HLH-like toxicities predict poor survival after the use of tisagenlecleucel in children and young adults with B-ALL

Abstract

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.

Mechanisms and management of CAR T toxicity

“…Risk factors that have been implicated in the development of IEC-HS include baseline disease burden, CAR T proliferation dynamics, immune resistance mechanisms, target antigen, CAR T cell construct, costimulatory domain, T cell selection, cell dose and patient characteristics (baseline inflammation, immune suppression, cytopenias, genetic predisposition). ( 45 , 118 , 119 , 125 , 126 ). While the underlying pathophysiology of IEC-HS remains to be fully elucidated, similarities to CRS have been observed.…”

Treatment strategies for progressive immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome: case series

“…As HLH-like toxicities independently predict poor survival, for instance after tisagenlecleucel, 1,17 effective treatment is urgently needed. Since guidance regarding the most appropriate second-and third-line agents is lacking, and systematic study may not be feasible, these cases highlight 3 different approaches for the treatment of IEC-HS.…”