Abstract 6208: Characterization of molecular evolution in myelodysplastic neoplasms
Authors: Civettini Ivan , Crippa Valentina , Malighetti Federica , Villa Matteo , Aroldi Andrea , Cavalca Fabrizio , Graudenzi Alex , Borin Lorenza Maria , Mologni Luca , Piazza Rocco , Gambacorti-Passerini Carlo , Ramazzotti Daniele 
Published: March 2024

Abstract
Myelodysplastic neoplasms (MDS) are hematopoietic stem cell disorders. The IPSS-Mol model, a scoring system that combines molecular and clinical features to stratify MDS patients, can identify individuals at high-risk of developing Acute Myeloid Leukemia (AML), enabling the targeted application of disease-modifying therapies. However, the molecular evolutionary patterns in MDS and their impact on Overall Survival (OS) and Leukemia-Free Survival (LFS) remain unexplored. Shifting from conventional static mutational analyses used by IPSS-Mol to a dynamic evolutionary approach, we employed the ASCETIC framework to analyze data from the IPSS-Mol Database (3,323 patients, 152 genes) and understand the dynamics of MDS progression. According to ASCETIC, genes related to DNA methylation displayed low ranks, indicating their tendency to manifest early in the progression of the disease. In contrast, genes associated with cellular signaling typically appeared in the later stages of tumor progression, while genes involved in RNA splicing exhibited intermediate ranks.Regarding molecular evolution in MDS, ASCETIC identified five clusters, each characterized by distinct evolutionary signatures and significantly different OS and LFS rates (p &lt; 0.001). The median OS for the C1, C2, C3, C4, and C5 clusters were 79.3, 64.1, 28.9, 16.2, and 14.8 months, respectively. Subsequently, we compared ASCETIC's clusters with the different risk groups defined by the IPSS-Mol score. Among the 1158 patients initially classified as V-Low/M-Low risk by IPSS-Mol, ASCETIC identified 55 patients placed in C4 and C5. These patients exhibited lower OS (p = 0.005) and LFS (p = 0.02). Conversely, among the 905 IPSS-Mol M-High/V-High risk patients, ASCETIC identified 468 patients (51.7%) classified as low risk (C1-C2-C3), who were associated with longer median OS and LFS (p &lt; 0.001). The differences between conventional mutational analyses and our evolutionary approach primarily, but not exclusively, arise from the evaluation of TP53 mutations and ASXL1. In the IPSS-Mol model, a higher risk is conferred if multi-hit TP53 alterations occur or in the presence of ASXL1 mutations.Conversely, ASCETIC assesses the impact of mutations differently. It considers not only the Variant Allele Frequencies of individual- and/or co-mutations but also the evolutionary trajectories that lead to TP53 and/or ASXL1. This approach results in different risk weights assigned to each evolutionary trajectory.Lastly, we identified patients with NPM1 mutations, classified as MDS patients in the original dataset but now categorized as AML according to 2022-WHO. Within this high-risk context, ASCETIC differentiated between patients with shorter and longer Overall Survival (OS) (p &lt; 0.001).Our study reveals the influence of evolution on MDS prognosis, offering insights into the integration of the ASCETIC framework with the IPSS-Mol. Validation on external cohort is ongoing.
Citation Format: Ivan Civettini, Valentina Crippa, Federica Malighetti, Matteo Villa, Andrea Aroldi, Fabrizio Cavalca, Alex Graudenzi, Lorenza Maria Borin, Luca Mologni, Rocco Piazza, Carlo Gambacorti-Passerini, Daniele Ramazzotti. Characterization of molecular evolution in myelodysplastic neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6208.