Management of patients with higher risk myelodysplastic syndromes
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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Cited by (27)
Myelodysplastic Syndromes
2018, Hematology: Basic Principles and PracticeMyelodysplastic Syndromes
2017, Hematology: Basic Principles and PracticeEpigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease
2015, Cell Stem CellCitation Excerpt :The stem cells that clonally expand in MDS patients often have mutations in key epigenetic regulators and inappropriate DNA methyl-silencing appears to be a functional driver of MDS (Issa, 2013; Itzykson and Fenaux, 2014). The importance of dysregulated DNA methylation in the pathophysiology of MDS has been clinically validated by treatment with potent inhibitors of cytosine methylation, 5-Azacytidine and 5-Aza-2′-deoxycytidine (decitabine), that act by incorporating into DNA and inhibiting DNA methyltransferases (Wijermans et al., 2000; Kantarjian et al., 2006, 2007; Fukumoto and Greenberg, 2005). Though the exact mechanism through which these agents act is unknown, global demethylation appears to de-repress inappropriately silenced genes, allowing for re-establishment of normal stem cell function (Daskalakis et al., 2002).
Epigenetic regulation of hematopoietic stem cell aging
2014, Experimental Cell ResearchCitation Excerpt :The aberrant methylation profiles of HSCs isolated from MDS patients [81] together with the many studies showing that key epigenetic regulators are mutated in patients with MDS (reviewed by [90] and [91]), implicate methyl-silencing as a dominant mechanism in MDS. The mechanistic importance of DNA methylation in the pathophysiology of MDS been validated by the success of clinical trials with drugs that inhibit DNA methylation [92–95]. With this said, the precise mode of action of these demethylating agents in MDS remains unclear, although it appears to involve epigenetic reprogramming and re-establishment of normal stem cell function triggered by de-repression of genes that had been silenced by DNA hypermethylation and restoration of normal protein expression [96].
Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging
2013, Cell Stem CellCitation Excerpt :These facts, together with the fact that mutations in TET2, which encodes a DNA demethylase, are among the most common found in MDS patients (Shih et al., 2012), indicate that aberrant DNA hypermethylation in HSCs is likely central to the etiology of disease in these patients. This has been affirmed in clinical trials demonstrating that subsets of MDS patients are responsive to DNA hypomethylating agents (Fukumoto and Greenberg, 2005). Given the striking functional and molecular conservation of HSC aging in mice and humans (Pang et al., 2011), it will be important to determine if the alterations of the DNA methylation landscape we report here similarly underlie human HSC aging and/or progression to disease.
Stem cells and the aging hematopoietic system
2010, Current Opinion in Immunology
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.