Management of patients with higher risk myelodysplastic syndromes

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Abstract

Higher risk myelodysplastic syndromes (MDS) include patients in the Intermediate-2 and high-risk categories of the International Prognostic Scoring System, as well as patients with MDS secondary to radiation or chemical exposure. Ideally, the goal of therapy is to alter the natural history of disease in these patients to achieve cure or durable remission. High-intensity chemotherapy can achieve moderate rates of complete remission, however, durability of remission and overall survival tend to be short. Hematopoietic stem cell transplantation (HSCT) offers the possibility of cure, with long-term disease-free survival inversely related to age. Patients who are elderly or have poor functional status are candidates for reduced intensity HSCT, although this is still an experimental modality. Azacitidine is a hypomethylating agent that is a reasonable option for many patients ineligible for high-intensity therapies. Other therapies, such as immunomodulatory agents, arsenic trioxide, and farnesyl transferase inhibitors have thus far shown limited usefulness in higher risk MDS. This paper reviews the various therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.

Introduction

The myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a propensity to evolve to acute myeloid leukemia (AML). Both the French–American–British (FAB) [1] and the World Health Organization (WHO) [2] systems categorize MDS according to morphology and the percentage of bone marrow blasts, with higher blast percentage correlating with more advanced disease. A notable difference between the two systems is the categorization of AML, which is defined as a blast count >30% in the FAB system and ≥20% in the more recent WHO system (Table 1). Bone marrow karyotype also plays an important role in the pathogenesis and prognosis of MDS, and specific cytogenetic abnormalities have been identified which correlate with outcome. Taking these issues into account, the International Prognostic Scoring System (IPSS) for MDS was developed [3], which stratifies patients into Low, Intermediate-1 (Int-1), Intermediate-2 (Int-2), and High-risk categories, according to three prognostic factors: bone marrow blast percentage, karyotype, and number of cytopenias (Table 2). This system has provided a valuable method for assessing survival and potential for AML evolution in patients with MDS, as shown in Table 3. To standardize the reporting of responses to MDS therapies, the International Working Group (IWG) proposed criteria for complete remission (CR), partial remission (PR), and hematologic improvement (HI) [4]. Use of IWG criteria is recommended for all MDS trials to facilitate comparisons of results across studies.

For prognostic purposes, MDS patients have been characterized as being relatively lower risk (IPSS Low and Int-1) or relatively higher risk (IPSS Int-2 and High). Therapy-related, or secondary MDS, which may occur several years after significant exposure to radiation or chemicals, such as chemotherapeutic agents, is also considered relatively higher risk MDS, with greater resistance to therapy and worse prognosis than primary MDS [5], [6]. Whereas lower risk patients with stable disease can often be managed with observation or supportive care, higher risk patients, because of their increased morbidity and mortality due to bleeding and infections, increased risk of AML transformation, and decreased survival, require that the clinician consider initiation of treatment with more immediacy. The predominant goal of therapy in higher risk MDS patients is to alter the natural history of the disease, with the aim of cure or durable remission, as opposed to merely hematologic improvement in peripheral blood cell counts. This approach is often a challenge, however, as MDS tends to be a disease of older patients with median age 60–70 years, who may have co-morbidities and decreased functional status. Such patients are poor candidates for high-intensity therapies, such as induction chemotherapy or hematopoietic stem cell transplantation (HSCT). Thus, in addition to consideration of such high-intensity therapies, low-intensity therapies and supportive care have important roles in the management of higher risk MDS. This paper reviews the therapeutic options for higher risk MDS, providing rationale for specific management approaches for these patients.

Section snippets

Treatment algorithm

The National Comprehensive Cancer Network (NCCN) MDS Practice Guidelines Panel has made recommendations for treatment based on the patient's IPSS category, age, and functional performance status [7]. High-intensity therapies are recommended for higher risk patients ≤60 years of age with good functional status, with the goal of altering the natural history of the disease. An age of 60 years is used as a guideline, above which high-intensity therapies are generally not offered to patients due to

Supportive care

All patients with higher risk MDS should be offered supportive care, which includes antibiotics for treatment of infections and transfusions of red blood cells (RBC) and platelets (Plt), as needed. Erythropoietin (EPO) treatment should be considered for MDS patients with symptomatic anemias, with response rates of 24% [8] and 16% [9] reported in two meta-analyses of studies encompassing all MDS subtypes. Higher responses were generally found in the lower risk MDS patients. Relatively high doses

High-intensity chemotherapy

MDS can be treated with standard induction-consolidation chemotherapy regimens similar to those used for AML, which typically contain cytarabine in combination with another agent, such as an anthracycline. Despite modifications to these regimens over the years, these changes have not significantly improved patient outcomes. A large, single-center experience with high-intensity chemotherapy at MD Anderson [16] included 394 patients, at least 58% of whom were higher risk by IPSS, who had received

Hypomethylating agents

One of the more promising treatment strategies to emerge recently for higher risk MDS is the use of agents, which inhibit DNA methylation. Methylation of cytosine nucleotides located in CpG islands in the promoter regions of genes results in transcriptional silencing of those genes [61]. It is postulated that aberrant hypermethylation contributes to the pathogenesis of MDS by producing epigenetic changes in gene expression that render the MDS clone resistant to differentiation, apoptosis,

Conclusion

Patients with higher risk MDS remain a challenge to manage because of their poor prognosis and predominantly older age. All patients should be offered supportive care. High-intensity induction chemotherapy alone in higher risk patients can produce CR rates >50%, although the duration of remission with this approach is relatively short. High-intensity chemotherapy alone is predicted to increase median OS by several months compared to OS with supportive care as predicted by the IPSS. Unless used

Reviewers

Dr. Deeg HJ, Division of Clinical Research, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D1-100, P.O. Box 19024, Seattle, WA 98109-1024, USA.

Dr. Estey E, Section of Acute Leukemia and Myelodysplastic Syndrome, Division of Cancer Medicine, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.

Acknowledgment

The authors wish to thank Dr. Jason Gotlib for critical review of this manuscript.

Dr. Fukumoto is a clinical fellow in the Division of Hematology, Stanford University School of Medicine. He received his medical degree from New York University and trained in internal medicine at Los Angeles County- University of Southern California Medical Center.

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    Dr. Fukumoto is a clinical fellow in the Division of Hematology, Stanford University School of Medicine. He received his medical degree from New York University and trained in internal medicine at Los Angeles County- University of Southern California Medical Center.

    Dr. Greenberg is professor of medicine in the Division of Hematology, Stanford University School of Medicine, and chief of the Hematology Section, Veterans Affairs Palo Alto Health Care System, Palo Alto, California. He is director of the Stanford Myelodysplastic Syndrome (MDS) Center and Chair of the U.S. National Comprehensive Cancer Network Guidelines Panel for Myelodysplastic Syndromes. He has served on hematologic journal editorial boards and has written extensively regarding his clinical and biological investigations in MDS and leukemia.

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