OUTCOMES OF SONIC HEDGEHOG (SHH) MEDULLOBLASTOMA (MB) IN CHILDREN AND ADULTS TREATED WITH RISK-ADAPTED THERAPY ON A PROSPECTIVE INTERNATIONAL PROTOCOL (SJMB12)

Abstract

BACKGROUND: SJMB12 (NCT01878617) was among the first protocols to treat newly diagnosed MB incorporating molecular subgrouping. METHODS: Tumors were subtyped and TP53 mutation assessed via immunohistochemistry. SHH patients were grouped into 2 strata: S1 (GTR/ NTR; M0) and S2 (residual > 1.5 cm2; MYC/MYCN amplification; M+). Treatment consisted of maximal surgical resection followed by risk adapted craniospinal irradiation (CSI) (S1 = 23.4 Gy CSI; S2= 36); 54 Gy primary site. Patients then received 4 cycles of chemotherapy consisting of Vincristine 1 mg/m2 on Day 1 and Day 8; Cisplatin 75 mg/m2 on Day 1 and Cyclophosphamide 1.5 gm/m2 on Day 2 and 3 with Mesna and IV fluid support. PEG Filgrastim was administered on Day 4. Skeletally mature pts (males with bone age ≥ 17 yrs.; females with bone age ≥ 15 yrs.) were also treated with the smoothened inhibitor Vismodegib for 12 months. RESULTS: Of the 660 patients accrued from 2013-2022, 110 were SHH (107 evaluable, 62 in S1 and 45 in S2). Median age was 12.2 yrs. (3.1-39.7) and 67 were males. 98 patients had GTR/NTR, 31 had M+ disease and 63 had nodular desmoplastic histology. TP53 mutation was detected in 7 (11.5%) S1 and 18 (40%) S2 pts. 5-year EFS for S1 and S2 were 84.5 } 6.4% and 61 } 11.5%, respectively. Five-year EFS of the S1 was 91.7 } 5.4% and 28.6 } 13.9% for TP53 wildtype and TP53 mutant cases, respectively, and 84.2 } 10.1% and 25.0 } 21.7% in the S2 cohort. CONCLUSION: Patients with low-risk SHH MB lacking TP53 mutation have excellent survival and may be considered for therapy reduction. TP53 mutation, with or without M+ disease, leads to a dismal outcome that needs novel therapy for cure.