What is Myelodysplastic Syndrome (MDS)?

Myelodysplastic Syndrome (MDS)

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias, bone marrow dysplasia, and a variable risk of progression to acute myeloid leukemia (AML). 1

Definition and Pathophysiology

MDS represents a heterogeneous group of myeloid clonal hemopathies with the following key characteristics:

• Clonal disorder of hematopoietic stem cells 1
• Characterized by peripheral blood cytopenias despite typically hypercellular bone marrow 1
• Dysplastic changes in at least 2 of 3 hematopoietic cell lines (erythroid, myeloid, megakaryocytic) 1
• Pathophysiology involves a multistep process including:
  • Cytogenetic changes and/or gene mutations
  • Abnormalities of bone marrow microenvironment
  • Widespread gene hypermethylation at advanced stages 1, 2

Epidemiology

• Primarily affects older adults with median age at diagnosis of approximately 70 years 1, 2
• Incidence of approximately 4 cases per 100,000 people per year 1, 2
• Incidence increases with age to 40-50 per 100,000 in those ≥70 years 1, 2, 3
• More common in men than women (5.4 vs 2.9 per 100,000 per year) 3
• Ethnic variations exist:
  • Asian populations tend to develop MDS at earlier ages
  • Asian patients more often have hypocellular marrow
  • Lower incidence of 5q deletion syndrome in Asian populations
  • Higher frequency of trisomy 8 in Asian populations 1, 2

Risk Factors

Genetic Factors

• Inherited predisposition in one-third of pediatric MDS cases 1, 2
• Associated genetic conditions:
  • Down syndrome
  • Fanconi anemia
  • Neurofibromatosis 2
• Germline mutations in familial cases (DDX41, GATA2, RUNX1, etc.) 2

Environmental and Occupational Factors

• Previous exposure to chemotherapy (especially alkylating agents and purine analogues) 1, 2
• Radiotherapy or ionizing radiation 1, 2
• Benzene and its derivatives 1, 2
• Tobacco smoking 1, 2
• Agricultural and industrial work 1, 2

Clinical Presentation and Diagnosis

MDS typically presents with signs and symptoms related to cytopenias:

• Anemia (fatigue, weakness)
• Thrombocytopenia (bleeding, bruising)
• Neutropenia (recurrent infections)

Diagnostic Criteria

Diagnosis requires:

• Peripheral blood counts and smear examination
• Bone marrow aspiration and biopsy showing dysplasia
• Cytogenetic analysis
• Exclusion of other causes of cytopenias 1

Essential diagnostic tests include:

• Complete blood count with differential and reticulocyte count
• Peripheral blood smear examination
• Bone marrow aspiration with iron stain and biopsy
• Cytogenetic analysis
• Serum erythropoietin level
• RBC folate and serum B12
• Iron studies (ferritin, iron, TIBC) 1

Classification

MDS has been classified using different systems:

1. French-American-British (FAB) Classification:

   • Refractory anemia (RA)
   • RA with ringed sideroblasts (RARS)
   • RA with excess blasts (RAEB)
   • RAEB in transformation (RAEB-T)
   • Chronic myelomonocytic leukemia (CMML) 1

2. World Health Organization (WHO) Classification:

   • Lowered the threshold for AML diagnosis from 30% to 20% blasts
   • Created a category of MDS/myeloproliferative disorders for CMML 1

Prognosis

Prognosis varies significantly based on several factors:

• International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) are widely used prognostic tools based on:

  • Bone marrow blast percentage
  • Cytogenetic abnormalities
  • Number and severity of cytopenias 1

• Survival varies by risk category:

  • Lower-risk MDS: median survival of 3-10 years
  • Higher-risk MDS: median survival <3 years 3

• Risk of transformation to AML:

  • 5-15% in low-risk groups (RA/RARS)
  • 40-50% in high-risk groups (RAEB/RAEB-T) 1

Treatment

Treatment is based on risk stratification, transfusion needs, bone marrow blast percentage, cytogenetic profile, and comorbidities 4:

Lower-Risk MDS

• Goal: Improve cytopenias, reduce transfusion needs, improve quality of life
• Options include:
  • Erythropoiesis-stimulating agents for anemia
  • Lenalidomide (especially for 5q deletion)
  • Luspatercept (recently approved) 3, 4

Higher-Risk MDS

• Goal: Prolong survival, reduce risk of AML transformation
• Options include:
  • Hypomethylating agents (azacitidine, decitabine) 5, 3
  • Intensive chemotherapy in selected patients
  • Allogeneic hematopoietic stem cell transplantation (only potential cure) 3, 4, 6

Important Clinical Considerations

• Secondary MDS (especially therapy-related) typically has poorer prognosis with complex cytogenetic abnormalities 1, 2
• Regular monitoring is essential to detect disease progression
• Supportive care (transfusions, infection prophylaxis) remains an important component of management
• Allogeneic stem cell transplantation should be considered early for eligible patients with higher-risk disease 3, 6

MDS represents a spectrum of disorders with variable clinical courses. Early diagnosis, accurate risk stratification, and appropriate treatment selection are crucial for optimizing outcomes and quality of life for patients with this challenging condition.