Achievements in Understanding and Treatment of Myelodysplastic Syndromes

Abstract

The myelodysplastic syndromes (MDS) constitute a challenge for the biologist as well as for the treating physician. In Section I, Dr. Willman reviews the current classifications and disease mechanisms involved in this heterogeneous clonal hematopoietic stem cell disorder. A stepwise genetic progression model is proposed in which inherited or acquired genetic lesions promote the acquisition of "secondary" genetic events mainly characterized by gains and losses of specific chromosome regions. The genetic risk to develop MDS is likely multifactorial and dependent on various constellations of risk-producing and -protecting alleles. In Section II Dr. Barrett with Dr. Saunthararajah addresses the immunologic factors that may act as important secondary events in the development of severe pancytopenia. T cells from patients with MDS may suppress autologous erythroid and granulocytic growth in vitro, and T cell suppression by antithymocyte globulin or cyclosporine may significantly improve cytopenia, especially in refractory anemia. Recent studies have also demonstrated an increased vessel density in MDS bone marrow, and a phase II trial of thalidomide showed responses in a subgroup of MDS patients especially in those with low blast counts. In Section III Dr. Hellström-Lindberg presents results of allogeneic and autologous stem cell transplantation (SCT), intensive and low-dose chemotherapy. The results of allogeneic SCT in MDS are slowly improving but are still poor for patients with unfavorable cytogenetics and/or a high score according to the International Prognostic Scoring System. A recently published study of patients between 55-65 years old showed a disease-free survival (DFS) at 3 years of 39%. Consolidation treatment with autologous SCT after intensive chemotherapy may result in long-term DFS in a proportion of patients with high-risk MDS. Low-dose treatment with 5-azacytidine has been shown to significantly prolong the time to leukemic transformation or death in patients with high-risk MSA. Erythropoietin and granulocyte colony-stimulating factor may synergistically improve hemoglobin levels, particularly in sideroblastic anemia. Recent therapeutic advances have made it clear that new biological information may lead to new treatment modalities and, in combination with statistically developed predictive models, help select patients for different therapeutic options.