Resistance to HMAs is a major issue. Outcomes after HMA failure are poor, with studies showing a median survival of 4 to 6 months in patients with high-risk MDS. HMA failure can be categorized into primary or secondary failure. Patients who experience primary HMA failure do not respond to HMA therapy from the outset, while those who experience secondary failure do respond initially but then lose their response over time. Some data from clinical trials suggest differences in survival based on the form of failure; however, resistance is almost inevitable with the use of HMAs, whether the patient has primary or secondary failure. Although there are many predictors of HMA failure, we currently have very few treatments for high-risk MDS, and we often must use a treatment that we know is not going to be as effective as we would hope because we lack other options. 

Several factors are associated with HMA resistance, including the complexity of the cytogenetics and the presence of circulating blasts. In addition, there are several patient-related factors that are linked to HMA resistance, such as functional status and adherence to the regimen itself. Molecular biology is also involved in resistance to therapy. For instance, TP53 mutations are present in approximately 20% of the high-risk MDS population, and we see that patients with these mutations respond to HMA therapy, but the responses are very short lived. Even with newer therapies such as venetoclax, the adverse impact of TP53 mutations has not been overcome. 

Recent work by Rahmani et al linked ASXL1 mutations to enhanced sensitivity to venetoclax and azacitidine via epigenetic upregulation of BCL2 expression, suggesting that venetoclax may perhaps be able to overcome resistance in this setting. Indeed, at the 63rd American Society of Hematology Annual Meeting and Exposition, we presented some real-world data exploring the addition of venetoclax to HMA therapy in patients with higher-risk MDS. The combination did appear to improve the complete response rates, including in ASXL1-mutant MDS. Clearly, an overall survival benefit for this combination can only be evaluated in a randomized clinical trial, but our data suggest promising activity.

I think that TP53 mutations, in particular, continue to be a real challenge. We are hopeful that several drugs that are currently in development may be combined with HMAs to be effective in a manner that is agonistic with respect to somatic mutations. Initial signals from some studies of magrolimab (an anti-CD47 monoclonal antibody that targets the innate immunity) and sabatolimab (a TIM-3 inhibitor that targets the stem cells and engages the T cells) have been encouraging; work is ongoing in this area.