Therapies and outcomes following extramedullary relapse of pediatric and young adult ALL after CD19 CAR T-cell therapy

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy (CAR19) produces remarkably high remission rates in relapsed/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL); however, approximately 50% of children and young adults experience another relapse within 2 years after infusion. [1][2]2][3][4] Although the majority of post-CAR19 relapses are isolated to the bone marrow (BM), extramedullary disease (EMD) is not uncommon.Up to 34% of post-CAR19 relapses include EMD, either in isolation or in combination with BM disease. 5,6Outcomes after post-CAR19 relapse are poor overall, 6,7 but data regarding outcomes after EMD relapse are limited.To address this gap, we sought to describe the incidence, patterns, salvage strategies, and long-term outcomes of post-CAR19 EMD relapses in patients treated at our center.We conducted a retrospective review of patients aged <30 years treated on 5 CAR19 clinical trials or with commercial tisagenlecleucel (Kymriah, Novartis) for B-ALL at Children's Hospital of Philadelphia (CHOP) between 2012 and 2022.Patients treated on clinical trials received either the murine CD19/ 4-1BB CAR construct, CTL019 (US Food and Drug Administration approved as tisagenlecleucel; ClinicalTrials.govidentifiers: NCT01626495, NCT02906371, NCT02228096, and NCT02435849), or the humanized CD19/4-1BB CAR construct, humanized CD19-targeted CAR T-cell therapy (NCT02374333). 4,[8][9]][10] The EMD relapse cohort included patients who experienced a relapse with central nervous system (CNS) and/or non-CNS EMD involvement after CAR19 infusion but before consolidative hematopoietic cell transplant (HCT) or other antileukemia therapy.CNS relapse was defined as cerebrospinal fluid (CSF) with 5 white blood cells per L and positive for blasts or parenchymal or cranial nerve involvement.Non-CNS EMD was defined as focal bony, soft tissue, or mass lesions diagnosed by biopsy or characteristic imaging findings.To note, before CAR19 infusion, all patients had CSF sampling, but only those with a history of or clinical suspicion for EMD underwent imaging.Data were abstracted from clinical trial databases and electronic health records using REDCap electronic data capture tools hosted at CHOP. 11 This retrospective study was reviewed and considered exempt by the institutional review board of CHOP.The primary objective was to determine the overall survival (OS) rate from post-CAR19 EMD relapse.Secondary objectives were to evaluate the incidence of EMD relapse and to describe salvage regimens and their associated outcomes.OS was calculated using Kaplan-Meier methods from the day of post-CAR19 relapse identification to the time of death or censored at the last follow-up, with a data cutoff of 1 September 2023.Statistical