The myelodysplastic syndromes (MDS) are a collection of disorders that predominately affect older patients with the median age of 63 at diagnosis. MDS is a heterogenous group of disorders characterized by abnormal growth of the myeloid bone marrow components. This section examines the common mechanism believed to underlie the MDS and then relates that to the propensity of these conditions to evolve into acute leukemia. In addition, we discuss the classification, natural history, and treatment options for MDS.
The pathogenesis of MDS is complicated. Current theory holds that MDS results from chromosomal injury that occurs in stepwise progression. Beginning with an initial predisposition to genomic instability, progressive insults result in chromosomal damage that culminates in MDS and can further progress to AML. Common chromosomal alterations involve 5, 7, 8, and 20. The involved chromosome areas are usually rich in hematopoietic genes. In addition to gross chromosome alterations, submicroscopic DNA mutations result in abnormal oncogene expression. Because of secondary DNA damage, exposure to chemicals or prior chemotherapy increases the risk for developing MDS. Although these genes may play a pathologic role in the development of MDS, we still do not understand the critical molecular events that lead to these diseases. The progression of MDS to leukemia is likely the result of additional genetic mutations that provide the evolving clone further growth advantages.
The biology of the disease is further complicated by other abnormalities, including aberrant cytokine production and responsiveness, altered stem cell adhesion, abnormal marrow microenvironment, early cell death secondary to accelerated apoptosis, and immunomediated marrow suppression. With all these contributing factors, MDS is ultimately a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and peripheral cytopenias.
The WHO classification system was recently proposed to replace the previous FAB classification system. Some of the subsets are listed here. The distinction among these groups is based on the appearance of the bone marrow. The clinical presentation, however, can be very similar. Low blood counts (cytopenias) are the hallmark, and anemia occurs in the majority of patients. Isolated neutropenia or thrombocytopenia also occurs, but the usual picture is trilineage cytopenias. On examination of the peripheral blood, abnormal morphology is usually apparent. The findings in the marrow are more obvious, with hypercellularity, bizarre nuclear morphology, abnormal iron granules (sideroblasts), and nuclear/cytoplasmic maturation dysynchrony evident. All lines are affected, although frequently one lineage is more markedly dysplastic. An important determinant of overall prognosis is the percentage of blast cells in the bone marrow.
Some of the major types of MDS are (1) refractory anemia (RA); (2) refractory anemia with ringed sideroblasts (RARS); (3) refractory anemia with excess of blasts (RAEB); and (4) chronic myelomonocytic leukemia (CMML). CMML has features of both the dysplastic syndromes and the myeloproliferative disorders (discussed in the next section). There is usually a significant increase in circulating monocytes, as well as trilineage dysplasia in CMML. This classification system is dependent on the percentage of blast cells in the marrow and also stratifies the risk of progression to leukemia. The risk of leukemia is low (5%-15%) in RA and RARS and higher (20%-40%) in RAEB. Still, up to 50% of patients with MDS die of complications of cytopenias rather than leukemia. The classification system also predicts median survivals, ranging from about 60 months for RA to less than 2 years for RAEB.
The International Prognostic Scoring System (IPSS) has been proposed, which identified significant prognostic indicators; these include the number of cytopenias, percentage of blasts, and cytogenetic features. This system may be more useful in comparing results of interventions across clinical trials.
Treatment of MDS remains problematic. For younger patients with high-grade disease, intensive chemotherapy and bone marrow transplant have been successful. Autologous and submyeloablative allogeneic bone marrow transplants are now being offered to older patients; however, the majority of older patients are still excluded because of either age or comorbid illness. Acute myelocytic leukemia (AML)-type treatment has produced some improvement in patients with severe disease, but this is usually transient and not generally applicable to elderly patients.
- Acute Leukemias
- Myeloproliferative Disorders
Less aggressive treatment options are actively being developed. Most are not of curative intent, but hematologic response and overall survival can be influenced. Use of recombinant growth factors to stimulate an increase in specific lineages has been explored recently. The use of myeloid growth factors has been approached cautiously because of fear of increasing the risk of leukemia. Trials of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) were effective in improving peripheral neutropenia but did not influence leukemic transformation, hemoglobin levels, or overall survival. G-CSF and GM-CSF are not recommended for routine therapy.
Erythropoietin can improve anemia in MDS with an overall response rate of 16%. However, subgroup analysis reports response rates as high as 40% in patients with RA (versus RARS and RAEB) and low serum erythropoeitin levels. The addition of G-CSF to erythropoietin can induce erythroid responses in erythropoietin- resistance patients. The mechanism of synergy is unknown. A predictive model for treatment with G-CSF and erythropoietin found the highest response in patients who have low serum erythropoietin levels and low RBC transfusion requirements.
Low-dose chemotherapy has met some success in older patients. Low-dose Ara-C induces a response in 30% of patients. Whether this translates to a survival advantage is unclear. More recently, melphalan has emerged as a well-tolerated oral chemotherapy regimen, with response rates as high as 40% and a significant improvement in survival. Additionally, 5-azacytidine trials report a response rate of 50% to 60% with tolerable toxicity and improved survival.
Research is opening new frontiers in treatment of MDS. Thalidomide, an immunosuppresant and angiogenesis inhibitor, shows promise in preliminary trials. Antithymocyte globulin and cyclosporin are being explored as immunosuppressive agents capable of modulating disease. Finally, cytokine inhibition trials with amifostine and pentoxifylline are underway. As we learn more about the pathophysiology of MDS, we will be able to better tailor therapy to effectively treat the disease with less toxicity.
Revision date: June 21, 2011
Last revised: by Tatiana Kuznetsova, D.M.D.