Myelodysplastic syndrome

Overview

Myelodysplastic syndrome (MDS) refers to a group of heterogeneous bone marrow disorders characterized by ineffective blood cell production (hematopoiesis) and an increased risk of progression to acute myeloid leukemia (AML). In MDS, the bone marrow produces abnormal, immature blood cells that either die prematurely or fail to function properly, leading to low levels of one or more types of blood cells (cytopenias) in circulation—most commonly red blood cells, white blood cells, and platelets.

MDS primarily affects older adults, with most cases occurring after the age of 60. It can range from indolent (slow-growing) to aggressive forms and is classified as a type of cancer due to the potential for malignant transformation. Early detection and classification are essential for prognosis and guiding treatment decisions.

Causes

The exact cause of MDS is often unknown. It is broadly categorized into two groups based on etiology: primary (idiopathic) and secondary (treatment-related or exposure-related).

Primary (De Novo) MDS

• Most common form, occurring without an identifiable cause

• May be related to age-related genetic mutations or environmental factors

Secondary MDS

• Develops as a consequence of prior chemotherapy or radiation therapy (therapy-related MDS)

• Can be associated with occupational or environmental exposures, such as:

  • Benzene

  • Pesticides

  • Heavy metals (e.g., lead, mercury)

Genetic and Molecular Factors

• Mutations in genes like TP53, TET2, ASXL1, and SF3B1 have been implicated

• Chromosomal abnormalities, such as deletions in chromosomes 5q, 7q, or trisomy 8

While some cases may have a hereditary component, MDS is not typically inherited.

Symptoms

Symptoms of MDS result from low levels of healthy blood cells and vary depending on which cell lines are affected. In early stages, MDS may be asymptomatic and detected incidentally during routine blood tests.

Common Symptoms

• Anemia (low red blood cells):

  • Fatigue

  • Shortness of breath

  • Pale skin

• Neutropenia (low white blood cells):

  • Frequent infections

  • Slow recovery from illness

• Thrombocytopenia (low platelets):

  • Easy bruising

  • Prolonged bleeding

  • Petechiae (tiny red skin spots)

Advanced or High-Risk Symptoms

• Unexplained weight loss

• Bone pain

• Enlarged spleen or liver (in some cases)

• Progression to acute myeloid leukemia (AML)

Because these symptoms are nonspecific, diagnosis often requires further hematologic testing and bone marrow evaluation.

Diagnosis

Diagnosing MDS involves a combination of blood tests, bone marrow analysis, and cytogenetic studies to confirm the presence of dysplasia and determine the subtype and risk category.

Diagnostic Tests

• Complete blood count (CBC): Reveals one or more cytopenias (anemia, neutropenia, thrombocytopenia)

• Peripheral blood smear: Shows abnormal cell shapes and sizes (e.g., macrocytosis, hypogranular neutrophils)

• Bone marrow aspiration and biopsy:

  • Assesses cellularity and morphology of blood cell precursors

  • Confirms presence of dysplasia (abnormal development) in one or more cell lines

• Cytogenetic analysis: Identifies chromosomal abnormalities, such as del(5q), del(7q), or complex karyotypes

• Molecular testing: Detects gene mutations relevant for prognosis (e.g., TP53, RUNX1, DNMT3A)

Classification

• World Health Organization (WHO) classification system is commonly used to categorize subtypes based on the number of dysplastic cell lines and blast percentage

• Revised International Prognostic Scoring System (IPSS-R) helps stratify patients into risk groups (very low to very high) based on:

  • Bone marrow blast percentage

  • Cytogenetics

  • Hemoglobin level

  • Platelet and neutrophil counts

Treatment

Treatment for MDS depends on the patient’s age, overall health, subtype, and risk classification. Goals range from symptom control and improving quality of life to delaying progression to AML or achieving remission.

1. Supportive Care (All Risk Levels)

• Blood transfusions: Red cells for anemia, platelets for thrombocytopenia

• Growth factors:

  • Erythropoiesis-stimulating agents (ESAs) for anemia

  • G-CSF or GM-CSF for neutropenia

• Antibiotics: For treating infections in neutropenic patients

2. Disease-Modifying Therapies

• Hypomethylating agents: Azacitidine and decitabine to delay progression and improve survival in intermediate to high-risk MDS

• Immunosuppressive therapy: Anti-thymocyte globulin (ATG) and cyclosporine, especially in younger patients with hypocellular marrow

• Lenalidomide: Particularly effective in patients with deletion 5q (del(5q)) cytogenetic abnormality

3. Curative Therapy

• Allogeneic hematopoietic stem cell transplantation (HSCT):

  • The only potential cure for MDS

  • Typically offered to younger, fit patients with high-risk disease

Treatment is often adjusted over time based on response, tolerance, and disease progression. Clinical trials may also be considered for novel agents or regimens.

Prognosis

The prognosis of MDS is highly variable and depends on multiple factors including disease subtype, cytogenetic profile, blast percentage, and patient health. While low-risk MDS can be managed for years, high-risk disease may progress rapidly to acute leukemia.

Favorable Prognostic Factors

• Lower percentage of blasts in bone marrow

• Good performance status and minimal symptoms

• Normal or favorable cytogenetics (e.g., isolated del(5q))

• Effective response to treatment (e.g., ESAs, hypomethylating agents)

Poor Prognostic Indicators

• High bone marrow blast percentage (>10%)

• Complex cytogenetic abnormalities (e.g., three or more chromosomal changes)

• TP53 mutations

• Refractory cytopenias or rapid clinical deterioration

Survival Estimates

• Low-risk MDS: Median survival of 5–10 years

• High-risk MDS: Median survival of 1–3 years

• Post-AML transformation: Significantly worse outcomes

Ongoing monitoring and periodic re-evaluation are essential for adapting treatment strategies and improving long-term outcomes in patients with MDS.