Myelodysplastic Syndromes

A heterogeneous group of syndromes in which the hematopoietic precursors are abundant but morphologically abnormal.

The actual incidence of the myelodysplastic syndromes is not known, but they are fairly common in the elderly. Ineffective erythropoiesis, which is a key feature of these syndromes, increases with age, and in some studies, up to 20% of people > 65 have unexplained refractory anemia. The syndromes are twice as common in men and are rare in persons < 40.

Etiology and Pathophysiology

In most patients, the cause is unknown, but prior treatment with alkylating agents increases the risk of developing a myelodysplastic syndrome--the longer a patient is treated, the greater the risk. Myelodysplastic syndrome tends to progress into acute myelogenous leukemia (AML); a protracted myelodysplastic syndrome lasting up to 20 years precedes 5 to 10% of cases of AML. The AML that develops in 2 to 7% of patients treated with alkylating agents is invariably fatal. This progression, a long-term complication of successful chemotherapy, may become more prevalent as more patients survive. Chemotherapeutic drugs that are not alkylating agents (eg, methotrexate, hydroxyurea) do not seem to produce this complication.

Other possible causes of myelodysplastic syndromes include RNA viruses, somatic mutations, radiation, environmental toxins, and autoimmune mechanisms. Yet, the ability of any of these factors to induce myelodysplasia may be enhanced by aging. Accumulated genetic mutations from various causes, including aging, are more likely to result in dysplastic and malignant change than are single genetic insults, a concept sometimes called the multihit theory. Familial instances of myelodysplastic syndromes are rare.

Myelodysplastic syndromes are thought to arise from an undefined cytopathologic alteration of the pluripotential hematopoietic stem cell pool, evolving from the clonal expansion of a single stem cell (or a very small number of stem cells). The major pathophysiologic consequence is ineffective hematopoiesis caused by defective maturation of marrow precursor cells. Proliferation of progenitor and early precursor cells is usually normal or enhanced (creating a hypercellular marrow). However, circulating mature cells are deficient; they also have a slightly shorter life span, which contributes to cytopenia.

Classification

Exact characterization is difficult; refractory anemia often progresses to a refractory dysmyelopoietic anemia involving the red cell, white cell, and megakaryocytic lines.

The syndromes are classified by morphologic criteria. In refractory anemia and refractory anemia with ringed sideroblasts, platelets and WBCs are usually normal. In refractory anemia with excess blasts, chronic myelomonocytic leukemia, and refractory anemia with excess blasts in transformation, all three cell lines are often abnormal. These terms have generally replaced the term preleukemia, because only about 10 to 30% of patients with a myelodysplastic syndrome develop an acute leukemia.

Symptoms and Signs

Because cytopenia develops slowly, many patients are asymptomatic, and the diagnosis is made incidentally or the anemia is falsely attributed to aging. Symptomatic patients generally seek medical care for symptoms of anemia, thrombocytopenia, or leukopenia, such as fatigue, decreased exercise tolerance, purpura, fever, or infections. Hepatomegaly occurs in about 5% of patients, splenomegaly in about 10%, and pallor in about 50%. Often the patient complains of arthralgias.

Most patients have increased iron stores, and many have clinical hemochromatosis with diabetes, cirrhosis, infiltrative heart disease, and pituitary dysfunction.

Diagnosis

The hallmark of myelodysplastic syndromes is anemia with reticulocytopenia. The RBC morphologic appearance is usually abnormal. The RBCs are usually dimorphic; some cells are microcytic and hypochromic, and others are normochromic and normocytic or macrocytic. At first analysis, laboratory values may result in the anemia being classified as normochromic-normocytic, but the red cell distribution width will likely be elevated. Basophilic stippling, target cells, schistocytes, siderocytes, and nucleated RBCs often appear.

