Myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are a group of clonal hematopoietic stem cell neoplasms characterized by impaired proliferation and differentiation of myeloid stem cells within the bone marrow. Primary (idiopathic) MDS, likely related to spontaneous mutations, is most common; secondary MDS may result from inciting events such as exposure to chemotherapy. MDS is typically seen in older adults and is evidenced by laboratory abnormalities, symptoms of cytopenia(s), and findings of extramedullary hematopoiesis. To diagnose and classify MDS, other causes of cytopenia and/or dysplasia must be excluded and bone marrow and genetic studies should be conducted. These studies typically show dysplasia and cytopenia in at least one mature myeloid cell line on CBC, bone marrow hypercellularity of myeloid precursors, and MDS-associated genetic abnormalities. All patients should receive supportive therapy as needed, including transfusions and treatment of associated iron overload. Additional treatment is guided by risk stratification in MDS. Individuals with high-risk disease are treated with hypomethylating agents and possibly intensive chemotherapy; they should also all be assessed for fitness for allogeneic hematopoietic stem cell transplantation, which is the only curative option. Treatment options for individuals with low-risk disease include expectant management, hypomethylating agents, and drugs such as lenalidomide. Close surveillance is required to determine treatment response and monitor for disease progression (e.g., to acute myelogenous leukemia or bone marrow failure).

• Primary MDS (90% of cases) ^[1]
  • Most commonly manifests in older adults ^[1]
  • Idiopathic: likely due to spontaneous mutations ^[1]
• Secondary MDS (10% of cases): due to exogenous bone marrow damage ^[2]
  • Treatment-related: 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

MDS and AML are differentiated based on the number of myeloblasts in bone marrow or peripheral blood cells: < 20% in MDS and ≥ 20% in AML. ^[3][4]

In a previous WHO classification system, refractory anemia was a subtype of MDS. ^[5]

• Asymptomatic in 20% of cases
• Depending on the affected cell line: ^[6]
  • 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)

Approach ^[7][8][9]

Workup for MDS may be prompted by symptoms related to cytopenias or by the discovery of incidental cytopenia.

• Obtain initial studies, including workup for other causes of cytopenia and dysplasia.
• If the cause is still unexplained, refer to hematology-oncology for:
  • Advanced diagnostic studies (i.e., bone marrow and genetic studies)
  • Confirmation of diagnosis and classification of MDS, based on the presence of ≥ 1 of the following: ^[3][4]
    • ≥ 10% dysplastic cells in ≥ 1 myeloid cell line on bone marrow smear (see “Myeloid cell line abnormalities in MDS”)
    • Increased myeloblasts ^[3]
    • MDS-associated genetic abnormality

MDS is often identified during evaluation for unexplained cytopenia.

Initial studies ^[7][8][10]

• CBC with peripheral smear: will show myeloid cell line abnormalities in MDS
• Studies to exclude other causes of cytopenia and/or dysplasia
  • Infectious disease studies (e.g., HIV test, viral hepatitis panel)
  • Micronutrient levels (e.g., B₁₂, folate, copper, iron) ^[11]
  • BMP: to assess for chronic kidney disease
  • Liver chemistries: to assess for chronic liver disease
• Possible additional studies: may show nonspecific abnormalities ^[9]
  • ↑ LDH
  • ↑ Uric acid
  • Gamma globulins: may be decreased or elevated (both monoclonal and polyclonal gammopathies)

Advanced studies for MDS ^[3][7][12]

• Bone marrow studies (aspiration and/or biopsy): to evaluate for myeloid cell line abnormalities in MDS
• Genetic evaluation ^[4]
  • Karyotype +/- FISH: to evaluate for chromosomal aberrations (e.g., 5q or 7q deletion) ^[13]
  • Mutation analysis: to evaluate for specific mutations (e.g., SF3B1 and TP53)

Genetic evaluation is required for classification of MDS, as well as for risk-stratification of patients to estimate prognosis and guide treatment. ^[3][7]

Overview of hematological findings in MDS ^[12][14][15]

Anemia is the most common cytopenia in MDS, and may manifest as macrocytic anemia or normocytic anemia. ^[9]

The pseudo-Pelger-Huet anomaly is also seen in patients receiving certain medications (e.g., chemotherapy, transplant medications) and in other hematological disorders (e.g., myeloproliferative disorders). ^[16][17]

