The myelodysplastic syndromes (MDS) are a heterogeneous spectrum of clonal hematopoietic diseases characterized by bone marrow hypercellularity, dysplasia of cellular elements, and consequent inadequate hematopoiesis, with resultant peripheral blood cytopenias. Put simply, MDS represents a collection of cancers, with various subtypes related to differences in morphology, types and number of involved cell lines, bone marrow blast counts, and underlying cytogenetic abnormalities.[1-4]
According to data collected from 2001 to 2003 through the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute and the Centers for Disease Control and Prevention (CDC), the age-adjusted incidence rate of MDS in the United States was estimated to be 3.4 per 100,000 people, which translates to approximately 10,000 new cases per year. This is likely an underestimate, as the rate increased over these 3 years, from 3.3 per 100,000 people in 2001 to 3.6 in 2003, in large part due to improved reporting practices within cancer registries. In 2004, the incidence rate was estimated at 3.8 per 100,000 people – higher than that for acute myeloid leukemia (AML), and potentially making MDS the most common type of leukemia, with new yearly diagnoses in the United States estimated to be closer to 15,000 cases. The US incidence rate is similar to rates reported in western European countries such as England/Wales and Sweden (3.6 per 100,000), Germany (4.1 per 100,000), and France (3.2 per 100,000), but is higher than that seen in Japan (1.0 per 100,000).[7-10] Though difficult to identify with precision, it is estimated that approximately 60,000 people are living with MDS in the United States.
Approximately 75% of newly-diagnosed patients have lower-risk disease: French-American-British (FAB) categories of refractory anemia (RA) and RA with ring sideroblasts (RARS); World Health Organization (WHO) categories of RA, RARS, refractory cytopenia with unilineage or multilineage dysplasia (RCUD, RCMD), MDS with deletion of chromosome 5q (del [5q]), and MDS unclassified; and International Prognostic Scoring System (IPSS) categories of low-risk and intermediate-1). The remaining 25% have higher-risk MDS: FAB categories of RA with excess blasts (RAEB); WHO categories of RAEB-1 and RAEB-2; and IPSS categories of intermediate-2 and high-risk).[1,2,4,12] The disease biology of higher-risk MDS predicts that patients with these subtypes will have symptoms and a disease course similar to those seen in older adults with AML, thus warranting immediate initiation of disease-modifying therapy, regardless of peripheral blood values. Patients with lower-risk disease, on the other hand, may have the luxury of delaying treatment.
The decision of when to start treating a patient with lower-risk disease is far from straightforward. Only 6% to 7% of these patients have even been told they have a “cancer” or “leukemia.” Most have had their MDS described to them as being a much more benign-sounding condition, such as a “bone marrow disorder” (80%) or “anemia” (56%). Thus, the first step in initiating therapy often is to undo the “trick” that has been played on an unsuspecting patient and to educate the patient about the severity of his or her diagnosis, and about the need to start therapy.
The next trick is to determine when to start therapy. No study has demonstrated an outcome benefit for early initiation of transfusions, erythropoiesis-stimulating agents (ESAs), or disease-modifying therapies. Similarly, hematopoietic stem cell transplantation (HSCT) is recognized as the only curative therapy for MDS, but clear survival advantages for HSCT over other MDS therapies have been shown only in the context of a Markov decision analysis with narrow inclusion criteria, and even then specifically in higher-risk patients and when offered as initial therapy. Thus, all other therapies can be viewed as being essentially palliative, with a focus in lower-risk patients on improving quality of life.
It stands to reason, then, that intervention is required only when a patient’s quality of life suffers, either from MDS- or cytopenia-related symptoms, or from the need for frequent transfusions. Naturally, the toxicity profile of the treatment should be less severe than the adverse effects being experienced by the patient from the disease itself. ESAs are a good first step, and in appropriately selected patients (eg, those with lower-risk MDS without excess blasts who have serum erythropoietin(Drug information on erythropoietin) levels < 500 IU/L and low red blood cell transfusion needs [< 2 units/4 weeks]), 40% can be expected to respond, with median response durations of 2 years, and some retrospective studies showing a survival advantage when ESAs were compared to best supportive care or disease-modifying approaches.[16,17] The trick here is to not actually treat MDS at all, but instead to maximize production of remaining functional hematopoietic precursors.
When ESAs fail in lower-risk patients, or when they would be predicted to fail—or in any higher-risk patient—disease-modifying therapy must be initiated in an effort to delay transformation to AML, and hopefully to prolong survival. Lower-risk patients in this category have few options: for those 5% to 10% fortunate enough to have the del(5q) cytogenetic abnormality, lenalidomide (Revlimid) can yield transfusion independence response rates of 67%, with a median duration of approximately 2 years, although a survival advantage has yet to be demonstrated prospectively.[19,20] In those without the del(5q) abnormality, transfusion independence responses are more modest, at 26%, and less durable, at a median of 41 weeks. While hypomethylating agents, such as azacitidine (Vidaza) and decitabine (Dacogen), can be used in lower-risk patients in whom other approaches fail or in whom ESAs would not be effective, response rates are similar to those for off-label lenalidomide use and to typical historic responses to other disease-modifying drugs used in clinical trials.
Higher-risk MDS patients should be offered HSCT up-front, while recognizing that patient reticence, comorbidities, lack of available donors, and lack of insurance coverage will make this a viable option in < 5% of patients. Most, then, should be treated with one of the hypomethylating agents. While structurally nearly identical to decitabine and with similar biologic activity and response rates, azacitidine has demonstrated a survival advantage in treated higher-risk patients when compared to patients receiving conventional care regimens (the majority of which were best supportive care).[22,23] Although criticisms of the comparability of the phase III azacitidine and decitabine trials are certainly valid, this fact must be conveyed to patients as they make their decision regarding therapy.
Financial Disclosure: Dr. Sekeres has served on an advisory board for and received honoraria from Celgene.