Few areas in the field of malignant hematology are as frustrating for both patients and their physicians as the myelodysplastic syndromes (MDS). These syndromes represent a heterogeneous group of clonal disorders manifested by hypercellularity of the bone marrow, varying degrees of peripheral pancytopenia, and dysplastic changes in the blood cells. Although the exact incidence is not known and difficult to determine precisely, the crude incidence rate is 12.6/100,000/yr.[1] The incidence rate per 100,000 per year rises very significantly with age, from 0.5 for ages < 50 years to 89 for age > 80.

The frustration stems from the fact that the majority of patients with MDS are older adults, the clinical manifestations are heterogeneous, and most important, historically, there have been few effective therapies for most patients. Furthermore, while many patients develop MDS de novo, others do so after exposure to chemotherapy for another malignancy.

Expanding the Armamentarium

Although the pathogenesis of MDS remains unclear, there appears to be a disequilibrium between the apoptotic and proliferative activity of the myeloid stem cell. With time, the disease may evolve into acute myeloid leukemia (AML). Both the International Prognostic Scoring System (IPSS) and the World Health Organization (WHO) classifications are useful in evaluating risk of death and transformation to AML. Other than allogeneic hematopoi—etic stem cell transplantation (HSCT)—an option generally reserved for younger individuals—there are no curative strategies for MDS. Indeed, for the majority of patients, supportive care has been considered the standard approach. However, help is on the way! Recently, the therapeutic armamentarium has expanded, generating considerable excitement.

In this issue of ONCOLOGY, Drs. Steensma and Tefferi provide a comprehensive review of both the historic approaches and the newer therapeutic options, including DNA methyltransferase inhibitors (eg, azacitidine [Vidaza], decitabine [Dacogen]), histone deacetylase inhibitors (eg, valproic acid, vorinostat [Zolinza]), and immunomodulatory agents (eg, lenalidomide [Revlimid]). Drs. Steensma and Tefferi emphasize that with prognostic factors and new classifications, given the new FDA-approved agents and the wide variety of other agents available in the context of a clinical trial, therapy often now can be somewhat risk-adapted. Their practical clinical approach reflects their perspective as clinicians as well as clinical investigators and will be well-received by the clinical community.

Choosing the Best Therapy

For several relatively small groups of patients, Steensma and Tefferi indicate that the best therapy for MDS may be reasonably clear. As the only potentially curable therapy for patients with MDS, matched-sibling donor allogeneic HSCT should always be a serious consideration for younger patients with intermediate-2- or high-risk disease.

A recent large series from Germany compared the patient characteristics and outcome of 232 patients younger than age 50 (less than 10% of the patients with MDS seen at the authors' institution over a 23-year period) with approximately 2,500 older adults.[2] Not unexpectedly, overall survival was significantly longer among younger patients than among adults over age 50 years. However, this improvement was observed among patients with low- and intermediate-1-risk disease. Patients with intermediate-2 and high-risk disease had a poor outcome independent of age. For younger patients with low-risk disease, the 20-year overall survival was 86%. Therefore, such patients are not likely to benefit from HSCT.

Even younger patients with intermediate-2- and high-risk disease have a sufficiently poor outcome that HSCT should be strongly considered, as the transplant-related mortality should be acceptably low. Younger patients with intermediate-1 disease have an overall survival of approximately 40%. The best timing for HSCT for these patients may be when there is a change in the biology of the disease, such as evolution in the karyotype or IPSS score. Novel transplant strategies including reduced-intensity conditioning and even unrelated umbilical cord HSCT have been explored in an effort to expand the population of patients who may benefit.[3,4] While HSCT continues to be a potentially curable strategy for a selected group of patients, its impact on the general population of patients with MDS is limited.

Novel Agents