Myelodysplastic

Overview of Myelodysplastic Syndromes (MDS)

Definition: A group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, resulting in cytopenias (anemia, thrombocytopenia, and/or neutropenia) and a variable risk of transformation to acute myeloid leukemia (AML)
Key Features:
- Dysplasia: Abnormal morphology and maturation of hematopoietic cells in the bone marrow
- Ineffective Hematopoiesis: Increased apoptosis (programmed cell death) of hematopoietic precursors in the bone marrow, leading to decreased production of mature blood cells
- Cytopenias: One or more peripheral blood cytopenias (anemia, thrombocytopenia, and/or neutropenia)
- Risk of Transformation: Variable risk of progression to acute myeloid leukemia (AML)
Epidemiology: Primarily affects older adults (median age at diagnosis is >65 years)
Etiology:
- Most cases are de novo (arising without a known cause)
- Some cases are therapy-related (t-MDS), occurring after exposure to cytotoxic chemotherapy or radiation therapy
- Genetic predisposition plays a role in a small number of cases

Pathophysiology

Clonal Hematopoiesis: MDS arises from a mutated hematopoietic stem cell that has a proliferative advantage over normal stem cells
Genetic Mutations: Acquired mutations in genes involved in:
- Splicing factors (e.g., SF3B1, SRSF2, U2AF1)
- DNA methylation (e.g., TET2, DNMT3A)
- Transcription factors (e.g., RUNX1, TP53)
- Signaling pathways (e.g., RAS pathway)
Impaired Differentiation: Mutations disrupt normal differentiation and maturation of hematopoietic cells
Dysplasia: Abnormal morphological features in one or more cell lines (erythroid, myeloid, megakaryocytic)
Increased Apoptosis: Dysplastic cells are prone to apoptosis (programmed cell death) in the bone marrow, contributing to ineffective hematopoiesis
Cytokine Dysregulation: Abnormal production of cytokines by bone marrow cells can contribute to ineffective hematopoiesis and cytopenias
Immune Dysregulation: Abnormal immune responses may contribute to bone marrow failure in some cases

WHO Classification of MDS (2016 Revision)

The World Health Organization (WHO) classification is used to categorize MDS based on:

Morphological Features: Dysplasia in one or more cell lines, blast percentage
Cytogenetic Abnormalities: Specific chromosomal abnormalities
Blast Percentage: Percentage of blasts in the bone marrow and peripheral blood

Key Subtypes of MDS:

MDS with Single Lineage Dysplasia (MDS-SLD):
- Cytopenia in one cell line (anemia, thrombocytopenia, or neutropenia)
- Dysplasia in one cell line only
- <5% blasts in the bone marrow and <1% blasts in the peripheral blood
MDS with Ring Sideroblasts (MDS-RS):
- Subclassified as:
  - MDS-RS-SLD: Single lineage dysplasia with ≥15% ring sideroblasts in the bone marrow
  - MDS-RS-MLD: Multilineage dysplasia with ≥15% ring sideroblasts in the bone marrow
- Cytopenia in one or more cell lines
- <5% blasts in the bone marrow and <1% blasts in the peripheral blood
- Often associated with SF3B1 mutation
MDS with Multilineage Dysplasia (MDS-MLD):
- Cytopenia in one or more cell lines
- Dysplasia in ≥50% of cells in at least two cell lines
- <5% blasts in the bone marrow and <1% blasts in the peripheral blood
MDS with Excess Blasts (MDS-EB):
- Subclassified as:
  - MDS-EB-1: 5-9% blasts in the bone marrow or 2-4% blasts in the peripheral blood
  - MDS-EB-2: 10-19% blasts in the bone marrow or 5-9% blasts in the peripheral blood
- Cytopenias in one or more cell lines
- May have Auer rods
MDS with Isolated del(5q):
- Anemia
- Normal or increased platelet count
- <5% blasts in the bone marrow and <1% blasts in the peripheral blood
- Isolated del(5q) cytogenetic abnormality
- Often responsive to lenalidomide

Clinical Manifestations

Symptoms of Cytopenias:
- Anemia: Fatigue, weakness, pallor, shortness of breath
- Thrombocytopenia: Bleeding, bruising, petechiae (small, pinpoint hemorrhages)
- Neutropenia: Increased susceptibility to infections
Other Symptoms:
- Some patients are asymptomatic and MDS is found incidentally in the blood test
- Splenomegaly (enlarged spleen): Less common than in myeloproliferative neoplasms
- Hepatosplenomegaly (enlarged liver and spleen)
- Systemic Symptoms (Less Common): Fever, weight loss, night sweats

