Unified platforM for a Better integRal Evaluation of MyeLodyspLastic Syndromes in SpAin-Strategy for Unraveling Personalized genoMic Medicine in Public heAlth System (UMBRELLA-SUMMA)

Overview

Myelodysplastic Syndromes (MDS) are heterogeneous clonal diseases characterized by difficult diagnosis, complex prognostic stratification and unsatisfactory treatment. Based on that, UMBRELLA SUMMA aims to provide better clinical management and personalized medicine to MDS patients in Spain through improving diagnosis (1), prognosis (2 and 3), and treatment (2), and facilitating future investigations (4) of the disease. More concretely, we propose: 1. The application of new technologies such as Optical Genome Mapping (OGM) in the diagnosis of those MDS cases whose cytogenetic alterations cannot be identify by other methods, as well as the implementation of this technology using peripheral blood avoiding more invasive methods for patients. 2. To provide all Spanish Group of MDS (GESMD) members who require it with the newly prognostic stratification of their patients (IPSS-M) by making Next Generation Sequencing (NGS) accessible for all of them. 3. Validate and improve a new prognostic system (AIPSS-MDS) previously developed within the GESMD, thanks to artificial intelligence, one of the tools with the most projection in the field of medicine currently. 4. To build and register ISCIII collections of cells, genetic material and/or plasma from all prospective MDS patients. On the other hand, the dynamics of coexisting mutations in a specific context of chromosomal abnormalities could be defining the clinical fate of each patient. Based on that, the IBSAL team recently proposed three models of MDS evolution based on NGS data from three different cytogenetic subgroups: normal karyotype, trisomy 8 and 5q deletion. The IBSAL proposal aims to deepen into the pathophysiological mechanisms of MDS evolution in these three models through in vitro and in vivo functional studies and single-cell multiomics approaches.

Myelodysplastic syndromes (MDS) are hematologic malignancies characterized by bone marrow dysplasia, cytopenias (anemia, infections, bleeding), and a high risk of progression to acute myeloid leukemia (AML). Diagnosis and prognostic stratification are challenging, and treatment outcomes remain suboptimal, especially in elderly patients, who represent the majority of cases. Beyond structural cytogenetic abnormalities found in 40-70% of patients, over 90% of MDS cases harbor somatic mutations impacting cellular function. Next-generation sequencing (NGS) has improved diagnosis, prognostication, and therapeutic decision-making. The Spanish Group of MDS (GESMD) brings together over 400 professionals across 100+ centers and maintains RESMD, the world's largest MDS patient registry. In 2020, GESMD launched UMBRELLA to provide NGS access to participating centers, addressing a key clinical gap. Building on UMBRELLA's success, the UMBRELLA-SUMMA project will: 1. Implement Optical Genome Mapping (OGM) to enhance detection of chromosomal alterations, especially in cases where standard cytogenetics fail. We will explore the use of peripheral blood samples to minimize invasiveness. 2. Expand access to NGS to GESMD members lacking this technology, supporting prognostic classification based on the IPSS-M, an updated molecularly integrated scoring system. 3. Apply Artificial Intelligence (AI) to validate and improve a new AI-driven prognostic model for MDS developed within GESMD. Additionally, the project will create biobanks of biological samples from GESMD patients, linked to clinical and epidemiological data within RESMD, ensuring optimal and regulated access for future research. Given MDS heterogeneity, personalized medicine is essential. UMBRELLA-SUMMA will address this through the study of different patient subgroups (low-risk, high-risk, AML-transformed MDS) with a multidisciplinary team comprising clinicians, biologists, biotechnologists, and bioinformaticians. Results will be disseminated among healthcare professionals, patients and their families via GESMD's patient resources, institutional websites, social media, and public engagement activities.