Post-transplant relapse in pediatric acute lymphoblastic leukemia in the era of CAR-T cell therapy. A multicenter analysis of Grupo Español de Trasplante Hematopoyetico y Terapia Celular (GETH-TC) Pediatric Committee.
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BACKGROUND: The management of relapsed acute lymphoblastic leukemia (ALL) after hematopoietic stem cell transplantation (HSCT) has evolved significantly. Initially, treatment options were limited to palliative care, salvage chemotherapy, and second HSCT. Currently, the focus has shifted to innovative immunotherapies, particularly CAR T-cell therapy. AIMS: This study aims to: (i) Analyze outcomes after relapse following HSCT and identify prognostic factors associated with prolonged survival. (ii) To evaluate and compare treatment strategies, including immunotherapy (e.g., CAR T-cell therapy) and second HSCT after achieving a new remission, or both treatments in high-risk cases. METHODS: This retrospective, multicenter study will evaluate the outcomes of HSCT relapse in pediatric ALL patients. Key endpoints include disease-free survival (DFS), relapse rate, and NRM. We enrolled 73 children with ALL who relapsed after HSCT in 10 hospitals of the Pediatric Committee of the Spanish Group of Transplantation (GETH-TC) between 2013 and 2021. Among them, 56 patients (77%) had B-cell ALL and 17 (23%) had T-cell ALL. RESULTS: The median time to relapse was 6 months after the first HSCT. CAR-T cell therapy was administered to 31 patients, all of whom achieved complete remission with negative MRD. However, two patients died prematurely due to cytokine release syndrome (CRS), resulting in a NRM of 7 ± 4%. Sixteen patients relapsed after CAR-T therapy with a cumulative incidence (CI) of 65 ± 11%. Seven of these patients subsequently underwent a second HSCT. The only significant prognostic factor for DFS was the MRD level prior to CAR-T therapy: DFS was 20 ± 8% with MRD ≥3% compared to 100% with MRD <3% (p = 0.002). At a median follow-up of 17 months after CAR-T therapy, DFS was 28 ± 10% and overall survival (OS) was 40 ± 10%. Second allogeneic HSCT was performed in 23 patients, including 7 who had previously received CAR-T therapy. Three patients died from NRM (CI: 19 ± 10%). Eight patients relapsed after the second HSCT (CI: 52 ± 13%), of which 2 were successfully treated with CAR-T therapy. At a median follow-up of 33 months after the second HSCT, DFS was 29 ± 11% and OS was 32 ± 10%. Of 17 patients with T-cell ALL, only 2 survived after a second HSCT with a DFS of 12 ± 9%. Of the 73 patients, 20 are alive with a median follow-up of 4 years (DFS: 20 ± 5%). Time to relapse after HSCT was the strongest predictor of outcome; no patient who relapsed within 6 months after the first HSCT survived. There was a trend towards worse DFS in patients who developed chronic GVHD during the first transplant, with 8 out of 9 relapsing despite rescue therapy (p < 0.07). CONCLUSIONS: Children with relapsed ALL after HSCT have a substantial chance of long-term survival if relapse occurs more than 6 months after the first transplant and if chronic GVHD was not present. The treatment paradigm has shifted to immunotherapy, including monoclonal antibodies and CAR-T therapy. The role of bridging to a second allogeneic HSCT after CAR-T therapy to improve long-term survival remains a subject of ongoing debate.