistic regression and Cox proportional hazard models were constructed to identify independent risk factors for infection. Across 350 patients receiving CAR T-cells, 79 (23%) developed a severe infection within day+60 post-CAR, including 8 patients with grade 4 (life-threatening) infection and 5 patients with grade 5 (fatal) infections. Bloodstream infections were the most common, comprising 67% of those with severe infections. In multivariable analysis, pre-infusion factors associated with severe infection included older age (OR 1.35 (1.1-1.6), p=0.002), prior severe infection (OR 2.1 (1.2-3.7), p=0.009), and a higher ALL-HT score (OR 1.15 (1.01-1.31), p=0.04). Patients classified as high-risk (HR) by ALL-HT had a greater risk of infection compared with low-risk patients (HR 1.4 (1.1-2.7), p=0.014).Multiple severe infections occurred in 24 patients (7%). In a subanalysis, ALL-HT risk of infection was primarily driven by baseline thrombocytopenia, with a cut-off of≤50 000 platelets/µL strongly predicting risk of infection (HR 2.2 (1.3-3.6), p=0.002). Post-infusion infection risk was driven by a longer duration of neutropenia (OR 1.26 (1.1-1.4), p<0.001). Older age, prior infection history, baseline thrombocytopenia, and higher ALL-HT scores are strong independent risk factors for severe infection among patients with B-ALL receiving CAR T-cells. These factors may guide individualized risk mitigation to prevent severe infections in this high-risk patient population. NCT03827343.