ASH 2023 | Potential MDS targets beyond HMAs
Aditi Shastri, MD, Montefiore Medical Center, Bronx, NY, outlines promising approaches for treating myelodysplastic syndromes (MDS), especially high-risk (HR) MDS, in those patients who have experienced treatment failure with hypomethylating agents (HMAs). Patients should be enrolled on a clinical trial following HMA failure wherever possible, alone or as a bridge to allogeneic stem cell transplantation (alloSCT). Dr Shastri also discusses potential MDS targets beyond HMAs, such as the BCL2 inhibitor venetoclax or sabatolimab, an immuno-myeloid therapy which binds to TIM-3. This interview took place at the 65th ASH Annual Meeting and Exposition, held in San Diego, CA.
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Transcript (edited for clarity)
MDS, as we know, it’s a very heterogeneous disease. And hypomethylating agents are really, you know, important treatments in lower-risk MDS, but really the cornerstone of therapy in high-risk MDS, and patients with high-risk MDS that fail hypomethylating agents have a poor prognosis and definitely need better treatments at this time. I would say our priority as a medical community treating MDS, is really to offer the best possible care to our patients, and sometimes this involves offering a clinical trial -which may be by itself, but also as a potential bridge to a curative therapy, which is allogeneic stem cell transplant, which in this day and age is still considered a curative treatment for MDS...
MDS, as we know, it’s a very heterogeneous disease. And hypomethylating agents are really, you know, important treatments in lower-risk MDS, but really the cornerstone of therapy in high-risk MDS, and patients with high-risk MDS that fail hypomethylating agents have a poor prognosis and definitely need better treatments at this time. I would say our priority as a medical community treating MDS, is really to offer the best possible care to our patients, and sometimes this involves offering a clinical trial -which may be by itself, but also as a potential bridge to a curative therapy, which is allogeneic stem cell transplant, which in this day and age is still considered a curative treatment for MDS.
Beyond the HMAs, there are some interesting agents which are currently in clinical trials and appear promising. One of them is a immunomyeloid therapy called sabatolimab, and this is a drug which targets a specific target on the surface of the leukemic stem cells as well as the T-cells, called TIM-3. And it enhances antibody-dependent phagocytosis and reduces the amount of leukemic stem cell renewal.
Another therapy that I can think of, which is currently in trials, and is potentially exciting is the BCL2 inhibitor venetoclax. So venetoclax in combination with azacitidine has also been tested in a large Phase III randomized study, the VERONA trial, of which I hope we will have the readout soon. And the activity appears very encouraging, and we hope that this can become an option for our patients in the future.
There are various other targets like the RARA agonist tamibarotene, XPO inhibitor eltanexor… You can even modify the backbone of the drugs of the HMA and the venetoclax to make it low dose and give it in a way that’s more tolerable to the patients without compromising responses. So, in short, I think these are the most promising approaches in the clinic right now.
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Disclosures
Honoraria: Gilead Sciences, Rigel Pharmaceuticals, Kymera Therapeutics, Janssen Pharmaceuticals, Inc.
Research Funding: Kymera Therapeutics
Consultancy: Janssen Pharmaceuticals, Inc.
