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.

Low incidence and molecular heterogeneity of pediatric T‐cell lymphoblastic lymphoma (T‐LBL) require an international, large‐scale effort to identify novel clinical biomarkers. The ongoing international clinical trial LBL2018 (NCT04043494) represents an ideal opportunity to implement a common analytic approach. Targeted next‐generation sequencing is well‐suited for this purpose; however, selection of relevant target genes for T‐LBL remains subject of ongoing debates. Our group has recently designed and evaluated a first target panel of 80 candidate genes for T‐LBL. The present study aimed at developing a novel optimized gene panel for large‐scale application and to promote an international agreement on a common core panel. Small sequence variants obtained from our former study were systematically analyzed and classified with regards to pathogenic relevance, to prioritize candidate genes. Additional genes were curated from literature and online databases for a more comprehensive analysis of relevant functions and signaling pathways. The new target panel TGP‐T‐LBL entails 84 candidate genes which are key actors in NOTCH, PI3K‐AKT, JAK–STAT, RAS signaling, epigenetic regulation, transcription, DNA repair, cell cycle regulation, and ribosomal function. From our former gene panel, 35 out of 80 candidate genes were selected for the novel panel. Forty‐six out of 84 genes are currently being analyzed in the ongoing international trial LBL2018. Exploratory analysis of prognostic relevance on mutation‐level suggested a potential association of PIK3CA variants c.1624G>A(p.Glu542Lys) and c.1633G>A(p.Glu545Lys) to occurrence of relapse, emphasizing particular relevance of mutation analysis in PI3K‐AKT signaling. Our approach promotes comprehensive and clinically relevant mutational profiling of pediatric T‐LBL.

Background: Mature aggressive B-cell lymphomas are heterogenous malignancies that make up more than half of all diagnosed non-Hodgkin lymphoma in children and adolescents. The overall survival rate increased over the last decades to 80%-90% due to fine tuning of polychemotherapy. However, new therapeutic implications are needed to further increase the overall survival. Current clinical trials analyze the therapeutic effect of rituximab in pediatric patients, while the mechanism of action in vivo is still not fully understood. Methods:Effector molecules important for tumor defense were analyzed before and at day 5 after rituximab treatment via flow cytometry. Serum rituximab levels were measured with an ELISA. Results:We evaluated patient parameters that may affect treatment response in relation to rituximab administration and serum rituximab levels. We indeed found a reduction of Fcγ receptor (FcγR) II levels after rituximab treatment in monocyte subtypes, whereas FcγRI expression was significantly increased. Serum levels of proinflammatory marker proteins S100A8/A9 and S100A12 significantly decreased after treatment to normal levels from an overall proinflammatory state before treatment. CD57, perforin, and granzyme B expression decreased after treatment, comprising a less cytolytic natural killer (NK) cell population. Conclusion:The highlighted effects of rituximab treatment on patient's immune response help in understanding the biology behind tumor defense mechanisms and effector function. After subsequent studies, these novel insights might be translated into patient care and could contribute to improve treatment of pediatric patients with mature aggressive B-cell lymphoma.

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