13-28: Myelodysplastic Syndromes

The myelodysplastic syndromes are a group of acquired clonal disorders of the hematopoietic stem cell. They are characterized by the constellation of cytopenias, a usually hypercellular marrow, morphologic dysplasia, and genetic abnormalities. The disorders are usually idiopathic but may be caused by prior exposure to cytotoxic chemotherapy, radiation or both. In addition to cytogenetics, sequencing can detect genetic mutations in 80–90% of MDS patients. Importantly, acquired clonal mutations identical to those seen in MDS 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 (greater than 5% of marrow elements). The category of MDS with excess blasts represents a more aggressive form of the disease, often leading to AML. Those 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 ringed sideroblasts is used to define a subcategory of the lower-risk MDS 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. Lastly, a proliferative syndrome including sustained peripheral blood monocytosis more than 1000/mcL (1.0 × 10⁹/L) is termed chronic myelomonocytic leukemia (CMML), a disorder that shares features of myelodysplastic and myeloproliferative disorders. An International Prognostic Scoring System (IPSS) classifies patients by risk status based on the percentage of bone marrow blasts, cytogenetics, and severity of cytopenias. The IPSS is associated with the rate of progression to AML and with overall survival, which can range from a median of 6 years for the low-risk group to 5 months for the high-risk patients.

A. Symptoms and Signs

Patients are usually over age 60 years. Many patients are asymptomatic when the diagnosis is made because of the finding of abnormal blood counts. Fatigue, infection, or bleeding related to bone marrow failure are usually the presenting symptoms and signs. The course may be indolent, and the disease may present as a wasting illness with fever, weight loss, and general debility. On examination, splenomegaly may be present in combination with pallor, bleeding, and various signs of infection. Myelodysplastic syndromes can also be accompanied by a variety of paraneoplastic syndromes prior to or following this diagnosis.

B. Laboratory Findings

Anemia may be marked with the MCV normal or increased, and transfusion support may be required. On the peripheral blood smear, macro-ovalocytes may be seen. The white blood cell count is usually normal or reduced, and neutropenia is common. The neutrophils may exhibit morphologic abnormalities, including deficient numbers of granules or deficient segmentation of the nucleus, especially a bilobed nucleus (Pelger-Huet abnormality) (eFigure 13–26). The myeloid series may be left shifted, and small numbers of promyelocytes or blasts may be seen. The platelet count is normal or reduced, and hypogranular platelets may be present.

The bone marrow is characteristically hypercellular but occasionally may be hypocellular. Erythroid hyperplasia is common, and signs of abnormal erythropoiesis include megaloblastic features, nuclear budding, or multinucleated erythroid precursors (eFigure 13–27). The Prussian blue stain may demonstrate ringed sideroblasts. In the marrow, too, the myeloid series is often left shifted, with variable increases in blasts. Deficient or abnormal granules may be seen. A characteristic abnormality is the presence of dwarf megakaryocytes with a unilobed nucleus. Genetic abnormalities define MDS; there are frequent cytogenetic abnormalities involving the long arm of chromosome 5 as well as deletions of chromosomes 5 and 7. Some patients with an indolent form of the disease have an isolated partial deletion of chromosome 5 (MDS with isolated del[5q]). Aside from cytogenetic abnormalities, the most commonly mutated genes are SF3B1, TET2, SRSF2, ASXL1, DNMT3A, RUNX1, U2AF1, TP53, and EZH2.

Myelodysplastic syndromes should be distinguished from megaloblastic anemia, aplastic anemia, myelofibrosis, HIV-associated cytopenias, and acute or chronic drug effect. In subtle cases, cytogenetic evaluation of the bone marrow may help distinguish this clonal disorder from other causes of cytopenias. As the number of blasts increases in the bone marrow, myelodysplasia is arbitrarily separated from AML by the presence of less than 20% blasts.

Myelodysplasia is a heterogeneous disease, and the appropriate treatment depends on a number of factors. For patients with anemia who have a low serum erythropoietin level (500 milliunits/mL or less), erythropoiesis-stimulating agents may raise the hematocrit and reduce the red cell transfusion requirement in 40%. Addition of intermittent granulocyte colony-stimulating factor (G-CSF) therapy may augment the erythroid response to epoetin. Unfortunately, the patients with the highest transfusion requirements are the least likely to respond. Patients who remain dependent on red blood cell transfusion and who do not have immediately life-threatening disease should receive iron chelation in order to prevent serious iron overload; the dose of oral agent deferasirox is 20 mg/kg/day in divided dosing. Patients affected primarily with severe neutropenia may benefit from the use of myeloid growth factors such as filgrastim. Oral thrombopoietin analogs, such as romiplostim and eltrombopag, have shown effectiveness in raising the platelet count in myelodysplasia. Finally, occasional patients can benefit from immunosuppressive therapy including ATG. Predictors of response to ATG include age younger than 60 years, absence of 5q–, and presence of HLA DR15.

For patients who do not respond to these interventions, there are several therapeutic options available. Lenalidomide is approved for the treatment of transfusion-dependent anemia due to myelodysplasia. It is the treatment of choice in patients with MDS with isolated del(5q) with significant responses in 70% of patients, and responses typically lasting longer than 2 years. In addition, nearly half of these patients enter a cytogenetic remission with clearing of the abnormal 5q– clone. The recommended initial dose is 10 mg/day orally. The most common side effects are neutropenia and thrombocytopenia, but venous thrombosis occurs and warrants prophylaxis with aspirin, 325 mg/day orally. For patients with high-risk myelodysplasia, azacitidine is the treatment of choice. It can improve both symptoms and blood counts and prolong both overall survival and the time to conversion to acute leukemia. It is used at a dose of 75 mg/m² daily for 5–7 days every 28 days and up to six cycles of therapy may be required to achieve a response. Decitabine, a related hypomethylating agent, given at 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. Unfortunately, the progress that has been made over the past decade in understanding the complex molecular mechanisms underlying MDS has not yet translated into new therapeutic options.

Allogeneic stem cell transplantation is the only curative therapy for myelodysplasia, but its role is limited by the advanced age of many patients and the variably indolent course of the disease. The optimal use and timing of allogeneic transplantation are controversial, but the use of reduced-intensity preparative regimens and alternative donor sources (cord blood, haplotype-matched) has expanded the role of this therapy.

Myelodysplasia is an ultimately fatal disease, and allogeneic transplantation is the only curative therapy, with cure rates of 30–60% depending primarily on the risk status of the disease. Patients most commonly die of infections or bleeding. Patients with MDS with isolated del(5q) have a favorable prognosis, with 5-year survival over 90%. Other patients with low-risk disease (with absence of both excess blasts and adverse cytogenetics) may also do well, with similar survival. Those with excess blasts or CMML have a higher (30–50%) risk of developing acute leukemia, and short survival (less than 2 years) without allogeneic transplantation.

All patients with myelodysplasia should be referred to a hematologist.

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