Myelodysplastic Syndrome

Myelodysplastic Syndrome (MDS) / Myelodysplastic Neoplasms: A Comprehensive Medical Overview

Introduction

Myelodysplastic syndromes (MDS), now referred to by the World Health Organization (WHO) 2022 classification as myelodysplastic neoplasms, are a group of clonal hematologic malignancies affecting the bone marrow and blood. In MDS, immature blood cells (hematopoietic stem cells) in the bone marrow do not mature properly and fail to produce enough healthy red cells, white cells, or platelets. This ineffective hematopoiesis leads to blood cytopenias, marrow dysplasia, and in some cases, progression to acute myeloid leukemia (AML).


Understanding the Basics: Normal vs. Abnormal Blood Formation

In a healthy individual, the bone marrow continuously produces:

  • Red blood cells (carry oxygen)

  • White blood cells (fight infection)

  • Platelets (help blood clot)

This production process begins with blood stem cells, which mature through tightly controlled pathways. In MDS, genetic and epigenetic changes disrupt this process, leading to immature or dysfunctional blood cells that may die prematurely or fail to function properly.


How Serious Is Myelodysplasia?

MDS ranges from mild, slowly progressing forms to aggressive subtypes that can evolve into acute myeloid leukemia (AML). This progression, known as "leukemic transformation", can occur over months to years, depending on the risk category.

The disease's seriousness depends on:

  • Type and number of cytopenias

  • Cytogenetic abnormalities

  • Percentage of blasts in the bone marrow

  • Presence of high-risk mutations


Signs, Symptoms, and Red Flags

MDS symptoms are typically due to bone marrow failure, resulting in:

Red Flags and Common Symptoms

SymptomCause
Fatigue, weakness, pallor    Anemia (low red cells)
Shortness of breath, lightheadedness, headache    Anemia
Frequent infections    Neutropenia (low white cells)
Bruising and bleeding    Thrombocytopenia (low platelets)
Mouth sores, sore throat, or sinus infections    Neutropenia
Bone or joint pain    Marrow expansion or infiltration (less common but possible in MDS)

    Immunophenotyping. ...
    Genetic profiling using Next Generation Sequencing (NGS) of DNA.

Is Myelodysplasia Painful?

While MDS itself does not always cause pain, bone or joint pain can occur in some patients—especially if the disease progresses or becomes inflammatory. This pain is typically felt in:

  • Long bones (arms, legs)

  • Ribs

  • Sternum (breastbone)

  • Large joints (hips, shoulders)

Pain may precede transformation to more aggressive disease.


Diagnosis of Myelodysplastic Neoplasms

Diagnostic Criteria (ESMO/WHO Guidelines)

MDS diagnosis is based on a combination of:

  • Persistent cytopenias in peripheral blood

  • Dysplasia in ≥10% of cells in one or more myeloid lineages

  • Hypercellular or hypocellular bone marrow with abnormal maturation

  • Blasts <20% (if ≥20%, it's considered AML)

  • Cytogenetic or molecular abnormalities


Diagnostic Tests for MDS

TestPurpose
Complete Blood Count (CBC)Detects anemia, neutropenia, and thrombocytopenia
Peripheral Blood SmearIdentifies dysplastic features (e.g., abnormal red cell shapes, hypo- or hypersegmented neutrophils)
Bone Marrow Aspiration and BiopsyEssential to assess cellularity, dysplasia, and blast percentage
Cytogenetic Analysis (Karyotyping, FISH)Identifies chromosomal abnormalities (e.g., del(5q), -7, +8)
Molecular Testing / Next-Generation Sequencing (NGS)Detects mutations in key genes (e.g., SF3B1, TET2, ASXL1, RUNX1)
Immunophenotyping (Flow Cytometry)Evaluates cell surface markers, especially if transformation to AML is suspected

Genetic and Epigenetic Pathogenesis

MDS arises due to acquired somatic mutations and epigenetic alterations in hematopoietic stem cells, leading to abnormal blood cell development.

Key Pathogenic Mechanisms:

1. Genetic Mutations

Commonly mutated genes in MDS include:

  • RNA splicing: SF3B1, SRSF2

  • DNA methylation: TET2, DNMT3A

  • Chromatin modification: ASXL1

  • Transcription factors: RUNX1

  • Signaling pathways: JAK2, NRAS

2. Cytogenetic Abnormalities

Frequent chromosomal changes include:

  • del(5q): Often associated with a better prognosis

  • Monosomy 7 / del(7q): High-risk

  • Complex karyotypes: Very poor prognosis

3. Epigenetic Changes

Altered DNA methylation and histone modification lead to:

  • Silencing of tumor suppressor genes

  • Dysregulation of cell growth and differentiation


Classification of MDS

WHO 2022 Classification Highlights

  • Introduced the term "myelodysplastic neoplasms"

  • Includes genetic-defined entities (e.g., MDS with mutated SF3B1)

  • Categories based on blast count, genetic alterations, and cell lineage involvement

IPSS-R (Revised International Prognostic Scoring System)

Stratifies patients into very low to very high-risk groups based on:

  • Cytopenias

  • Cytogenetics

  • Bone marrow blast percentage

This system is crucial for determining prognosis and therapy.

Treatment Options for MDS

1. Supportive Care

  • Blood transfusions (for anemia)

  • Platelet transfusions

  • Iron chelation (for transfusion-dependent iron overload)

  • Growth factors: Erythropoietin (EPO), G-CSF

  • Antibiotics for infections

2. Disease-Modifying Therapies

  • Lenalidomide: Especially effective in del(5q) MDS

  • Hypomethylating agents:

    • Azacitidine and decitabine improve survival and delay AML progression

  • Luspatercept: For MDS with ring sideroblasts and transfusion dependency

  • Immunosuppressive therapy: In select patients (e.g., younger, hypocellular marrow)

3. Curative Therapy: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

  • Only curative treatment for MDS

  • Suitable for fit patients, especially under age 65 with high-risk MDS

     

 Prognosis and Transformation to AML

The natural history of MDS is variable:

  • Some patients live for years with mild disease

  • Others progress to AML—especially those with high-risk cytogenetics or multiple gene mutations

Transformation to AML is typically associated with:

  • Increase in bone marrow blasts (>20%)

  • Worsening cytopenias

  • Acquisition of additional mutations


Conclusion

Myelodysplastic neoplasms represent a complex, heterogeneous group of bone marrow cancers characterized by ineffective hematopoiesis, genetic instability, and risk of leukemic transformation. Diagnosis requires a multimodal approach, including morphology, cytogenetics, and molecular studies. Treatment ranges from supportive care to curative stem cell transplantation, depending on disease severity, risk category, and patient factors.


References and Resources


© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742


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