Myelodysplastic syndromes

Myelodysplastic syndromes (MDS) are a group of hematological cancers in which malfunctioning pluripotent stem cells lead to hypercellularity and dysplasia of the bone marrow. This, in turn, leads to cytopenia of one or more cell lines (thrombocytopenia, erythrocytopenia, leukocytopenia). Most cases of MDS have a primary, idiopathic etiology, while a minority of cases are secondary to an underlying cause. MDS usually affects elderly patients and has a slowly progressive course. Clinical features vary depending on the type of MDS and the affected cell lines, and may include signs of anemia (e.g., fatigue, weakness, pallor), recurrent infections, and/or petechial bleeding. Diagnosis of MDS requires blood tests, bone marrow biopsy, and possibly genetic analysis. While mild cases may be closely monitored, severe disease typically requires blood transfusions supplemented with erythropoietin, vitamins, and, in some cases, granulocyte colony-stimulating factor. Medical therapy (e.g., chemotherapy or immunosuppressants) may also help to manage the disease, but allogenous stem cell transplantation is the only curative treatment. In 30% of cases, the disease progresses to acute myeloid leukemia.

• Primary MDS (90% of cases) ^[1]
  • Tends to occur in elderly patients
  • Unknown etiology: likely due to spontaneous mutations
• Secondary MDS (10% of cases): caused by exogenous bone marrow damage ^[2]
  • Treatment-related MDS: following cytostatic therapy (alkylating agents, topoisomerase II inhibitors, azathioprine, etc.)
  • Benzene and other organic solvents
  • Radiation damage: therapeutic radiation, radioiodine therapy, ionizing radiation
  • Paroxysmal nocturnal hemoglobinuria

• Asymptomatic in 20% of cases
• Depending on the affected cell line: ^[3]
  • Erythrocytopenia; (70% of cases) → symptoms of anemia
  • Leukocytopenia; with increased susceptibility to bacterial infections, especially of the skin
  • Thrombocytopenia; with impaired primary hemostasis → petechial bleeding
• Hepatosplenomegaly (uncommon)

• CBC with peripheral smear ^[3][4]
  • Normocytic or macrocytic anemia (rarely microcytic) of refractory type (refractory anemia)
  • Other possible findings
    • Leukocytopenia and/or thrombocytopenia
    • Nucleated RBCs, Howell-Jolly bodies, basophilic stippling
    • Pseudo-Pelger-Huet anomaly
      • Neutrophils with hyposegmented nuclei (usually bilobed)
      • Seen in peripheral blood smears of patients undergoing chemotherapy
    • Large, agranular platelets, and megakaryocytes (in MDS with myelofibrosis)
• Bone marrow biopsy: hypercellular, dysplastic bone marrow with numerous cells of all three cell lines with blasts, megakaryocytes, etc.
  • The amount of dysplastic cells depends on the type (see “Classification” above).
  • Ringed sideroblasts
• Chromosome analysis: : In > 50% of patients, chromosomal aberrations can be detected at the time of diagnosis.

WHO Classification of Primary Myelodysplastic Syndromes ^[5][6]

• The WHO classification distinguishes between six types of myelodysplastic syndromes, based on the number of dysplastic cell lines and the percentage of blasts in the bone marrow, among other criteria:
  • MDS with multilineage dysplasia (MDS-MLD; most common)
  • MDS with single lineage dysplasia (MDS-SLD)
  • MDS with ring sideroblasts (MDS-RS), with two subtypes:
    • MDS-RS with single lineage dysplasia (MDS-RS-SLD)
    • MDS-RS with multilineage dysplasia (MDS-RS-MLD)
  • MDS with excess blasts (MDS-EB), with two subtypes:
    • MDS-EB1
    • MDS-EB2
  • MDS with isolated del(5q) (rare)
  • MDS, unclassifiable (MDS-U; very rare)
• WHO also has a clinical classification
  • Primary MDS: no identifiable cause
  • Secondary MDS: cause is known

The therapeutic approach depends on a patient's presentation, age, and comorbidities. More aggressive therapy (e.g., chemotherapy, stem cell transplantation) is generally reserved for younger, healthier patients. ^[7]

• Mild cytopenia: "watch and wait"
• Severe cytopenia
  • Supportive treatment
    • Mainstay of treatment: RBC and platelet transfusions depending on cell counts
    • To compensate for the high cell turnover: vitamin supplementation (vitamin B₆, B₁₂, folate)
    • In cases of symptomatic anemia and low erythropoietin (EPO) levels: synthetic EPO
    • In cases of neutropenia: granulocyte colony-stimulating factor
    • If infection occurs: antibiotics
  • Medical therapy
    • Chemotherapy: if myeloblasts are elevated and since the disease may progress to acute myeloid leukemia (AML)
    • Immunosuppressive agents
    • Lenalidomide: the drug of choice for patients with 5q deletion
  • Allogenous stem cell transplant is the only curative option: indicated for patients < 55 years of age with late-stage MDS ^[8]

• Depending on the chromosomal aberrations detected in pluripotent stem cells, up to 30% of MDS cases may progress to acute myelogenous leukemia. ^[9]
• See “Clinical features” above.

We list the most important complications. The selection is not exhaustive.