Myelodysplastic syndromes (MDS) are heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective and dysplastic hematopoiesis resulting in peripheral blood cytopenias (anemia, neutropenia, thrombocytopenia) despite hypercellular or normocellular bone marrow, with morphologic dysplasia in one or more lineages and increased risk of progression to acute myeloid leukemia. Annual incidence is 4 per 100,000 (rising to 30+ per 100,000 in those over 70), with median age 70 and slight male predominance. Risk factors include prior chemotherapy/radiotherapy (therapy-related MDS, 10-20% of cases), benzene/pesticide exposure, smoking, ionizing radiation, and inherited bone marrow failure syndromes.
Classification has evolved significantly: WHO 2022 and ICC 2022 incorporate molecular features into MDS subtypes. WHO 2022: MDS with defining genetic abnormalities (MDS-low blasts with SF3B1 mutation; MDS with biallelic TP53 inactivation regardless of blast percentage; MDS with del(5q)), MDS morphologically defined (MDS-low blasts, MDS-hypoplastic, MDS-increased blasts including IB1 5-9% and IB2 10-19%, MDS-fibrotic). ICC 2022 has similar approach with detailed molecular classification. Diagnostic workup includes peripheral blood smear, bone marrow aspirate/biopsy with iron staining, cytogenetics (clonal abnormalities in 50-60%), FISH, and next-generation sequencing for SF3B1, TP53, RUNX1, ASXL1, EZH2, U2AF1, SRSF2, ETV6, IDH1/2, KRAS, NRAS, NPM1, FLT3.
IPSS-Molecular (IPSS-M, 2022) integrates 31 gene mutations with cytogenetics, hemoglobin, platelet count, neutrophil count, and bone marrow blast percentage to stratify into 6 risk categories (very low, low, moderate-low, moderate-high, high, very high) with median overall survival ranging from 9.7 to 0.8 years. Treatment is risk-adapted: lower-risk MDS (very low/low/moderate-low) focuses on supportive care for transfusion-dependent anemia: erythropoiesis-stimulating agents (darbepoetin, epoetin alfa) for serum erythropoietin <500 mU/mL; lenalidomide for del(5q); luspatercept for SF3B1-mutated MDS-RS or refractory MDS post-ESA; iron chelation for transfusion-dependent patients with serum ferritin >1000-2000 ng/mL. Higher-risk MDS (moderate-high/high/very high) treated with hypomethylating agents (azacitidine 75 mg/m2 SC or IV days 1-7 every 28 days; decitabine 20 mg/m2 IV days 1-5 every 28 days; oral cedazuridine-decitabine 35-100 mg daily days 1-5) achieving 30-50% response rates and median 2-year overall survival; venetoclax-azacitidine combinations under study; allogeneic stem cell transplantation in eligible patients (<70 years, intermediate-2/high-risk, fit) is the only curative option; clinical trials with novel agents (magrolimab, sabatolimab, pevonedistat) ongoing.