T-cell lymphoblastic lymphoma (T-LBL) is a heterogeneous malignancy of lymphoblasts committed to T-cell lineage. Dismal outcomes (15-30%) in case of T-LBL relapses warrants for establishing risk-based treatment in future. This is a first comprehensive, systematic, integrated genome-wide analysis including relapse cases aimed towards identifying molecular markers of prognostic relevance for T-LBL. NOTCH1 was identified as putative driver for T-LBL. Activated NOTCH/PI3K-AKT signaling axis and alterations in cell cycle regulators constitutes the core oncogenic program for T-LBL. Mutated KMT2D was identified as a prognostic marker. The cumulative incidence of relapse was 47±17% in patients with KMT2D mutations compared with 14±3% in KMT2D wildtype. Structural analysis of the mutated domains of KMT2D revealed plausible impact on the structure and functional consequences. These findings provide new insights into the pathogenesis of T-LBL including high translational potential. The ongoing trial LBL 2018 (NCT04043494) allows prospective validation and subsequent fine-tuning of the stratification criteria for T-LBL risk groups to improve survival of the pediatric patients.

Despite poor survival, controversies remain in the treatment for refractory or relapsed pediatric non-Hodgkin lymphoma (r/r NHL). The current project aimed to collect international experience on the re-induction treatment of r/r NHL, hematopoietic stem cell transplantation (HSCT), risk factors associated with outcome, and to suggest treatment recommendations. Inclusion criteria were (i) refractory disease, disease progression or relapse of any NHL subtype except anaplastic large cell lymphoma, (ii) age < 18 years at initial diagnosis, (iii) diagnosis in/after January 2000. Data from 639 eligible patients were evaluable. The eight-year probability of overall survival was 34 ± 2% with highly significant differences according to NHL subtypes: 28 ± 3% for 254 Burkitt lymphoma/leukemia, 50 ± 6% for 98 diffuse large B-cell lymphomas, 57 ± 8% for 41 primary mediastinal large B-cell lymphomas, 27 ± 3% for 177 T-lymphoblastic lymphomas, 52 ± 10% for 34 precursor-B-cell lymphoblastic lymphomas and 30 ± 9% for 35 patients with rare NHL subtypes. Subtype-specific factors associated with survival and treatment recommendations are suggested. There were no survivors without HSCT, except in few very small subgroups. Conclusions: There is an urgent need to further improve survival in r/r NHL. The current study provides the largest real-world series, which underlines the role of HSCT and suggests treatment recommendations.

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