What is Myelodysplastic Syndromes (MDS), a pre-leukemia condition?

Myelodysplastic Syndromes (MDS): A Pre-Leukemia Condition

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to blood cytopenias, with approximately one-third of cases progressing to acute myeloid leukemia (AML). 1

Definition and Pathophysiology

MDS represents a group of myeloid clonal hemopathies with heterogeneous presentations. The pathophysiology involves:

• A multistep process with cytogenetic changes and/or gene mutations 1
• Abnormalities of the bone marrow microenvironment 1
• Widespread gene hypermethylation at advanced stages 1

The hallmarks of MDS include:

• Ineffective hematopoiesis causing peripheral blood cytopenias
• Dysplastic changes in at least 2 of 3 hematopoietic cell lines
• Hypercellular bone marrow with dysplasia
• Variable risk of transformation to AML

Epidemiology

MDS primarily affects older adults:

• Median age at diagnosis: ~70 years 1
• Incidence: 4 cases per 100,000 people per year 1
• Incidence increases to 40-50 per 100,000 in people aged ≥70 years 1
• More common in men than women 2
• Only 10% of patients are younger than 50 years 1

Etiology

The cause of MDS is known in only about 15% of cases 1:

• Primary (de novo) MDS: No identifiable cause
• Secondary MDS: Associated with:
  • Previous chemotherapy (especially alkylating agents and purine analogues) 1
  • Radiation therapy or ionizing radiation exposure 1
  • Tobacco smoking 1
  • Occupational exposure to benzene and its derivatives 1
  • Inherited genetic predisposition (more common in pediatric cases) 1

Clinical Presentation

MDS typically presents with symptoms related to cytopenias:

• Fatigue, weakness (anemia)
• Increased infections (neutropenia)
• Easy bruising, bleeding (thrombocytopenia)

Diagnosis

Diagnosis of MDS requires:

1. Peripheral blood evaluation:

   • Complete blood count showing cytopenias
   • Examination of peripheral blood smear 1

2. Bone marrow assessment:

   • Bone marrow aspiration and biopsy showing dysplasia 1
   • Iron stain to identify ringed sideroblasts 1
   • Cytogenetics to detect chromosomal abnormalities 1

3. Exclusion of other causes of cytopenias:

   • Vitamin deficiencies (B12, folate)
   • Iron deficiency
   • Medication effects
   • Autoimmune disorders
   • Infections 1

Classification

MDS is classified according to the World Health Organization (WHO) criteria, which evolved from the French-American-British (FAB) classification 1:

• Lower-risk MDS:

  • Refractory anemia (RA)
  • RA with ringed sideroblasts (RARS)

• Higher-risk MDS:

  • RA with excess blasts (RAEB)
  • RAEB in transformation (RAEB-T)
  • Chronic myelomonocytic leukemia (CMML) 1

Prognosis

Prognosis is determined by several factors, primarily assessed using the International Prognostic Scoring System (IPSS) or the Revised IPSS (IPSS-R) 1:

• Key prognostic factors:

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

• Survival rates:

  • Lower-risk MDS: Median survival 3-6 years 1
  • Higher-risk MDS: Median survival 5-12 months 1

• Risk of AML transformation:

  • Lower-risk MDS: 5-15% 1
  • Higher-risk MDS: 40-50% 1, 2

Management

Treatment is based on risk stratification, age, comorbidities, and transfusion needs:

1. Lower-risk MDS:

   • Supportive care with transfusions
   • Erythropoiesis-stimulating agents for anemia 2
   • Lenalidomide (especially for 5q deletion syndrome) 3

2. Higher-risk MDS:

   • Hypomethylating agents (azacitidine, decitabine) 4, 2
   • Allogeneic stem cell transplantation (the only potentially curative option) 2, 3

Complications and Supportive Care

Major complications include:

• Transfusion dependence (associated with worse outcomes) 5
• Iron overload from chronic transfusions 6
• Infections due to neutropenia 6
• Bleeding from thrombocytopenia 6

Key Points to Remember

• MDS is primarily a disease of the elderly
• It represents a spectrum of disorders with variable risk of progression to AML
• Diagnosis requires bone marrow examination showing dysplasia
• Treatment ranges from supportive care to stem cell transplantation based on risk
• Regular monitoring is essential as the disease may progress over time