Myelodysplastic Syndromes (MDS): Diagnosis, IPSS-R Staging, and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cytopenias, dysplastic blood cell morphology, and risk of transformation to acute myeloid leukemia (AML) in 10-30% of patients. Approximately 20,000 new US cases are diagnosed annually. Median age at diagnosis is 70 years. WHO 2022 classification recognizes subtypes based on morphology, cytogenetics, and molecular features: MDS-LB (low blasts), MDS-RS (ring sideroblasts), MDS-EB (excess blasts), MDS del(5q), MDS-h (hypoplastic), and MDS-biTP53.

Most MDS cases are de novo without identifiable cause, arising from acquired somatic mutations in hematopoietic stem cells. Prior chemotherapy (especially alkylating agents: cyclophosphamide, melphalan) and radiation are the most important causes of therapy-related MDS, which arises 5-10 years after exposure. Benzene exposure is the primary occupational carcinogen. Age-related clonal hematopoiesis (CHIP) involving DNMT3A, TET2, and ASXL1 mutations precedes MDS in many patients. Hereditary predisposing conditions include germline GATA2 mutations, Fanconi anemia, Diamond-Blackfan anemia, Shwachman-Diamond syndrome, and severe congenital neutropenia.

MDS presents primarily with symptoms of cytopenias. Anemia (hemoglobin less than 10 g/dL) causes fatigue, dyspnea on exertion, pallor, and reduced exercise tolerance — the most common presenting complaint. Neutropenia results in recurrent bacterial infections, fever, and sepsis. Thrombocytopenia causes easy bruising, petechiae, purpura, and mucosal bleeding. Approximately 50% of MDS patients are transfusion-dependent. Constitutional symptoms (weight loss, fatigue, night sweats) are common in higher-risk disease. Splenomegaly is present in approximately 10-15% of patients.

Bone marrow aspiration and biopsy are essential for diagnosis: evaluation of blast percentage, dysplastic features in two or more cell lines, ring sideroblasts, and cellularity. Cytogenetics (conventional karyotype and FISH) are critical for IPSS-R scoring and diagnosis. Conventional karyotypes: del(5q) (favorable, lenalidomide-responsive), -7 or del(7q) (adverse), complex karyotype (greater than 3 abnormalities, very adverse). NGS panel for somatic mutations (SF3B1, TET2, DNMT3A, ASXL1, RUNX1, TP53, IDH1/2, U2AF1, SRSF2) informs prognosis and guides targeted therapy. IPSS-R scoring guides treatment intensity.

Very low/low IPSS-R risk: supportive care (RBC and platelet transfusions), EPO or darbepoetin for EPO-responsive anemia, lenalidomide for del(5q) anemia, luspatercept for SF3B1-mutant or ring sideroblast MDS, iron chelation for transfusion iron overload. Intermediate/high/very high risk: azacitidine or decitabine (hypomethylating agents, HMA) prolongs survival vs. conventional care in AZA-001 trial. Allogeneic SCT for eligible patients with intermediate to very high risk. IDH2-mutant MDS: enasidenib or enasidenib plus azacitidine. TP53-mutant MDS: clinical trials (eprenetapopt plus azacitidine). Magrolimab (anti-CD47) plus azacitidine for TP53-mutant MDS is under investigation.

Median OS by IPSS-R risk group: very low 8.8 years, low 5.3 years, intermediate 3 years, high 1.6 years, very high 0.8 years. AML transformation rate at 5 years: very low 3%, low 10%, intermediate 22%, high 33%, very high 55%. TP53-mutant MDS has the worst prognosis (median OS approximately 12 months, high AML transformation rate). SF3B1-mutant MDS-RS has the best prognosis among molecular subtypes. Allogeneic SCT achieves cure in 30-50% of eligible patients, offset by transplant-related mortality. Achievement of complete remission and MRD negativity after HMA therapy are favorable prognostic indicators.

Minimizing cumulative alkylating agent and topoisomerase II inhibitor exposure reduces therapy-related MDS risk. Benzene and ionizing radiation exposure limits in occupational settings are regulatory prevention measures. Patients with hereditary bone marrow failure syndromes (Fanconi anemia, Shwachman-Diamond syndrome, severe congenital neutropenia) require regular bone marrow surveillance (annually) for MDS and AML transformation. Individuals with CHIP identified incidentally on NGS panels should be monitored for MDS and discussed regarding avoidance of additional cytotoxic exposures. No population-based screening exists for MDS.