How I treat MDS after hypomethylating agent failure

Abstract

Hypomethylating agents (HMA) azacitidine and decitabine are standard of care for myelodysplastic syndrome (MDS). Response to these agents occurs in ∼50% of treated patients, and duration of response, although variable, is transient. Prediction of response to HMAs is possible with clinical and molecular parameters, but alternative approved treatments are not available, and in the case of HMA failure, there are no standard therapeutic opportunities. It is important to develop a reasoned choice of therapy after HMA failure. This choice should be based on evaluation of type of resistance (primary vs secondary, progression of disease [acute leukemia or higher risk MDS] vs absence of hematological improvement) as well as on molecular and cytogenetic characteristics reassessed at the moment of HMA failure. Rescue strategies may include stem-cell transplantation, which remains the only curative option, and chemotherapy, both of which are feasible in only a minority of cases, and experimental agents. Patients experiencing HMA failure should be recruited to clinical experimental trials as often as possible. Several novel agents with different mechanisms of action are currently being tested in this setting. Drugs targeting molecular alterations (IDH2 mutations, spliceosome gene mutations) or altered signaling pathways (BCL2 inhibitors) seem to be the most promising.

Traditional Chinese Medicine Containing Arsenic Treated MDS Patients Effectively through Regulating Aberrant Hypomethylation

“…e response rate is approximately 50% in treated patients; however, the duration of response is transient, and HMAtreated MDS patients eventually lose responsiveness. For MDS patients with HMA treatment failure, standard therapeutic opportunities are few [18]. Our study showed that CM treatment may be a good choice for MDS patients.…”

Double remission of simultaneously occurring secondary AML and CLL by venetoclax monotherapy

“…The patient responded well to azacitidine with good quality of life and presented an optimal hematological control for over two years. The poor prognosis and the very dismal outcome [13,14] after azacitidine-failure are unfortunately currently unmet challenges for which no approved treatments as well as no standard therapeutic opportunities are available [14]. In our case, the coincidence of AML progression and CLL onset suggested the use of the BCL2 inhibitor venetoclax [15,16].…”

Emerging treatment options for patients with high-risk myelodysplastic syndrome

“…While HMA therapy is approved only for IPSS higher-risk MDS patients in Europe, AZA and DEC are approved for the treatment of all patients with MDS in the US. 17 The National Comprehensive Cancer Network (NCCN) is recommending HMA use primarily for patients with intermediate- or high-risk MDS who are not candidates for intensive therapy, who are unlikely to respond to other treatment modalities (e.g., immunosuppressive therapy), or as a bridge to allo-SCT. 8 …”

“…Various expert recommendations have been published recently. 17 , 38 Furthermore, novel agents in MDS therapy have often been extrapolated from active agents for the treatment of AML. While both disorders are related, the direct applicability of AML study results to MDS patient cohorts cannot be assumed.…”

“… 11 – 15 Subsequent real-world data have nuanced these results with lower benefits of HMA compared with the original studies, which might be due to differences in adherence to dosing schedules, treatment duration, and less rigorous patient selection compared with the landmark clinical trials. 16 , 17 …”