The Myelodysplastic Syndromes: Help Is On The Way!

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

Steensma and Tefferi's review also highlights the exciting development of lenalidomide for patients with a clonal deletion of 5q31.1.[5] This agent induces a response in more than 80% of patients and a complete cytogenetic response in 75% and has generated excitement reminiscent of that associated with all-trans-retinoic acid (tretinoin, Vesanoid) in acute promyelocytic leukemia and imatinib (Gleevec) in chronic myeloid leukemia. Unfortunately, this specific cytogenetic abnormality is found in only a small proportion of patients. Although lenalidomide appear to be relatively specific for patients with the 5q31.1 abnormality, even among patients without this specific abnormality, more than 50% of patients have a response with elimination of transfusion requirements and restoration of hemoglobin levels to normal or near normal.

A third aspect of the review by Steenmsa and Tefferi suggests that for the great majority of patients with MDS, despite the introduction of several new approved agents into clinical practice, the best treatment is less clear. Other than lenalidomide for patients with the 5q31.1 abnormality, the new agents approved by the FDA have promising but generally modest benefits. For example, the DNA methyltransferase inhibitors azacitidine and decitabine have been rapidly introduced into routine clinical practice. These agents induce complete plus partial responses in 11% and 17%, respectively. Interestingly, a low-dose schedule of the latter agent was associated with an encouraging complete response rate of approximately 40%.[6] A delay in time to progression to AML in high- and intermediate-2-risk patients is an important endpoint. Bearing in mind the potential toxicities, these agents should probably not be administered solely for this purpose if the peripheral blood counts are not low enough to justify treatment.

Drs. Steensma and Tefferi emphasize the importance of entering patients on clinical trials. These investigations should include correlative laboratory studies to elucidate the precise mechanisms of action of new therapies, which, in general, remain unknown. Given the cumbersome route and schedule required for the delivrey of deferoxamine, the new oral chelator deferasirox (Exjade) should be a welcome addition to the supportive care approach for patients with MDS who require multiple transfusions. However, many questions regarding the true benefit of iron chelation remain to be answered. Understandably, the authors are cautious about routinely recommending oral iron chelation in all patients requiring transfusions.

Combination Therapy

Given the heterogeneity of MDS and the multiple perturbed signaling pathways inherent in its etiology, combinations of several active agents may be the next fruitful avenue of research. For example, the combination of DNA methyltransferase and histone deacetylase inhibitors appears safe and promising.[7] This combination currently is being studied by the North American Intergroup (Eastern Cooperative Oncology Group, Southwest Oncology Group, Cancer and Leukemia Group B) in a randomized phase II trial in patients with intermediate-2- or high-risk MDS and the dysplastic type of chronic myelomonocytic leukemia or low- or intermediate-1-risk disease with cytopenias. Patients receive azacitidine alone or with the synthetic benzamide histone deacetylase inhibitor MS-275.[8] For symptomatic anemic patients with low- and intermediate-1-risk disease, the North American Intergroup will soon activate a randomized phase III trial of darbepoetin (Aranesp) with or without lenalidomide, based on in vitro studies showing that lenalidomide potentiates the clonogenic response to erythropoietin by ligand activation of STAT5.[10]

The prevalence of MDS may well increase as patients receive more intensive therapies and combinations of novel agents for other diseases.[9] Nevertheless, even more help will be on the way with further studies to elucidate the specific genes responsible for the initiation and progression of both de novo and therapy-related MDS.[11]

—Martin S. Tallman, MD
—Syed A. Abutalib, MD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Williamson PJ, Kruger AR, Reynolds PJ, et al: Establishing the incidence of myelodysplastic syndrome. Br J Haematol 88:896-897, 2004.

2. Kuendgen A, Strupp C, Aivado M, et al: Myelodysplastic syndromes in patients younger than age 50. J Clin Oncol 24:5358-5365, 2006.

3. Taussig DC, Davies AJ, Cavenagh JD, et al: Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced intensity allografting. J Clin Oncol 21:3060-3065, 2003.

4. Ooi J, Iseki T, Takahashi S, et al: Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome. Blood 101:4711-4713, 2003.

5. List A, Kurtin S, Roe D, et al: Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352:549-557, 2005.

6. Kantarjian H, Oki Y, Garcia-Manero G, et al: Results of a randomized study of three schedules of low-dose decitabine in higher risk myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 109:52-57, 2007.

7. Gore SD, Baylin S, Sugar E, et al: Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res 66:6361-6369, 2006.

8. Gojo I, Jiemjit A, Trepel JB, et al: Phase I and pharmacological study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood Dec 19, 2006 (Epub ahead of print).

9. McLaughlin P, Estey E, Glassman A, et al: Myelodysplasia and acute myeloid leukemia following therapy for indolent lymphoma with fludarabine, mitoxantrone, and dexamethasone (FND) plus rituximab and interferon alpha. Blood 105:4573-4575, 2005.

10. List AF, Estes M, Williams A, et al: Lenalidomide (CC-5013, Revlimid) promotes erythropoiesis in myelodysplastic syndromes (MDS) by CD45 protein tyrosine phosphatase (PTP) inhibition. Blood 108:397a, 2006.

11. Miyazato A, Ueno S, Ohmine K, et al: Identification of myelodysplastic syndrome-specific genes by DNA microarray analysis with purified hematopoietic stem cell fraction. Blood 98:422-427, 2001.