Myelodysplastic Syndromes

Myelodysplastic syndromes are characterized by dysplastic and ineffective hematopoiesis – bone marrow failure**.** It is sometimes described as “pre-leukemic” since there is a risk of transformation into acute leukemia (30%). In MDS, there is varied anemia, thrombocytopenia, and leukopenia. Hence there is a risk of life-threatening infection and bleeding. Patients require multiple blood transfusions in the form of pRBCs and platelets.

Most patients are > 70 years old.

Myeloproliferative neoplasms (MPN) vs. myelodysplastic Syndrome (MDS) vs. acute Myelogenous Leukemia (AML)

• WHO Classification of Myelodysplastic Syndromes (MDS)
  • MDS with single lineage dysplasia (MDS-SLD)
    • Dysplasia in >10% of one cell line, 1 or 2 blood cytopenias, <5% blasts
  • MDS with multiple lineage dysplasia (MDS-MLD)
    • >10% dysplasia in 2 or more lineages, 1-3 blood cytopenias, <5% blasts, <15% ring sideroblasts
  • MDS with ring sideroblasts (MDS-RS)
    • MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD)
    • MDS with ring sideroblasts and multiple lineage dysplasia (MDS-RS-MLD)
    • Anemia, No blasts, >15% of erythroid precursors with sideroblasts, Dysplasia in one or more cell lines
  • MDS with isolated del (5q)
  • MDS with excess blasts (MDS-EB)
  • MDS unclassifiable (MDS-U)
    • With 1% blasts
    • With single lineage dysplasia and pancytopenia
    • Based on defining cytogenetic abnormality
  • Refractory cytopenia of childhood
• Causes of MDS ***Unclear, but there is a stepwise acquisition of oncogenic mutations
  • de novo mutations
  • Chemotherapy (alkylating agents)
  • Environmental toxins (benzene)
  • Radiation (therapeutic or accidental)
• Risk factors for MDS
  • Genetic
    • Constitutional genetic disorders: Down Syndrome, Trisomy 8, Mosaicism, Monosomy 5, Monosomy 7, Del 5q
    • NFT1
    • Germ cell tumors (embryonal dysgenesis),
    • Congenital neutropenia: Kostmann’s or Schwachmnan-Diamond syndrome
    • DNA repair deficiencies: Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, Xeroderma pigmentosum
    • Mutagen-detoxification (GSTQ1-null)
  • Acquired
    • Old age
    • Cytotoxic therapy: Alkylating agents, Topoisomerase II inhibitors, Beta-emitters such as radioactive p-32,
    • Hematopoietic cell transplantation;
    • Environmental and occupational toxins: Benzene, Tobacco use
    • Aplastic anemia
    • Paroxysmal nocturnal hemoglobinuria (PNH),
    • Polycythemia vera
    • Obesity
• Signs and symptoms
  • Fatigue, pallor, breathlessness (due to anemia)
  • Severe and/or frequent infections (due to neutropenia0
  • Easy bruising and bleeding (due to thrombocytopenia)
• Investigation
  • Complete Blood Count – Cytopenias
    • Macrocytic or normocytic anemia
    • Low reticulocyte count
    • Neutropenia
    • Thrombocytopenia (Variable)
    • Pancytopenia (50% of cases at presentation)
  • Reticulocyte count – decreased
  • Peripheral blood film – Cytopenias in peripheral blood
    • Erythroid: Ovalomacrocytes, elliptocytes, acanthocytes, stomatocytes, teardrops, nRBC, basophilic stippling, Howell-Jolly bodies
    • Myeloid: Pseudo Pelger-Huet anomaly, Auer rods, Hypogranulation, nuclear stick, hypersegmented, ringed-shaped nuclei, very coarse granules
    • Megakaryocytes: Giant platelets, hypogranular or agranular platelets
  • Bone marrow Studies – Dysplasia of all nonlymphoid lineages associated with cytopenia, ineffective hematopoiesis
    • Erythroid: Megaloblastoid erythropoiesis, Nuclear budding, Ringed sideroblasts, internuclear bridging, Karyorrhexis, nuclear fragments, cytoplasmic vacuolization, multinucleation – dysplastic changes in erythroid precursors with megaloblastic changes and presence of ringed sideroblast in iron stain
    • Myeloid: Defective granulation, maturation arrest at myelocyte stage, increase in monocytoid forms, abnormal localization of immature precursors – Hyperplasia with dysgranulopoiesis
    • Megakaryocytes: Micromegakaryocytes, Large mononuclear forms, hypogranulation, multiple small nuclei – Dysmegakaryopoiesis – pawn ball megakaryocytes
    • Iron stores: increased with ring sideroblasts
    • Refractory anemia with excess blasts (RAEB) – Abnormal localization of immature precursors (ALIP)
  • Cytochemistry
    • Iron staining (Perls-prussian reaction) to ID ringed sideroblasts
    • PAS staining of erythroblasts to assess dyserythropoiesis
    • Peroxidase or Sudan Black B to detect myeloid lineage of blasts
    • NSE or CAE to assess myeloid blasts
  • Immunocytochemistry and Flow cytometry
    • Exclude lymphoid origin of primitive blasts
    • Distinguish Erythroid precursors: glycophorin (CD235a) or transferrin receptor (cd71)
    • Quantify Myeloblasts: CD34, CD117, CD13, CD14, CD33
    • Detect dysplastic or immature Megakaryocytes: vWF, CD41, CD61, HPI-ID monoclonal antibody
    • Detect lineage infidelity
  • Genetics/ Molecular (TR-PCR, FISH, Karyotyping)
    • Detection of chromosomal abnormalities by RT-PCR, FISH (Distinguished between MDS and AML, aids in the classification of MDS, Major factor in determining prognostic risk group and therapy)
      • Constitutional genetic disorders: Down Syndrome, Trisomy 8, Mosaics, Monosomy 5, Monosomy 7, Del 5q
      • Other syndromes: NFT1, Germ cell tumors, Kostmann’s, Schwachman-Diamond syndrome, Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, Xeroderma pigmentosum etc.
• What is meant by Abnormal Localization of Immature Precursors (ALIP) in MDS?
  • ALIP refers to the ****localization of myeloblasts and promyelocytes (immature precursors) in the intertrabecular region in abnormal clusters instead of the endosteum where they are normally found.
  • It is commonly seen in MDS refractory anemia with excess blasts (RAEB)
• Treatment of MDS
  • Multiple transfusions – pRBCs and Platelets
  • Erythropoietin +/- G-CSF
  • Bone marrow transplant: curative but inappropriate since most patients are > 70 years
  • Thalidomide analogues (Lenalidomide) or hypomethylating agents (azacitidine and decitabine) may improve quality of life