Evaluation of the Prognostic Impact of STAG2 in the Molecular International Prognostic Scoring System for Myelodysplastic Syndromes

Introduction

The molecular international prognostic scoring system (IPSS-M) for patients with myelodysplastic syndrome (MDS) has demonstrated added value beyond hematological parameters and cytogenetic risk groups. The IPSS-M incorporates mutations in 16 main effect genes and 15 residual genes. The main objective of this study was to evaluate the potential prognostic impact of two residual genes, STAG2 and PHF6, for which recent studies suggest a potential underestimation of their value.

Methods

Two-hundred and nine patients consecutively diagnosed with MDS between 2019 and 2024 were included. Bone marrow aspirate material at diagnosis was sequenced using next-generation-sequencing (NGS) with two panels targeting recurrent mutated genes in myeloid pathology: Oncomine Myeloid (Thermo) from 2019 to 2022 and Haematology OncoKitDX (Healthincode) from 2023 onwards. With a target depth of x1400, both panels covered the 16 main effect genes of the IPSS-M and within the residual group, at least the two genes of interest in this study: PHF6 and STAG2. Statistical analysis included univariate and multivariate analysis, adjusted for variables considered as confounding factors in the IPSS-M design: aged, sex and previous cytotoxic therapy.

Results

The mean age of the cohort was 71 years with a male predominance (61%). The distribution according to the 2017 WHO classification was MDS-unilineage dysplasia (10%), MDS-multilineage dysplasia (40%), MDS with ring sideroblasts (12%, including both unilineage and multilineage dysplasia), MDS with isolated del(5q) (4%), MDS with excess blasts type 1 (16%), MDS with excess blasts type 2 (17%) and 1 case of unclassifiable MDS. Stratification into the six IPSS-M groups showed prognostic value for progression to acute myeloid leukemia (AML) with a hazard ratio (HR) of 2.4 (95% CI 1.7-3.4; p≤0.001) and for a lower overall survival (OS) (HR 1.6; 95% CI 1.4-1.9; p≤0.001).

Seventeen cases (8%) had mutations in STAG2. At diagnosis, patients with STAG2 mutations had significantly lower levels of hemoglobin (8.8 vs 10.1 g/dl; p=0.012), lower platelet counts (138 vs 171 x10⁹/L, p=0.024) and a higher percentage of blasts in bone marrow (7.3 vs 3.9%, p=0.006). The presence of a STAG2 mutation showed significant prognostic value for progression to AML in both univariate and multivariate analysis once adjusted for confounding factors included in the pivotal IPSS-M design (HR 6.8; 95% CI 2.6-17.5; An independent prognostic value for OS was not reached in the multivariate model.

In contrast, the presence of mutations in the other residual gene studied, PHF6 (present in nine patients), did not provide prognostic value in univariate analysis regardless of the event considered (progression free survival to AML or OS).

Conclusions

In our cohort of consecutive patients diagnosed with MDS over the past 6 years, we found a significant and relevant prognostic value of acquired variants in STAG2. These variants would meet the required criteria in the IPSS-M to move from a residual value gene to a main effect gene, regarding progression to AML. These results should be confirmed in future multicentric studies.

Puyuelo:Novartis: Honoraria; MSD: Honoraria. Bosch:BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Advantage Allogene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Lava Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Enterome: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: payment for expert testimony. Valcarcel:TAKEDA: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Kite/Gilead: Consultancy, Honoraria, Speakers Bureau; Jazz Pharmaceuticials: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; SOBI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Gebro: Honoraria, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Meeting and travel accommodation, Research Funding, Speakers Bureau; Astellas: Consultancy, Honoraria; Agios: Honoraria, Other: Meeting and travel accommodation, Speakers Bureau; AbbVie: Consultancy, Other: Meeting and travel accommodation. Jerez:BMS: Consultancy; Novartis: Consultancy; GILEAD: Research Funding; Aztrazeneca: Research Funding.