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Chimeric antigen-receptor (CAR)-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities involving hyperferritinemia, multi-organ dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-acute lymphoblastic leukemia (B-ALL) who develop HLH-like toxicities, although larger outcomes analyses of children and young adults (CAYA) with B-ALL who develop these toxicities following commercial tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYA with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-like toxicities, high grade CRS without HLH-like toxicities, or no to low grade CRS without HLH-like toxicities. Primary objectives included characterizing the incidence, outcomes, and pre-infusion factors associated with HLH-like toxicities. Among 185 CAYA infused with tisagenlecleucel, 26 (14.1%) met criteria for HLH-like toxicities. One-year overall survival and relapse-free survival were 25.7% and 4.7% in those with HLH-like toxicities, compared with 80.1% and 57.6% in those without. In multivariable analysis for death, meeting criteria for HLH-like toxicities carried a hazard ratio of 4.61 (95% confidence interval: 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-like toxicities had higher pre-tisagenlecleucel disease burden, ferritin, C-reactive protein levels, and lower platelet and absolute neutrophil counts than patients with high grade or no/low grade CRS without HLH-like toxicities. Overall, CAYA with B-ALL who developed HLH-like toxicities following tisagenlecleucel experienced high rates of relapse and non-relapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-like toxicities following tisagenlecleucel.

Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved forthis indication. Currently, patients receive a single dose of tisagenlecleucel across a wide doserange of 0.2 to 5.0× 106 and 0.1 to 2.5× 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7× 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300× 106 (n= 48 [27%]), 1.301 to 1.700× 106 (n= 46 [26%]), 1.701 to 2.400×106 (n= 43 [24%]), and 2.401 to 5.100× 106 (n= 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P= .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard totargeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.