EHA 2022 | Unmet needs in high-risk MDS and future therapeutic strategies

The high-risk MDS field remains an area of major unmet need. For the last 20 plus years, we’ve only had approval of the HMAs, azacitidine and decitabine. Numerous drugs have been evaluated in this space combined with azacitidine, such as Revlimid, vorinostat, and others, and we’ve seen multiple negative results. Five drugs have recently been evaluated in the frontline setting combined with azacitidine. Two of these have read out: APR combined with azacitidine in TP53-mutated MDS, unfortunately, did not meet the primary efficacy endpoint of CR. Although there was a benefit, it did not meet the statistical requirement. Azacitidine/pevonedistat versus azacitadine/placebo also did not meet the primary endpoint. But the other studies that are ongoing include drugs magrolimab, venetoclax, sabatolimab. We’re especially quite excited about both venetoclax and magrolimab. These have now quite a good number of patients with follow-up mature data both in MDS and AML.

And of course, venetoclax has already been approved in frontline AML. The data in MDS frontline looks very encouraging, high response rates, CR rates, good tolerability. And similarly for azacitidine/magrolimab. So, they are both in randomized studies, which in the next year, year and a half, we should have data. And we’re hoping both of the drugs could get approved. And then, the question will be do we select patients based on their underlying mutation? For example, IDH1, IDH2, SRSF2 respond very well to venetoclax-based therapies in AML and probably in MDS, whereas TP53 secondary MDS, adverse [inaudible] respond well to magrolimab. And so, we could select patients based on their underlying cytogenetic molecular profile, as well as fitness and tolerability. But then also, we would evaluate the combination of the azacitidine/venetoclax/magrolimab in MDS. So, we have to wait to see what happens, but we’re hoping both those studies will be positive, and we should know soon.