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Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005–2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.

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BACKGROUND: Individuals with rhabdoid tumor predisposition syndrome (RTPS1 – SMARCB1, RTPS2 – SMARCA4) have a propensity to develop malignant rhabdoid tumors (MRT). Affected patients typically present < age 12 months with synchronous tumors (SYN) exhibiting an unusually aggressive clinical behavior. Due to the rarity of RTPS, standards for management are evolving. METHODS: Clinical, genetic, and treatment data of 90 patients with RTPS from 16 countries were analyzed (2004 – 2020). Therapy followed the EU-RHAB recommendations. Tumors and matching blood samples were investigated for SMARCB1 and/or SMARCA4 mutations using FISH, MLPA and sequencing. DNA-methylation subgroups were determined using DNA methylation arrays. RESULTS: The median age at diagnosis of 52 girls and 38 boys was 5.5 months (0 – 203). 55.5% (50/90) of patients presented with an atypical teratoid/rhabdoid tumor (ATRT), 23.5% (21/90) demonstrated SYN, and 21% (19/90) extracranial MRT. RTPS1 was present in 84-, RTPS2 in six patients. In 77% (65/84) complete data on SMARCB1 mutational status were generated. Methylation subgroup status was available in 59% (40/68) of ATRT or SYN. The 5-year overall- (OS) and event free survival rates of patients with RTPS1 were 19.8 ± 4.8% and 15 ± 4.2%, respectively. Age < 1 year at diagnosis (10.1±4.3% vs. 46.7±11.1%), presence of SYN (5.3±5.1% vs. 24.8±6%), histological diagnosis (ATRT vs. eMRT/RTK/SYN) (26.8±7.1% vs. 11.9±5.6%), localized disease (34.5±8 vs. 8.3±4.6%), and presence of PGV at C-terminal (33±8.6% vs. 9.4±5.3%) were significant prognostic factors for 5-year OS in univariate analysis. INTERPRETATION: In the largest cohort of patients with RTPS, predictors significant for positive outcome could be detected: age > 1 year, absence of SYN, histological diagnosis ATRT, localized disease and PGV located at C-terminal. In our research project, we aim to characterize the complete pheno- and genotype of patients with RTPS to develop a risk score including surveillance recommendation.

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Российский журнал ДЕТСКОЙ ГЕМАТОЛОГИИ и ОНКОЛОГИИ R u s s i a n J o u r n a l o f P e d i a t r i c H e m a t o l o g y а n d O n c o l o g y 12

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