Clinical and Genetic Profiles of Young Adult Patients with Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are heterogeneous neoplastic diseases affecting elderly individuals (median age in Italy 74 yrs). Although rarely, MDS can affect younger individuals and diagnosis is often insidious. We retrospectively examined a cohort of younger patients with MDS (2000-2018) to verify recurrent biological and clinical features as well as frequency of genetic predisposition. Fifty-four consecutive patients <60 years (median age 52) (8.3% of MDS patients diagnosed per year) were analysed. Data were collected at time of first bone marrow examination, corresponding to diagnosis or at revaluation consequent to second opinion. To better characterize the biology of this cohort, beside routine analysis, we performed low-coverage (0.2x) whole genome sequencing (lc-WGS) of peripheral plasma cell-free DNA (cf-DNA), and compared with genome coverage from healthy controls. Familiarity for haematological disorders were observed in 6/54 patients, and 3/54 carried germline predisposition (1 GATA-2 deficiency, 1 Noonan syndrome, 1 congenital dyskeratosis). Autoimmune phenomena were present in 22.2% of patients. Among all cases, 9 had ICUS at least 10 year before MDS diagnosis. According to WHO 2016, MDS patients were classified in MDS-SLD (single-lineage dysplasia) 18.4%, MDS-MLD (multilineage dysplasia) 42.9%, MDS with isolated del(5q) 4.1%, MDS-RS-SLD (ring sideroblasts) 8.2%, MDS-RS-MLD 6.1%, MDS-EB-1 (excess blasts) 10.2%, MDS-EB-2 10.2%. Multilineage dysplasia was seen in the majority (76%) of cases. IPSS-R risk categories were: very-low risk 18%, low 52%, intermediate 16%, high 10%, very-high 4%. Patients had also different numbers of cytopenia: 1 isolated (62.8%), 2 (25.6%) and pancytopenia (11.7%). Anaemia occurred in 68.5% of patients, neutropenia in 31.5% and thrombocytopenia in 38.9%; when considering patients aged <50 yrs, neutropenia prevalence raised to 42.1%. Recurrent cytogenetic aberrations were -Y, del(5q), del(20q), del(7q), +8, -7. lc-WGS identified low-level mosaicism and confirmed karyotype. MDS of young adults does not seem to have distinctive common clinical and biological characteristics. To optimize treatment, sensitive diagnostic tools should be adopted early to confirm diagnosis and to promptly detect germline predisposition. lc-WGS of cf-DNA is a non-invasive screening test for detection of low-level mosaicism and complex structural chromosome abnormalities and could be considered a new method to evaluate karyotype in younger MDS patients.