Risk Factors for Hematotoxicity Following Tisagenlecleucel for Pediatric B-Acute Lymphoblastic Leukemia

Introduction Hematotoxicity is the most frequent grade ≥3 toxicity following chimeric antigen receptor (CAR) T therapy. The CAR-HEMATOTOX score has been validated for prediction of post-CAR T hematotoxicity in adults with lymphoma, but risk factors in children and young adults (CAYA) with B-ALL are not well-defined. Objectives To identify risk factors for and outcomes of severe hematotoxicity in CAYA treated with tisagenlecleucel (tisa-cel). Methods Multi-institutional study involving CAYA ≤26 years infused with tisa-cel for B-ALL. Retrospective data was collected through the Pediatric Real World CAR Consortium (PRWCC). Of 185 CAYA infused, 41 were excluded due to missing data (n=10) or refractory disease or death before day 35 post-CAR T (n=31). Severe prolonged neutropenia (SPN) was defined as absolute neutrophil count (ANC) <500 cells/µL for ≥30 days in those alive and in remission at day 35 post-CAR T. Statistical analyses included comparisons using Mann-Whitney and Fisher's exact tests, receiver operating characteristic (ROC) curves, univariate logistic regression, and Kaplan-Meier analysis for overall survival (OS) and relapse-free survival (RFS). Results Of 144 patients, 23 (16%) met the definition of SPN and 121 (84%) did not. Patient characteristics are shown in Table 1. Pre-infusion, higher pre-infusion C-reactive protein (CRP), ferritin, bone marrow disease burden, and lower absolute neutrophil counts (ANC) and platelet counts were associated with SPN. Post-infusion, any grade cytokine release syndrome (CRS), severe CRS, CRS with hemophagocytic lymphohistiocytosis (HLH)-like manifestations, any grade neurotoxicity, peak CRP and ferritin, use of tocilizumab and steroids, and presence of infections within 30 days were associated with SPN. Cutpoints of continuous variables were chosen to maximize sensitivity and specificity for SPN. Pre-infusion, disease burden >15% had the highest odds ratio for SPN, while post-infusion, CRS with HLH-like toxicities, peak CRP >6.0mg/dL, and peak ferritin >3800ng/ml were among the variables with the highest odds ratios (Figure 1). In patients with SPN, OS was inferior (p<0.0001) and RFS trended towards being inferior (p=0.052), compared to those without (Figure 2). However, in patients without SPN, OS was similar between patients with high or low/no disease burden. Conversely, in patients with and without SPN, high disease burden was associated with reduced RFS. Conclusion We describe incidence, identify risk factors, and illustrate outcomes for the development of severe prolonged neutropenia in CAYA with B-ALL following tisa-cel. A multivariable model for SPN post-CAR T will be presented. Identification and validation of risk factors for severe hematotoxicity in the CAYA B-ALL population is critical for informing tailored risk mitigation practices in CAYA undergoing CAR T-cell therapy.