Laboratory Findings

Complete Blood Count (CBC):
- Cytopenias in one or more cell lines (anemia, thrombocytopenia, neutropenia)
  - May see macrocytosis (increased MCV) or dimorphic RBC population
- Variable WBC count (may be low, normal, or high)
- Presence of blasts in the peripheral blood (variable, depends on the subtype of MDS)
Peripheral Blood Smear:
- Dysplastic Features in One or More Cell Lines:
  - RBCs: Oval macrocytes, hypochromia, basophilic stippling, Howell-Jolly bodies, teardrop cells
  - Neutrophils: Pseudo-Pelger-Huët anomaly (bilobed or unsegmented neutrophils), hypogranulation, abnormal nuclear segmentation
  - Platelets: Large platelets, abnormal granulation
Reticulocyte Count:
- Low or Normal (inappropriately low for the degree of anemia)
Bone Marrow Aspiration and Biopsy:
- Increased Cellularity (Hypercellular) or Decreased Cellularity (Hypocellular)
- Dysplasia in One or More Cell Lines:
  - Erythroid dysplasia: Multinucleated erythroid precursors, nuclear budding, megaloblastoid changes
  - Myeloid dysplasia: Abnormal nuclear segmentation, hypogranulation, Auer rods (rare)
  - Megakaryocytic dysplasia: Micromegakaryocytes, hypolobated megakaryocytes
- Increased Blast Percentage: Used to classify MDS subtypes
- Ring Sideroblasts: Erythroid precursors with iron-laden mitochondria encircling the nucleus (≥15% ring sideroblasts in MDS-RS subtypes)
Cytogenetic Analysis:
- Chromosomal Abnormalities are Common in MDS
  - del(5q): Seen in MDS with isolated del(5q)
  - Trisomy 8 (+8)
  - del(20q)
  - del(7q) or monosomy 7 (-7)
  - Complex Karyotype: Presence of multiple cytogenetic abnormalities; associated with poor prognosis
Flow Cytometry Immunophenotyping:
- To Identify Abnormal Cell Populations and Assess for Dysplasia
  - Aberrant expression of cell surface markers
  - Abnormal cell ratios
  - Helps differentiate MDS from other conditions
Molecular Testing:
- To Detect Gene Mutations that are Important for Diagnosis, Prognosis, and Treatment Planning
  - Commonly Mutated Genes:
    - SF3B1 (splicing factor)
    - TET2 (DNA methylation)
    - DNMT3A (DNA methylation)
    - ASXL1 (chromatin modifier)
    - RUNX1 (transcription factor)
    - TP53 (tumor suppressor)
    - EZH2 (chromatin modifier)

Diagnostic Criteria

Presence of One or More Cytopenias (Anemia, Thrombocytopenia, and/or Neutropenia)
Dysplasia in at least One Cell Line (Erythroid, Myeloid, or Megakaryocytic) in the Bone Marrow
Blast Percentage in the Bone Marrow is <20%
Absence of Other Myeloid Neoplasms (e.g., CML, AML with recurrent genetic abnormalities)
Cytogenetic Abnormalities - Helpful for Classification and Prognosis

Prognostic Scoring Systems

Revised International Prognostic Scoring System (IPSS-R):
- Used to estimate the prognosis and risk of AML transformation in patients with MDS
- Based on:
  - Percentage of blasts in the bone marrow
  - Cytogenetic abnormalities
  - Number of cytopenias
  - Assigns patients to risk categories: Very low, low, intermediate, high, or very high

Treatment and Management

Goals of Treatment:
- Improve blood counts
- Reduce the risk of infections and bleeding
- Delay or prevent transformation to AML
- Improve quality of life and survival
Treatment Options:
- Supportive Care:
  - Transfusions (RBCs and platelets) to manage anemia and thrombocytopenia
  - Growth factors (e.g., erythropoietin, G-CSF) to stimulate blood cell production
  - Antibiotics to treat infections
  - Iron chelation therapy to manage iron overload from chronic transfusions (if needed)
- Hypomethylating Agents (HMAs):
  - Azacitidine and decitabine
  - Inhibit DNA methylation, leading to improved hematopoiesis and reduced risk of AML transformation
  - Used in higher-risk MDS
- Lenalidomide:
  - An immunomodulatory drug used for patients with MDS with deletion 5q
  - Effective in reducing transfusion dependence and improving cytopenias
- Luspatercept:
  - A recombinant fusion protein that binds to TGF-β superfamily ligands
  - Promotes erythroid maturation and reduces transfusion burden in patients with MDS-RS
- Hematopoietic Stem Cell Transplantation (HSCT):
  - Potentially curative option, especially for younger patients with high-risk MDS
  - Involves replacing the patient’s damaged bone marrow with healthy stem cells from a donor

Key Terms

Myelodysplastic Syndromes (MDS): Clonal hematopoietic stem cell disorders with ineffective hematopoiesis and dysplasia
Dysplasia: Abnormal cell development or maturation
Cytopenia: Deficiency of blood cells (e.g., anemia, neutropenia, thrombocytopenia)
Ring Sideroblasts: Erythroid precursors with iron-laden mitochondria encircling the nucleus
Refractory Anemia: Anemia that does not respond to standard treatments
Hypomethylating Agents: Drugs that inhibit DNA methylation
Hematopoietic Stem Cell Transplantation (HSCT): Procedure to replace damaged bone marrow with healthy stem cells

AML

Myeloproliferative