Hypomethylating agents and other novel strategies in myelodysplastic syndromes

Abstract

Over the last decade, treatment approaches for patients with myelodysplastic syndromes (MDS) have improved significantly. Treatment of MDS is tailored to the specific risk characteristics of the patient. In general, patients are divided into lower- and higher-risk categories. Without therapy, prognosis of patients with higher-risk MDS is poor, and treatments should be directed to improve survival. Prognosis of patients with lower-risk MDS is more heterogeneous, and therapies are usually directed to minimize transfusion needs and potentially to alter the natural course of the disease. Treatment options for patients with higher-risk MDS include hypomethylating agents (azacitidine and decitabine), intensive chemotherapy (ICT), and allogeneic stem-cell transplantation (alloSCT). The use of the hypomethylating agents has transformed the approach to this patient population, in particular older individuals, for whom ICT and alloSCT are not an option. In lower-risk MDS, treatment strategies are used sequentially and usually include observation in patients with low risk and no transfusion dependency, growth factors, and lenalidomide for patients with alteration of chromosome 5 and anemia. The use of hypomethylating agents is less understood in this group of patients. AlloSCT is usually reserved for patients with lower-risk MDS closer to the time of transformation. In this short review, we discuss treatment alternatives for patients with MDS and delineate some of the ongoing challenges, including the development of better front-line strategies for patients with higher-risk disease, the concept of altering the natural course of the disease in lower-risk MDS, and the development of new treatment approaches for patients who do not benefit from hypomethylating agents.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Prognosis of patients with lower-risk myelodysplastic syndrome (MDS). A prognostic model has been developed that allows the calculation of survival in patients with low and intermediate-1 MDS. Characteristics include age, hemoglobin level, platelet count, percentage of blasts, and cytogenetics (Table 1). Score can vary from 0 to 7 points (Table 2). Survival is indicated in months.

Fig 2.

Treatment algorithm for patients with myelodysplastic syndrome (MDS). The first step when evaluating a patient with MDS is confirmation of diagnosis. Risk can be calculated using a number of classifications. Traditionally, patients with lower-risk disease are those with low or intermediate-1 by the International Prognostic Scoring System. Patients with higher-risk disease are those with intermediate-2 and high risk. A number of options exist for patients with lower-risk disease. One option is observation (for patients who are transfusion independent and have an expected long survival and minimal risk of transformation,). Growth factor support with erythroid-stimulating agents is usually recommended for patients with anemia early in the course of disease. Lenalidomide is the standard of care for patients with anemia and a deletion of chromosome 5 (del5q). Results with lenalidomide are better in patients early in the course of their disease, patients who are minimally transfused, and patients with no severe thrombocytopenia. As indicated by the arrows, these approaches are sequential. A patient can be initially observed and started on growth factors and then eventually receive a hypomethylating agent. Investigational agents are considered in patients who have not benefitted from standard approaches. Allogeneic stem-cell transplantation (alloSCT) is usually reserved for patients who have received all of these approaches or who are considered to be at high risk of progression or death. Options for patients with higher-risk disease are more limited. Observation is rarely an option for this group of patients. Main options include intensive chemotherapy (ICT) or a hypomethylating agent. ICT is usually reserved for younger patients who are expected to transition to alloSCT in a short period of time after induction. Results with ICT are better in patients with diploid karyotypes. Most patients are candidates for a hypomethylating agent. Younger patients with abnormal karyotypes, particularly those with alterations of chromosome 7, should be considered for a hypomethylating agent instead of ICT. Finally, all potential candidate patients (younger, available donor, no excess comorbidities) should be considered for alloSCT. Most patients receive some form of therapy before proceeding to alloSCT. The timing of alloSCT for patients who respond to ICT or hypomethylating agent is controversial. Some investigators recommend proceeding with alloSCT as soon as possible, whereas others recommend using hypomethylating agents for as long as possible before relapse or transformation.