Myelodysplastic syndrome

Question 1

What is myelodysplastic syndrome (MDS)?

Answer 1

Myelodysplastic syndromes (MDS) are a group of hematological cancers (malignancies) in which malfunctioning pluripotent stem cells (due to mutations) lead to hypercellularity and dysplasia of the bone marrow. This, in turn, leads to cytopenia of one or more cell lines (thrombocytopenia, erythrocytopenia, leukocytopenia)

Question 2

What is etiology of MDS?

Answer 2

MDS are clonal neoplasms that arise from mutations in hematopoietic stem cells. The precise cause of the mutations is unknown for most patients, but in some it is associated with exposure to cytotoxic chemotherapy and/or ionizing radiation (ie, therapy-related MDS) or environmental toxins (eg, tobacco, benzene).

Primary MDS (90% of cases):

• Tends to occur in elderly patients.
• Unknown etiology.

Secondary MDS (10% of cases): caused by exogenous bone marrow damage.

• 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 (a rare, acquired hemolytic anemia caused by mutation in a gene).

Question 3

What is epidemiology of MDS?

Answer 3

MDS occurs most commonly in older adults, but the precise incidence is not well-defined. The median age at presentation is 70 years and disease onset before age 50 is unusual (except for therapy-related MDS). There is a male predominance in most categories of MDS.

Question 4

How can you classify MDS?

Answer 4

The FAB system classifies MDS into the following five subgroups, differentiating them from acute myeloid leukemia:

• Refractory anemia (RA) - (Do not respond to normal treatment)
• RA with ringed sideroblasts (RARS)
• RA with excess blasts (RAEB; 6-20% myeloblasts)
• Chronic myelomonocytic leukemia (CMML)
• RAEB in transition to AML (RAEB-T; 21-30% myeloblasts)

Question 5

Clinical manifestations of MDS?

Answer 5

Some patients present with fatigue, infections, bruising, or other symptoms or complications of cytopenias, while others are asymptomatic and come to medical attention due to abnormalities on a routine CBC.

Cytopenias:

• Erythrocytopenia (70% of cases) → symptoms of anemia such as fatigue, weakness, exercise intolerance, angina, dizziness, cognitive impairment.
• Leukocytopenia, with increased susceptibility to bacterial infections (most often skin)
• Thrombocytopenia, with impaired primary hemostasis → petechial bleeding, easy bruising, bleeding.

Systemic symptoms such as fever, sweats, or weight loss are uncommon and generally represent late manifestations of MDS or transformation to acute leukemia. Physical findings of MDS are nonspecific but may include pallor, petechiae, purpura, mucosal ulceration/gingivitis, or stigmata of infections. Hepatomegaly, splenomegaly, and lymphadenopathy are uncommon.

Question 6

What does CBC show in MDS?

Answer 6

Usually shows anemia, but neutropenia and thrombocytopenia are more variable.

Red blood cells – Anemia is almost always present.

• MCV may be macrocytic or normal.
• The RDW is often increased.
• MCHC is usually normal.

Leukocytes – 50% have a reduced total WBC count. Circulating immature neutrophils (myelocytes, promyelocytes, and myeloblasts) may be identified, but blasts constitute fewer than 20 percent of the leukocyte differential.

Platelets – Variable levels of thrombocytopenia are present in approximately 1/4 of patients.

Question 7

What does blood smear show in MDS?

Answer 7

The peripheral blood smear usually demonstrates dysplasia in the red and white blood cell series and may reveal platelet abnormalities.

Red blood cells – Red blood cells are usually normocytic or macrocytic (more commonly).

White blood cells – Dysplastic neutrophils are commonly found on the blood smear.

Question 8

What does bone marrow examination show in MDS?

Answer 8

The bone marrow features single- or multilineage dysplasia and is usually hypercellular (since the maturation and differentiation of these cells is impaired (dysplasia), there is peripheral cytopenia even though the bone marrow itself is hypercellular!).

• Blasts – Myeloblasts are increased, but by definition, the blast percentage is <20 percent.
• Erythroid hyperplasia (associated with ineffective erythropoiesis) is usually seen. Could see ring sideroblasts.
• Fibrosis – Mild to moderate degrees of myelofibrosis is seen in most patients.

Question 9

How to diagnose MDS?

Answer 9

MDS should be considered in any patient with unexplained cytopenias or clinical manifestations associated with these findings, such as symptoms of anemia, infections, or bleeding/bruising. Diagnosis include: CBC, Peripheral smear and Bone marrow examination.

The diagnosis of MDS is made based on:

• The presence of one or more cytopenias and,
• ≥10 percent of nucleated cells in at least one lineage are morphologically dysplastic,
• <20 percent blasts forms in blood and bone marrow, and/or characteristic cytogenetic or molecular findings.

The diagnosis of MDS is based on:
- Cytopenias – Hemoglobin <10 g/dL (100 g/L); absolute neutrophil count <1.8 x 109/L (<1800/microL); platelets <100 x 109/L (<100,000/microL).

• Dysplasia – Morphologic or immunophenotypic evidence of significant dysplasia in ≥10 percent of erythroid precursors, granulocytes, or megakaryocytes on the blood smear or bone marrow examination, in the absence of other causes of dysplasia.
• Cytogenetic abnormalities – Chromosomal abnormalities are presumptive evidence of MDS in patients with otherwise unexplained refractory cytopenia and no morphologic evidence of dysplasia. One example; unbalanced chromosomal abnormalities:
• Loss of chromosome 7 or del(7q)

Question 10

What is treatment of MDS?

Answer 10

Mild cytopenia: “watch and wait”.

Severe cytopenia:
- Supportive treatment
Mainstay of treatment: RBC and platelet transfusions depending on cell counts. Most of the patients need regular blood transfusions. Complications – secondary hemochromatosis.

• 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). If there is a blast cell increase as in RAEB, RAEB-t. However, the treatment is not curative, since its effect on slowly dividing dysplastic cells is limited.

• Immunosuppressive agents.
• Lenalidomide: the drug of choice for patients with 5q deletion.

Allogenous stem cell transplant is the only curative option. Is indicated in younger, medically fit patients.