Myelodysplastic syndrome (MDS) is difficult to treat, and the only curative treatment option to date is allogeneic hematopoietic stem cell transplant (HSCT). However, the applicability of HSCT has been limited by the advanced age of most patients and their attendant comorbidities. During the past 10 years, the hypomethylating agents (HMAs) azacitidine and decitabine have largely become the standard of care.1

Despite their ability to induce hematologic improvements and prolong survival, HMAs are not curative without HSCT. In addition, many patients have primary resistant disease, and onset of response and achievement of best response can take several months. Fewer than half of treated patients will respond to treatment and maintain response for a substantial period, and data suggest that patients treated in clinical trials have better outcomes than patients treated in “real life” settings. Furthermore, outcomes for refractory/relapsed patients are poor, highlighting the need for development of new agents and strategies beyond traditional HMAs.

So what can physicians do when a patient stops responding to HMA therapy?         

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In a review paper published in Blood, Valeria Santini, MD, of the University of Florence in Italy, described management options for patients with MDS post-HMA treatment.

Overall, therapeutic alternatives are limited after HMA failure, and experimental clinical trials are the recommended option. However, these are not always available. In those cases, alternative treatment suggestions include supportive care, erythropoietic stimulating agents (ESAs), transplantation, chemotherapy, lenalidomide, and alternative sequencing of HMAs. The choice of therapy, Dr Santini noted, “should be based on evaluation of type of resistance (primary [compared with] secondary), progression of disease (acute leukemia or higher risk MDS) [compared with] absence of hematological improvement, and molecular and cytogenetic characteristics reassessed at the moment of HMA failure.” She recommended that decisions regarding further treatment include a thorough discussion with the patient and caregivers in order to incorporate the patient’s personal choices.

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Established Therapies

Transplantation is the only curative therapy for MDS, but because most patients with MDS are in their seventies or older, they often have comorbidities and may be extremely frail. Thus, only a small number of patients are considered candidates for HSCT, though this number is growing as donor options increase and less severe conditioning regimens are developed. Although there are no prospective studies evaluating the outcome of MDS patients transplanted after HMA failure, a retrospective analysis showed that the relapse-free survival at 3 years is 23.8% in this patient population.

High-dose chemotherapy is another potential option; in one paper, receiving an intensive regimen similar to a regimen for patients with acute myeloid leukemia (AML) after HMA failure was associated with survival of 8.9 months.2 Another study of approximately 300 patients with MDS (31% IPSS lower-risk) who were treated with cytarabine plus anthracycline, intermediate- to high-dose cytarabine, or nucleoside analogues achieved a median overall survival of 10.8 months and overall response rate of 41%.3

Low-dose chemotherapy has yielded mixed results in studies. For example, one paper showed that subcutaneous low-dose cytarabine after HMA failure did not appear to offer any advantage over supportive care, and results from other studies for the combination of cytarabine with experimental agents have not been encouraging. Conversely, adding low-dose clofarabine to low-dose cytarabine was associated with a 44% overall response rate and overall survival of 10 months in an elderly population.4

Lenalidomide can also be an option for patients with lower-risk disease who are resistant/refractory to treatment with ESAs and HMAs. When administered following azacitidine, lenalidomide is generally well tolerated. However, one study found that in patients with MDS without deletion of chromosome 5q, lenalidomide induced a limited 12% erythroid improvement; the authors of this study suggested that lenalidomide ought to be considered for first-line therapy after ESA treatment failure in place of azacitidine.5 Additionally, in high-risk patients, both standard doses (15 mg) and high doses (50 mg) of lenalidomide have produced very limited or no clinical activity and extreme toxicity.

Finally, another established treatment alternative is the sequential use of HMAs. For patients unable to participate in clinical trials or those who are unfit or very elderly, an alternative HMA can be tried. However, Dr Santini cautioned that switching agents in patients who experienced intolerance is generally unsuccessful in patients who are truly resistant to these drugs. Data are limited, but some studies have reported rates of response to decitabine after azacitidine below 30%, and only 1 study has reported a response rate of 40% for patients treated with azacitidine after first-line decitabine.