Myelodysplastic Syndromes—Many New Drugs, Little Therapeutic Progress

Myelodysplastic syndromes (MDS) constitute a form of blood cancer that primarily affects the elderly and is characterized by anemia (or other cytopenias) and a high risk of leukemic transformation.1 The World Health Organization (WHO) system has formally classified MDS as 1 of 5 myeloid malignancies that also include acute myeloid leukemia (AML) and myeloproliferative neoplasms.2 All myeloid malignancies, including MDS, are clonal stem cell diseases. Unlike the case with BCR-ABL1-positive chronic myelogenous leukemia,3 the disease-causing mutation in MDS is currently unknown. It is generally believed that the MDS phenotype is additionally affected by secondary mutations, genetic haploinsufficiency, epigenetic changes, and altered host response that result in cytokine, immune, and bone marrow stromal changes.1 Unfortunately, none of this information has successfully been translated into a robust pathogenetic framework or effective targeted therapy. In routine clinical practice, MDS are suspected when an otherwise unexplained anemia is associated with other cytopenias, increased mean corpuscular volume, or increased red cell distribution width. The peripheral blood smear in MDS shows oval macrocytes, a dimorphic red blood cell population, or hyposegmented/hypogranulated neutrophils. Diagnosis requires bone marrow examination and cytogenetic studies. The consensual minimum criterion for diagnosis is the presence of erythroid, granulocyte, or megakaryocyte dysplasia in 10% or more of informative cells.2 In this regard, one must exclude the possibility of erythroid dysplasia associated with vitamin B12/folate/copper deficiency, viral infections, chemotherapy, or lead/arsenic poisoning. The detection of an abnormal karyotype confirms the morphologic diagnosis of MDS.4 The WHO system further subclassifies MDS into 6 subcategories depending on the percentage of blasts in the bone marrow or peripheral blood, presence or absence of bone marrow multilineage dysplasia, or excess ring sideroblasts: refractory cytopenia with unilineage dysplasia, refractory anemia with ring sideroblasts, refractory cytopenia with multilineage dysplasia, refractory anemia with excess of blasts, MDS associated with isolated 5q–, and MDS unclassifiable.2 Myelodysplastic syndromes are rare in young people, with an estimated incidence rate of less than 1 per 100,000 before age 50 years and approximately 2 per 100,000 between ages 50 and 60 years; however, the incidence rises significantly after age 60 years: approximately 8 per 100,000 between ages 60 and 70 years and greater than 20 per 100,000 after age 70 years.5 In 2004, close to 10,000 new US cases of MDS were registered, and approximately 7000 cases occurred in patients older than age 70 years.5 Prognosis is poor for patients with MDS, with 3-year survival rates estimated at less than 50%.5 The standard prognostic tool in MDS is the International Prognostic Scoring System (IPSS), which classifies patients into low-, intermediate-1, intermediate-2, and high-risk categories on the basis of the percentage of bone marrow blasts, the karyotype, and the number of cytopenias; the respective median survival rates are estimated at 8, 5.3, 2.2, and 0.9 years.6,7 Although additional IPSS-independent prognostic variables have since been described, their added practical value has been modest.8 From the standpoint of both disease biology and prognosis, it is important to distinguish primary MDS from therapy-related MDS; the latter is closely related to therapy-related AML and develops in the setting of prior exposure to chemotherapy (eg, alkylating agents, topoisomerase II inhibitors), radiotherapy, radiation accidents, benzene, or other toxins and is prognostically worse than primary MDS.9 Current management in MDS includes supportive care (eg, red blood cell transfusions), drug therapy, and allogeneic hematopoietic cell transplant (allo-SCT). Currently, allo-SCT is the only treatment modality for MDS with curative potential. However, because most patients with MDS are older than age 70 years,5 they are not good candidates for allo-SCT, and the value of allo-SCT in younger patients is undermined by the substantial risk of treatment-related death and morbidity.10-12 Furthermore, cure is not necessarily essential in the presence of drug therapy that can effectively control disease symptoms and prevent disease-related mortality.13,14 Unfortunately, drug therapy for MDS has had limited success, which reflects our inadequate insight into disease pathogenesis. Regardless, 4 new drugs (azacitidine, decitabine, lenalidomide, and deferasirox) were recently approved by the Food and Drug Administration for use in certain types of MDS. In the following sections, I comment on their true value in current practice.