Myelodysplastic Syndromes

Essentials of Diagnosis

• Cytopenias with hypercellular bone marrow

• Morphologic abnormalities in one or more hematopoietic cell lines

General Considerations

• Group of acquired clonal disorders of the hematopoietic stem cell, characterized by the constellation of cytopenias, a usually hypercellular marrow, morphologic dysplasia and genetic abnormalities

• Causes

  • Idiopathic (most common)

  • Prior exposure to cytotoxic chemotherapy or radiation therapy

• In addition to cytogenetics, sequencing can detect genetic mutations in 80–90% of patients

• Acquired clonal mutations identical to those seen in myelodysplastic syndrome can occur in the hematopoietic cells of ~10% of apparently healthy older individuals, defining the disorder of clonal hematopoiesis of indeterminate potential (CHIP)

• Myelodysplasia encompasses several heterogeneous syndromes; a key distinction is whether there is an increase in bone marrow blasts (> 5% of marrow elements)

  • MDS with excess blasts represents a more aggressive form of the disease, often leading to acute myeloid leukemia

  • Patients without excess blasts are characterized by the degree of dysplasia, eg, MDS with single lineage dysplasia and MDS with multilineage dysplasia

  • The morphologic finding of MDS with ringed sideroblasts is used to define a subcategory of lower risk syndromes

  • Patients with isolated 5q loss, which is characterized by the cytogenetic finding of loss of part of the long arm of chromosome 5, comprise an important subgroup of patients with a different natural history

  • Chronic myelomonocytic leukemia (CMML) is a proliferative syndrome, including sustained peripheral blood monocytosis > 1000/mcL (> 1.0 × 10⁹/L)

Demographics

• Occurs most often in patients aged > 60

Symptoms and Signs

• Asymptomatic, with incidentally found cytopenias

• Symptoms and signs are related to bone marrow failure

• Symptoms

  • Fatigue

  • Bleeding

• Signs

  • Fever

  • Infection

  • Wasting

  • Weight loss

  • Splenomegaly

  • Pallor

• Paraneoplastic syndromes of various sorts (prior to or following diagnosis)

Differential Diagnosis

• Acute myeloid leukemia (AML) (≤ 20% blasts)

• Aplastic anemia

• Anemia of chronic disease

• Vitamin B₁₂ or folate deficiency

• Megaloblastic anemia

• Myelofibrosis

• HIV-associated cytopenias

• Acute or chronic drug effect

Laboratory Tests

• Anemia may be marked

• Mean cell volume is normal or increased

• Peripheral blood smear may show macro-ovalocytes

• White blood cell count usually normal or reduced; neutropenia is common

• Neutrophils may exhibit morphologic abnormalities, including deficient numbers of granules, or bilobed nucleus (Pelger-Huet abnormality)

• Myeloid series may be left shifted with small numbers of promyelocytes or blasts

• Platelet count is normal or reduced; hypogranular platelets may be present

Diagnostic Procedures

• Bone marrow aspirate and biopsy are characteristically hypercellular (but may occasionally be hypocellular)

• Signs of abnormal erythropoiesis include

  • Megaloblastic features

  • Nuclear budding

  • Multinucleated erythroid precursors

• Prussian blue stain may demonstrate ringed sideroblasts

• Myeloid series is often left shifted with variable increases in blasts

• Deficient or abnormal myeloid granules may be seen

• A characteristic abnormality is dwarf megakaryocytes with unilobed nucleus

• Cytogenetics may be abnormal

• No specific chromosomal abnormality is seen, but abnormalities in chromosomes 5 and 7 are common

Medications

• For patients with anemia who have a low serum erythropoietin level (≤ 500 milli-units/mL), erythropoiesis-stimulating agents (epoetin alfa, darbepoetin) may

  • Raise the hematocrit

  • Reduce red blood cell transfusion requirement

• Addition of intermittent granulocyte colony stimulating factor (G-CSF) therapy may augment the erythroid response to epoetin or darbepoetin

• Oral deferasirox (20 mg/kg/day in divided dosing)

  • Used as iron chelation therapy

  • Prevents serious iron overload in patients who do not have immediately life-threatening disease but who depend on periodic red blood cell transfusions

• Lenalidomide

  • Recommended initial dose is 10 mg orally daily

  • Approved for treatment of transfusion-dependent anemia due to myelodysplasia

  • Treatment of choice in patients with MDS with isolated del(5q)

  • Most common side effects are neutropenia and thrombocytopenia, but venous thrombosis is also seen and warrants aspirin prophylaxis (325 mg/day orally)

  • Cost is extremely high, and it is not effective either for cell lines other than red blood cells or for patients with increased blasts

• Patients affected primarily with severe neutropenia may benefit from the use of myeloid growth factors such as filgrastim

• Romiplostim and eltrombopag have shown effectiveness in raising the platelet count in myelodysplasia

• Azacitidine

  • Treatment of choice for patients with high-risk myelodysplasia

  • Can improve both symptoms and blood counts and prolong both overall survival and the time to conversion to acute leukemia

  • Dosage: 75 mg/m² daily for 5–7 days every 28 days; up to six cycles of therapy may be required to achieve a response

• Decitabine

  • Dosage: 20 mg/m² daily for 5 days every 28 days

  • Can produce similar hematologic responses but has not demonstrated a benefit in overall survival compared to supportive care alone

Therapeutic Procedures

• Red blood cell transfusions are indicated for severe anemia

• Allogeneic stem cell transplantation

  • Only curative therapy for myelodysplasia

  • Role is limited by advanced age of many patients and variably indolent course of disease

Complications

• Infection

• Bleeding

Prognosis

• Myelodysplasia is ultimately fatal, most commonly because of infection or bleeding

• Allogeneic transplantation is the only curative therapy, with cure rates of 30–60% depending primarily on the risk status of the disease

• Patients with excess blasts or CMML have a higher (30–50%) risk of developing acute leukemia, and short survival (< 2 years) without allogeneic transplantation

• Prognosis is favorable in

  • Patients with MDS with isolated del(5q), with 5-year survival over 90%

  • Patients with low-risk disease (with absence of both excess blasts and adverse cytogenetics), with similar survival

• International Prognostic Scoring System (IPSS) classifies patients by risk status based on

  • Percentage of bone marrow blasts

  • Cytogenetics

  • Severity of cytopenias

When to Refer

• All patients should be referred to a hematologist

When to Admit

• Hospitalization is needed only for specific complications, such as severe infection