MEDB-35. Relationship between genetic profile, histology, clinical features and long-term outcome in young children medulloblastoma (YCMB) treated with upfront high dose chemotherapy (HDCT) in Italy

AIMS: We report a cohort of YCMB cases homogeneously treated with HDCT in two Italian institutions, and the prognostic impact of histology and genetics retrospectively evaluated. METHODS: All YCMB (aged≤3 years) treated with upfront HDCT in the period 1998-2019 were included, reclassified according to the WHO2021 classification of CNS tumours. Mutational status ofPTCH1, SUFU, and TP53 was analysed in selected cases. Histology and genetics were correlated with survival, secondary tumours(STs), and cancer predisposition syndromes(CPSs). RESULTS: Fifty-three patients were enrolled (62.3% male), median age 2.2 years. 21 had classic(CMB), 15 desmoplastic/nodular(DMB), 11 MBEN and 6 large-cell/anaplastic(AMB/LCMB) medulloblastoma. Metastases were present in 18. Genomic pattern showed SHH-TP53wt in 29 cases, non-WNT/non-SHH in 22; 2 were SHH-TP53mut. Induction chemotherapy (VCR/HDMTX, HDVP16, VCR/HDCTX and HDCARBO) was followed by 2-3 HDCT courses; irradiation reserved to cases with metastatic disease and/or residual tumours. 22 patients never received irradiation. SHH-TP53wt cases had significantly less metastasis (p=0.002), while non-WNT/non-SHH received more often irradiation (p<0.0001). OS at 5, 10, and 20 yrs was 0.73, 0.70 and 0.57 respectively in the entire cohort; stable at 0.85 (at 5, 10, and 20 yrs) in SHH-TP53wt patients while 0.58, 0.51 and 0.17 in the non-WNT/non-SHH. PFS at 5, 10, 20 yrs was stable at 0.89 in SHH-TP53wt and remained 0.35 in non-WNT/non-SHH. 13/53 patients presented Gorlin Syndrome; 1 had familial MB. 16 STs were reported in 14 cases; life-threatening, irradiation-related STs mainly in non-WNT/non-SHH cases. In SHH-TP53wt benign tumours or related to CPS were reported. CONCLUSIONS: This is one of the first series of YCMB treated with HDCT without stratification for stage and histology. The long follow-up highlights the frequency/types of associated CPS and STs; the latter, in non-WNT/non-SHH, were treatment-related and life-threatening.