What is Myelodysplastic Syndrome (MDS)?
Myelodysplastic syndromes are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral blood cytopenias despite a hypercellular bone marrow, with dysplasia of cellular elements and a risk of transformation to acute myeloid leukemia in approximately one-third of patients. 1
Core Pathophysiology
MDS represents a malignant clonal disorder originating from hematopoietic stem cells, where the bone marrow paradoxically appears hypercellular yet fails to produce adequate functional blood cells—a phenomenon termed "ineffective hematopoiesis." 1 This results in:
- Peripheral blood cytopenias (anemia, neutropenia, and/or thrombocytopenia) despite increased marrow cellularity 1
- Morphologic dysplasia affecting one or more myeloid lineages, including megaloblastoid erythropoiesis, nucleocytoplasmic asynchrony in early precursors, and dysmorphic megakaryocytes 1
- Increased apoptosis of developing blood cells within the marrow, preventing their maturation and release 1
The disease develops through a multistep genetic process involving mutations affecting DNA damage responses, transcription, RNA splicing, epigenetics, and cytokine signaling. 1
Epidemiology and Risk Factors
MDS predominantly affects elderly individuals with a median age at diagnosis of approximately 70 years, though more than 10% of patients are younger than 50 years. 1, 2 The incidence is:
- 4 per 100,000 in the general U.S. population 1, 2
- 22-45 per 100,000 among individuals older than 70 years 1
- Higher in males (5.4 per 100,000) compared to females (2.9 per 100,000) 2
Known etiologic factors account for only 15-20% of cases: 1
- Prior chemotherapy exposure (especially alkylating agents, purine analogues) 1
- Radiation therapy or ionizing radiation 1
- Benzene and its derivatives 1
- Tobacco smoking 1
- Inherited predisposition (more common in pediatric cases, including Down syndrome, Fanconi anemia) 1
The etiology remains unknown in more than 80% of patients. 1
Clinical Presentation
The major clinical problems stem from cytopenias and leukemic transformation risk: 1
- Anemia symptoms: fatigue, weakness, dyspnea
- Thrombocytopenia: bleeding, bruising, petechiae
- Neutropenia: recurrent infections
- Insidious onset with symptoms developing over months 1, 2
The disease typically presents with relatively stable blood counts over several months, distinguishing it from acute processes. 1
Leukemic Transformation Risk
Approximately 30-40% of MDS patients will progress to acute myeloid leukemia, with transformation rates varying by subtype: 1
- Lower-risk subtypes (refractory anemia, refractory anemia with ring sideroblasts): 5-15% transformation rate 1
- Higher-risk subtypes (refractory anemia with excess blasts): 40-50% transformation rate 1
When MDS transforms to AML, these patients experience lower response rates to standard therapy compared to de novo AML. 1
Prognosis and Heterogeneity
MDS demonstrates marked heterogeneity in clinical outcomes even within morphologic subtypes. 1 Survival varies dramatically:
- Lower-risk disease: median survival 3-10 years 2, 1
- Higher-risk disease: median survival less than 3 years, often 5-12 months 2, 1
- Overall 5-year survival: approximately 37% 2
The International Prognostic Scoring System (IPSS) and its revision (IPSS-R) stratify patients based on bone marrow blast percentage, cytogenetic abnormalities, and number/severity of cytopenias. 1 These scoring systems are critical for risk-based treatment selection and clinical trial design. 1
Historical Context and Nomenclature
MDS has been historically referred to by various names including oligoblastic leukemia, refractory anemia, smoldering acute leukemia, and preleukemia. 1 The French-American-British (FAB) classification system, established in 1982 and modified in 1985, remains widely used despite WHO modifications. 1 The WHO 2016 classification incorporates molecular markers (such as SF3B1 mutations) and lowered the blast threshold for AML diagnosis from 30% to 20%. 1