The Presence of SH2B3 mutations Identifies a Distinct Subtype of Myelodysplastic Neoplasms

Background & aim: SH2B3 is a gene involved in cell proliferation by negatively regulating the TPO/MPL/JAK2 pathway. Up to 7% of myeloproliferative neoplasms present mutations in this gene. However, the prevalence, prognosis, and mechanism of action of SH2B3 mutations in myelodysplastic neoplasms (MDS) are unknown. The study aimed to analyze the clinical characteristics and prognostic impact of SH2B3 mutations in patients with MDS.

Methods: We included patients with MDS and chronic myelomonocytic leukemia dysplastic variant (CMML-MD) according to 2017 WHO criteria. The study group comprised patients with mutations in the SH2B3 gene with a variant allele frequency (VAF) < 40% or VAF ≥ 40% if the germline origin was excluded (MDS-SH2B3^mut). As a control group, we included MDS and CMML-MD patients without SH2B3 mutations (MDS-SH2B3^wt). Clinical and biological characteristics were collected at diagnosis. Genetic profiling included G-banding cytogenetics and NGS for the analysis of mutations in myeloid-related genes. The Revised and Molecular International Prognostic Scoring System (IPSS-R and IPSS-M) were employed for patients' risk stratification. Clinical and molecular variables were evaluated for associations with progression to acute myeloid leukemia (AML) and overall survival (OS). Clinical and molecular parameters, along with outcomes, were compared between MDS-SH2B3^mut and MDS-SH2B3^wt groups. Statistical analysis was performed using R (version 4.2.2).

Results: A total of 245 MDS patients were included: 84 SH2B3^mut patients from 18 international institutions and 161 MDS-SH2B3^wt patients from 2 institutions. The median follow-up for the entire cohort was 27 months (95%CI 19-34). The median age of the overall cohort was 75 years (IQR, 68-82) and 62% (n=152) were male. Obtained from 2 institutions, the observed prevalence of SH2B3 mutations was 3% (5 out of 166). There were not significant differences in age, sex, bone marrow blasts and blood counts between MDS-SH2B3^mut and MDS-SH2B3^wt patients. However, more CMML-MD patients were allocated in the MDS-SH2B3^mut group (19% vs 4%; p <0.01). Conversely, more MDS-multilineage dysplasia and MDS-excess blasts-2 were present in the MDS-SH2B3^wt group (40% vs 24%; p=0.01, and 16% vs 6%; p=0.03; respectively). Considering cytogenetics, patients with MDS-SH2B3^mut presented less frequently high and very-high IPSS-R cytogenetics risk groups than those with MDS-SH2B3^wt (2% in MDS-SH2B3^mut and 16% in SH2B3^wt patients; p<0.01). Therefore, MDS-SH2B3^mut patients were less frequently categorized into the high and very-high IPSS-R risk groups than MDS-SH2B3^wt patients. Specifically, only 10% of MDS-SH2B3^mut patients fell into the high and very-high IPSS-R risk groups, compared to 25% of MDS-SH2B3^wt patients (p<0.01). There were no significant differences in the IPSS-M classification between the two subgroups. Of note, MDS-SH2B3^mut patients presented higher frequencies of ZRSR2 (20% vs. 8%; p=0.01), SRSF2 (28% vs. 9%; p<0.01), and TET2 (55% vs. 35%; p<0.01) mutations compared to MDS-SH2B3^wt.

Patients with MDS-SH2B3^mut exhibited better outcomes compared to patients with MDS-SH2B3^wt. The median OS for patients with MDS-SH2B3^mut was of 90 months (CI95% 62-NR), whereas it was of 51 months (95% CI: 31-95) for patients with MDS-SH2B3^wt (p=0.05). Additionally, 0% of MDS-SH2B3^mut and 16% of MDS-SH2B3^wt patients progressed to AML at 60 months (HR 3.7; CI95% 1-14; p=0.02). Furthermore, the favorable outcomes associated with SH2B3 mutations were maintained even in patients within the high- and very IPSS-R score. In the multivariate analysis including SH2B3 mutation and the IPSS-R, SH2B3 mutation (HR 0.4; CI95% 0.2-0.9) and lower-risk categories (IPSS-R <3.5 points) (HR 0.3; CI95% 0.2-0.5) were identified as independent factors for better survival. Finally, in the multivariate model including SH2B3 mutation and the IPSS-M, SH2B3 mutation (HR 0.5; CI95% 0.3-1) and IPSS-M very-low risk category (HR 0.1; CI95% 0.1-0.6) were identified as independent factors for better survival.

Conclusions: Our study, the first to describe a cohort of MDS patients with SH2B3 mutations, revealed that MDS-SH2B3^mut patients exhibit distinctive characteristics, including favorable outcomes and an enrichment of mutations in splicing factor genes. These findings could have significant implications for guiding treatment decisions.

Metzeler:BMS/Celgene: Consultancy, Honoraria; Menarini Stem Line: Honoraria; AstraZeneca: Honoraria; Otsuka: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Honoraria; Astellas: Honoraria; Abbvie: Honoraria, Research Funding; Sysmex: Honoraria. Jerez:Aztrazeneca: Research Funding; GILEAD: Research Funding; Novartis: Consultancy; BMS: Consultancy. Díaz-Beyá:BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Abbvie: Consultancy. 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