What is myelodysplastic syndrome (MDS)?

What is Myelodysplastic Syndrome (MDS)?

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders that predominantly affect the elderly, characterized by ineffective blood cell production leading to peripheral blood cytopenias (low blood counts) and a risk of progression to acute myeloid leukemia in approximately one-quarter to one-third of patients 1, 2.

Core Disease Characteristics

MDS represents a group of myeloid cancers with diverse presentations, but all share the fundamental problem of ineffective hematopoiesis—the bone marrow produces abnormal, dysfunctional blood cells that die prematurely rather than maturing properly 1, 3. This results in:

• Peripheral blood cytopenias (anemia, thrombocytopenia, neutropenia)
• Bone marrow dysplasia (abnormal-appearing cells under microscopy)
• Hypercellular bone marrow (paradoxically, despite low blood counts)
• Variable blast percentage (immature cells ranging from <5% to 20%)

Epidemiology and Risk Factors

Age and Incidence

• Median age at diagnosis: ~70 years 1, 2
• Incidence: 4-4.5 per 100,000 people annually in the general population 2, 4
• Dramatically increases with age: 40-50 per 100,000 in those ≥70 years, and 55.4 per 100,000 in those ≥80 years 1, 4
• Less than 10% of patients are younger than 50 years 1

Known Causes (15% of cases)

The etiology is identifiable in only a minority of cases 1:

Secondary/Therapy-Related MDS:

• Prior chemotherapy (especially alkylating agents, purine analogues) 1, 2
• Prior radiotherapy or ionizing radiation exposure 1
• These cases typically have poor prognostic features with complex cytogenetics involving chromosomes 5,7, and/or 17p 1

Environmental/Occupational:

• Benzene and its derivatives 1
• Tobacco smoking 1
• Agricultural and industrial work exposures 1

Inherited Predisposition:

• One-third of pediatric MDS cases (Down syndrome, Fanconi anemia, neurofibromatosis) 1
• Less common in adults but should be suspected in young adults or families with multiple cases of MDS, AML, or aplastic anemia 1
• Associated gene mutations: DDX41, GATA2, RUNX1, ANKRD26, ETV6, telomerase genes 2

Pathophysiology

The disease develops through a multistep process 1:

1. Cytogenetic changes and/or gene mutations 1
2. Abnormalities of the bone marrow microenvironment 2
3. Widespread gene hypermethylation at advanced stages 1, 2

Clinical Presentation and Major Morbidities

The two major clinical problems are 5, 4:

1. Cytopenia-related complications: fatigue, dyspnea, infections, bleeding, bruising 6
2. Risk of transformation to AML: occurs in 25-33% of cases 1, 2

Patients may be asymptomatic initially and discovered incidentally on routine blood work 6. As disease progresses, symptoms reflect the specific cytopenias present.

Diagnostic Approach

Diagnosis requires bone marrow examination showing blood cytopenias, dysplasia, with or without excess blasts 1. The gold standard remains bone marrow biopsy and aspirate 7.

Essential Diagnostic Components 1, 5:

• Complete blood count with differential and peripheral smear examination
• Bone marrow aspirate and biopsy with iron stain
• Cytogenetics (karyotype)
• Bone marrow blast percentage determination

Strongly Recommended 1:

• Bone marrow trephine biopsy histology (especially for difficult diagnoses and prognostic information)

Additional Testing to Consider 5, 2:

• Flow cytometry
• Next-generation sequencing myeloid mutation panels 4
• Serum erythropoietin level (before transfusions)
• Vitamin B12, folate, ferritin, iron studies
• Exclusion of other causes: autoimmune disorders, renal failure, chronic infections, aplastic anemia, paroxysmal nocturnal hemoglobinuria 1

Classification and Prognosis

MDS is classified according to WHO criteria and prognostication uses the Revised International Prognostic Scoring System (IPSS-R) or the newer molecular IPSS-M 1, 8. These systems incorporate:

• Bone marrow blast percentage
• Number and severity of cytopenias
• Cytogenetic abnormalities
• (In IPSS-M) Molecular mutations

Prognosis varies dramatically by subtype 5:

• Lower-risk disease (e.g., refractory anemia with <5% blasts): median survival 3-6 years, 5-15% transform to AML
• Higher-risk disease (e.g., refractory anemia with excess blasts 5-20%): median survival 5-12 months to <3 years, 40-50% transform to AML 5, 6

Treatment Landscape

Treatment selection is based on risk stratification, transfusion needs, blast percentage, cytogenetic/molecular profile, comorbidities, and transplant candidacy 8.

Lower-Risk MDS Goals:

• Decrease transfusion requirements
• Prevent transformation to higher-risk disease or AML
• Improve quality of life and survival 8

Higher-Risk MDS Goals:

• Prolong survival
• Decrease risk of AML transformation 8

Available Therapies 8:

• Growth factors and erythropoiesis-stimulating agents
• Lenalidomide (particularly for del(5q) MDS)
• Luspatercept (approved 2020)
• Hypomethylating agents (azacitidine, decitabine/cedazuridine)
• Imetelstat (approved 2024 for transfusion-dependent lower-risk MDS)
• Intensive chemotherapy
• Allogeneic stem cell transplantation: the only curative option 8, 3

Critical Caveat:

Despite being potentially curative, fewer than 10% of MDS patients receive allogeneic transplant due to advanced age, comorbidities, and donor scarcity 6, 3. When disease progresses after hypomethylating agent therapy, there are currently no approved interventions, representing a significant unmet need 8.