INTEGRATED IMMUNOPHENOTYPING AND DRUG RESPONSE PROFILING REVEALS SUBTYPE-SPECIFIC SUSCEPTIBILITIES IN PEDIATRIC MDS WITH EXCESS BLASTS

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Background and Aims: Pediatric myelodysplastic syndrome with excess blasts (MDS-EB) is a rare hematopoietic disorder with risk of progression to acute myeloid leukemia.Allogeneic hematopoietic stem cell transplantation remains the only curative option but carries a significant relapse risk, particularly in high-risk subtypes.Improved diagnostic tools and therapies are urgently needed.This multicenter pilot study (Zurich, Vienna, Freiburg) integrates genetic, immunophenotypic, and drug response profiling (DRP) to better characterize pediatric MDS-EB and identify actionable treatment sensitivities.Methods: Bone marrow samples from children with MDS-EB (≥5% blasts) underwent harmonized multiparametric flow cytometry and parallel drug testing.On our DRP platform we screened ≥25 targeted agents for 72h in six-point serial dilutions by image-based automated microscopy.Ex vivo drug sensitivities were correlated with immunophenotypic markers and genetic subtypes.Results: Of 17 samples collected, 13 passed quality control with successful data output within a turn-around time of 10 days from sample acquisition.UBTF tandem duplications (UBTF-TD) and monosomy 7 were found in 6 and 5 cases, respectively and were mutually exclusive.Immunophenotyping showed full concordance of blast populations in all samples across sites (Vienna-Zurich) and modalities (flow cytometryfluorescence microscopy).All UBTF-TD samples displayed high ex vivo sensitivity to BCL-2 inhibitor venetoclax, while showing lower sensitivity to cytarabine compared to monosomy 7 samples.Furthermore, a distinctive ex vivo response to menin inhibitors was observed in UBTF-TD cases.These findings suggest subtype-specific drug sensitivities.Conclusions: This study demonstrates the feasibility of harmonized immunophenotyping and drug response profiling in pediatric MDS-EB across international centers in the EWOG consortium.Our data highlight UBTF-TD as a biologically and pharmacologically distinct subgroup with sensitivity to venetoclax and menin inhibitors.The ongoing expansion of the cohort and correlation with clinical response data and among platforms aim to support future integration of DRP into clinical decision-making and the development of new treatment strategies.

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