AIM: Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). METHODS: Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. RESULTS: Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10-3), HR cytogenetics and TP53 alterations in BCP-ALL. CONCLUSION: Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT. TRIAL REGISTRATION: ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348.

Children's Cancer Group Division of Cancer Sciences School of Medical Sciences Faculty of Biology Medicine and Health Manchester Academic Health Science Centre The University of Manchester UK

Children's Cancer Group Division of Cancer Sciences School of Medical Sciences Faculty of Biology Medicine and Health Manchester Academic Health Science Centre The University of Manchester UK; Tata Translational Cancer Research Centre Tata Medical Center New Town Kolkata India

Children's Cancer Institute School of Women's and Children's Health University of New South Wales Sydney Australia

Department of Hematology Oncology SA Pathology at Women's and Children's Hospital and University of Adelaide Adelaide Australia

Department of Pediatric Hematology and Oncology Charles University 2nd Medical School and University Hospital Motol Prague Czech Republic

Department of Pediatric Hematology and Oncology Hannover Medical School Hannover Germany

Department of Pediatric Oncology Hematology Charité Universitätsmedizin Berlin Berlin Germany

Department of Pediatric Oncology Hematology Charité Universitätsmedizin Berlin Berlin Germany; German Cancer Consortium and German Cancer Research Center Im Neuenheimer Feld Heidelberg Germany

Department of Pediatric Oncology Hematology Charité Universitätsmedizin Berlin Berlin Germany; University Children's Hospital University Medical Center Rostock Rostock Germany

Department of Pediatric Oncology University Children's Hospital Zurich Switzerland

Princess Maxima Center for Pediatric Oncology Utrecht and Dutch Childhood Oncology Group Utrecht the Netherlands

Southmead Hospital Bristol Genetics Laboratory Bristol UK

St Anna Children's Research Institute and Children's Hospital Medical University of Vienna Vienna Austria

Wolfson Childhood Cancer Centre Translational and Clinical Research Institute Newcastle University Newcastle upon Tyne UK

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ClinicalTrials.gov
NCT00114348, NCT00967057