Myelodysplastic Syndromes

MDS Overview - Marrow Mayhem

• Clonal disorders of hematopoietic stem cells, primarily affecting the elderly.
• Leads to "marrow failure":
  • Ineffective hematopoiesis: marrow is active but produces defective, dysplastic cells.
  • Results in peripheral blood cytopenias (e.g., anemia, neutropenia, thrombocytopenia).
• Hallmark: Morphologic dysplasia in ≥1 myeloid lineage (erythroid, granulocytic, megakaryocytic).
• Variable risk of progression to Acute Myeloid Leukemia (AML).

⭐ MDS is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and a variable risk of transformation to acute myeloid leukemia (AML).

Etiology & Pathogenesis - Genesis of Grief

• Primary (De Novo) MDS: Most common (~80%); idiopathic, age-related.
• Secondary MDS:
  • Therapy-related (t-MDS): Alkylating agents (5-7 yrs, -5/del(5q), -7/del(7q)), Topo II inhibitors (1-3 yrs, 11q23).

    ⭐ Therapy-related MDS (t-MDS), often associated with prior exposure to alkylating agents or topoisomerase II inhibitors, typically carries a poorer prognosis and distinct cytogenetic abnormalities like -5/del(5q) or -7/del(7q).

  • Environmental: Benzene, radiation.
  • Inherited: Fanconi anemia.
• Pathogenesis:
  • Clonal HSC disorder: Somatic mutations (e.g., TET2, SF3B1, TP53).
  • Ineffective hematopoiesis: ↑ Apoptosis → cytopenias.
  • Epigenetic dysregulation & immune dysfunction.

WHO Classification & Features - Dysplasia Directory

WHO 2022 classifies MDS based on blast counts, dysplasia, and cytogenetics. Key categories:

• MDS with Low Blasts (MDS-LB):
  • Includes Single Lineage (SLD) & Multilineage Dysplasia (MLD).
  • MDS with SF3B1 mutation (MDS-SF3B1).

  ⭐ MDS-RS: strong SF3B1 association; ≥15% ring sideroblasts (RS) in erythroid precursors (or ≥5% RS if SF3B1 mutated).

• MDS with Increased Blasts (MDS-IB):
  • MDS-IB1: BM blasts 5-9%; PB blasts 2-4%.
  • MDS-IB2: BM blasts 10-19%; PB blasts 5-19%. (≥20% blasts = AML).
• MDS with del(5q): Isolated del(5q), blasts <5%.
• MDS, Hypoplastic (MDS-h)
• MDS with biallelic TP53 inactivation (MDS-biTP53)
• MDS, Unclassifiable (MDS-U)

Dysplasia (≥10% of cells in a lineage):

• Erythroid: Megaloblastoid changes, nuclear budding/irregularities, ring sideroblasts.
• Granulocytic (Myeloid): Pseudo-Pelger-Huët (bilobed/hypolobated nuclei), hypogranulation.
• Megakaryocytic: Micromegakaryocytes, monolobed/bilobed or multiple separated nuclei.

Diagnosis, Prognosis & Management Snippets - Spot, Score, Strategize

• Diagnosis "Spot":
  • CBC: Persistent cytopenia(s).
  • Peripheral Smear: Dysplastic features (Pelger-Huët like cells).
  • Bone Marrow Aspirate & Biopsy: Hypercellular (often), dysplasia in ≥10% cells of ≥1 lineage; BM blasts <20%.
  • Cytogenetics: Essential (e.g., del(5q), -7/monosomy 7, +8/trisomy 8).
• Prognosis "Score":
  • IPSS-R: Stratifies risk (Very Low to Very High).

    ⭐ The Revised International Prognostic Scoring System (IPSS-R) for MDS incorporates bone marrow blast percentage, karyotype, and depth of cytopenias (hemoglobin, platelet count, absolute neutrophil count) to stratify patients into risk categories.

• Management "Strategize" (Risk-Adapted):
  • Lower-Risk (LR-MDS):
    • Supportive: Transfusions, Erythropoiesis-Stimulating Agents (ESAs), G-CSF.
    • Specific: Lenalidomide (for del(5q)), Luspatercept (for MDS-RS).
  • Higher-Risk (HR-MDS):
    • Hypomethylating Agents (HMAs): Azacitidine, Decitabine.
    • Allogeneic Stem Cell Transplant (allo-SCT): Only curative option.

High‑Yield Points - ⚡ Biggest Takeaways

• Ineffective hematopoiesis leads to peripheral cytopenias despite a hypercellular bone marrow.
• Dysplastic changes in one or more myeloid cell lines are characteristic.
• MDS carries a significant risk of transformation to Acute Myeloid Leukemia (AML).
• Del(5q) is a key cytogenetic abnormality, often associated with a good prognosis.
• Ring sideroblasts (abnormal iron) are key in MDS-RS.
• Bone marrow shows <20% blasts; >20% defines AML.
• Predominantly a disease of the elderly.