Other causes of cytopenia and/or dysplasia include: ^[7][8][10]

• Nonmalignant causes
  • Deficiencies in micronutrients (e.g., B₆, B₁₂, folate, copper, iron) ^[10]
  • Medications ^[18]
  • Reactive changes due to acute viral illnesses
  • Chronic alcohol consumption
  • Infectious diseases (e.g., HIV, CMV, TB)
  • Autoimmune diseases (e.g., SLE, rheumatoid arthritis)
  • Chronic kidney disease
  • Chronic liver disease
• Other hematological conditions ^[3]
  • Clonal hematopoiesis
  • Acute myeloid leukemia
  • MDS/MPN overlap syndromes
  • Aplastic anemia
• Other malignancies associated with cytopenias

Precursor clonal hematopoietic conditions can progress to MDS. MDS can itself progress to acute myeloid leukemia. ^[4][13]

The differential diagnoses listed here are not exhaustive.

Approach ^[7][10][13]

Refer all patients to hematology-oncology for management.

• All patients
  • Assess for comorbidities and discuss goals of care.
  • Use scoring systems for risk stratification in MDS.
  • Provide supportive therapy for symptomatic and/or significant cytopenia(s).
  • Offer enrollment in clinical trials.
  • Monitor regularly for treatment response and disease progression.
  • Identify and treat complications (e.g., iron overload, infections, bleeding).
• High-risk MDS
  • Start pharmacotherapy for MDS, which may include hypomethylating agents and chemotherapy.
  • Assess suitability for allogeneic hematopoietic stem cell transplantation (HSCT). ^[7][13]
• Low-risk MDS: Screen for indications for pharmacotherapy for MDS.
  • If therapy is indicated:
    • Treat accordingly, e.g., with hypomethylating agents, lenalidomide (for 5q deletion), or immunosuppressive agents.
    • If disease is refractory to treatment, consider HSCT.
  • If therapy is not indicated: Expectant management (i.e., “watch and wait”) may be appropriate. ^[7]

Allogeneic stem cell transplantation is the only curative option for MDS.

Risk stratification in MDS ^[7][10][13]

• To determine treatment, patients with MDS are categorized as having either low-risk or high-risk MDS.
• Clinical scoring systems include:
  • Revised International Prognostic Scoring System (IPSS-R)
  • Molecular International Prognostic Scoring System (IPSS-M) ^[19][20]
• Common high-risk features:
  • Patient > 60 years of age ^[10]
  • Significant or multiple cytopenias
  • Increased myeloblasts (≥ 5%) in the bone marrow
  • Multiple and/or unfavorable genetic abnormalities

Patients with a high-risk feature may still have low-risk MDS if the total prognostic score is below the cutoff value for high-risk MDS.

Supportive therapy ^[7][10][13]

Disease-related cytopenias

• Anemia
  • pRBC transfusion
  • Erythropoietin-stimulating agents (e.g., recombinant EPO) ^[13]
• Neutropenia: recombinant granulocyte colony-stimulating factor (G-CSF) may be used in select cases ^[10]
• Thrombocytopenia: platelet transfusions ^[10][13]

Treatment-associated complications

• Iron overload: Provide iron chelation (e.g., deferasirox) to transfusion-dependent patients with elevated ferritin levels. ^[13]
• Infection
  • Suspected and/or confirmed infections: Treat with antibiotics (e.g., febrile neutropenia management).
  • Neutropenia in patients on immunosuppressive treatment: Consider prophylactic antibiotic therapy. ^[13]
• See also “Anticancer treatment-related complications” in “Principles of cancer care.”

Pharmacotherapy for MDS ^[7][10][13]

• Pharmacotherapy is noncurative but aims to:
  • Increase cell counts
  • Improve symptoms and quality of life
  • Reduce transfusion burden
  • Delay progression to AML

Lenalidomide may cause significant neutropenia and thrombocytopenia. ^[7]

Inadequate response to hypomethylating agents is associated with a poor prognosis. ^[13]

• Depending on the chromosomal aberrations detected in pluripotent stem cells, up to 30% of MDS cases may progress to acute myelogenous leukemia. ^[21]
• See “Clinical features” above.

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