Leukopenia is moderate; the WBC count ranges from 1000 to 4000/µL. Neutropenia is more pronounced than lymphopenia. The neutrophils are often sparsely granulated, and the acquired Pelger-Huët nuclear anomaly (hypolobulation of the nuclei of mature neutrophils) may be present. Neutrophil alkaline phosphatase activity may be low. Granulocytes often function abnormally, which further impairs resistance to infection. Monocytosis occurs in 30% of patients, which may elevate serum and urinary lysozyme levels. Thrombocytopenia is common, although occasionally, patients have thrombocytosis. The platelets may have functional defects. Immature myeloid cells may be present in the peripheral blood smear.

Diagnosis is made by histologic examination of a bone marrow aspirate and biopsy. Erythroblasts may have double or fragmented nuclei or intranuclear bridging; budding, ringed sideroblasts may be prominent. These are usually found in patients with abnormalities in the RBC precursors. With primarily erythroid dysplasia, the ratio of myeloid to erythroid precursors (M:E ratio) is between 1:1 and 1:10 (normal is 3:1). Dyserythropoiesis results in moderately elevated levels of serum lactic dehydrogenase and indirect bilirubin.

Marrow myeloid cells may show immature to mature neutrophils, may have the acquired Pelger-Huët nuclear anomaly, and are often sparsely granulated. Eosinophils and basophils may also be dysplastic. In patients with primarily myeloid dysplasia, the M:E ratio is between 3:1 and 20:1. Megakaryocytes may be immature and dysplastic as well.

Reticuloendothelial iron is increased, as are the serum iron and ferritin levels. Iron stores are increased in most patients. Iron turnover rate is increased, but incorporation of iron into circulating erythrocytes is decreased, indicating ineffective erythropoiesis.

Prognosis

Prognosis is highly variable, with survival ranging from a few months to 15 years. The median survival is about 3 years. Although about 10 to 30% of patients die as a result of acute blastic transformation (AML), individual prognosis cannot be predicted. Patients with primarily erythroid dysplasia are at lower risk than those with involvement of the other cell lines.

Treatment

Transfusion of blood products is the mainstay of treatment but should be limited and given only if the patient is symptomatic from the anemia or is in danger of cardiac compromise. Transfusing packed RBCs risks iron overload; alloimmunization to RBC, WBC, and platelet antigens; and transmission of various infections. Washed RBCs may slow the development of alloimmunization. Platelets should be transfused only if the patient is bleeding or if surgery is needed. Granulocyte colony-stimulating factor is used in neutropenic patients. Granulocyte transfusions should be given only to neutropenic patients with documented gram-negative infections that are unresponsive to antibiotics alone.

Occasionally, patients with ringed sideroblasts respond to pyridoxine 100 to 200 mg/day po. However, the response is only partial, and an abnormal RBC morphologic appearance usually persists. Androgens and corticosteroids have benefited a small number of patients. Recombinant hematopoietic growth factors including erythropoietin have been tried, but no consistent improvement has been shown in those whose serum erythropoietin level is lower than expected for the measured Hct. Continuous overnight (12-hour) IV or subcutaneous administration of deferoxamine by portable pump should be considered when the patient is receiving blood transfusions monthly or more often. A convenient regimen is 2 g of deferoxamine given sc over 12 h by portable infusion pump for 5 days/week.

Chemotherapy as early treatment of myelodysplasia with excessive blasts has not increased survival. Administering low-dose cytarabine to induce differentiation of blasts is controversial. For patients who develop AML, the remission rate is even lower than for patients with leukemia who did not previously have myelodysplasia. Patients with this secondary form of AML have prolonged marrow aplasia after chemotherapy. One approach in the elderly consists of giving supportive care with blood products and attempting to keep the WBC count < 50,000/µL by giving hydroxyurea 10 to 80 mg/kg/day po.

End-of-Life Issues

Seventy to ninety percent of patients with myelodysplasia will not die of the illness. However, in the patients with an increasing percentage of blasts and decreasing RBCs, WBCs, and platelets, the likelihood of AML transformation is great. The AML that develops is usually totally refractory to treatment. These patients and their families will need help in preparing for a rapid death.