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Oral HMAs in MDS: Personal Experience and Future Directions


Experts share their experience with oral hypomethylating agents in myelodysplastic syndrome and consider how else these agents might be used moving forward.


Amer Zeidan, MBBS, MHS: I was one of the investigators on the ASCERTAIN phase 3 clinical trial, and the experience is similar to what has been presented in terms of how the patients behave in terms of their ability to tolerate the drug. There aren’t any specific differences in terms of the [adverse] effects in my experience based on the oral and the IV [intravenous]. The ability to need less frequent visits is an attractive appeal for the use of oral agents, so my experience has been in line with what has been presented in the abstract at the American Society of Hematology [Annual] Meeting [and Exposition].

Bart Scott, MD, MS: As a clinical center, the Fred Hutchison [Cancer Research Center] participated in the ASCERTAIN phase 3 randomized study. We enrolled several patients in the clinical trial, and we were pleased with the compliance. Patients tended to tolerate the oral medication well without significant [adverse] effects. It’s important to keep in mind that, as physicians, we put our own observations into the appropriate context and results of the larger clinical trial.

The plural of anecdotal information is not data, as has often been said. I have anecdotal information about the ASCERTAIN trial based on my own clinical experience, which is useful, but it’s important that we always be careful about how we take our own anecdotal experiences and say what other people should do or what other people should get from conclusions of a study. It’s important that we look at the broader population as a whole. I want to be cautious in how people view or interpret my own clinical experience.

Amer Zeidan, MBBS, MHS: If the drug is approved, it’s going to have a major impact. In MDS [myelodysplastic syndrome], we have not had any drugs approved since 2006: decitabine. It is interesting that the last drug approved for higher risk MDS was IV decitabine in 2006. Since then, we only had luspatercept approved 3 weeks ago, but this was approved for lower risk MDS. If this drug, the oral decitabine, gets approved, it would be the first drug for high-risk MDS approved in 14 years, and it's probably going to change how patients are treated in the frontline setting, which is somewhat similar to how the study was done. Patients would be getting it from the get-go.

It would be interesting to see how the people choose between oral version versus IV decitabine or IV/subcutaneous azacitidine. There could be other factors that play in such as logistical reasons: how far are they from the center, what is their experience with IV injections, and what is their cost-sharing component? All of those factors are going to play in. The availability of oral agents, not only in terms of making things easier for patients, could also be a backbone for combination-based strategies. A lot of the clinical trial efforts in MDS are focused on combining hypomethylating agents with other agents, so having the availability of oral agents could open the door for clinical trials with oral hypomethylating agents, plus or minus other agents, and you could have total oral therapy. We have another hypomethylating agent, oral azacitidine, which also had a positive phase 3 trial in the maintenance setting for after chemotherapy induction or consolidation chemotherapy for older patients with AML [acute myeloid leukemia]. The availability of those oral versions could significantly affect how we treat patients with MDS and AML, and if those drugs are approved, then this could be a major change.

Bart Scott, MD, MS: If the oral cedazuridine/decitabine trial leads to approval of the oral medication, I would expect wide uptake of the medication in community practices. I would still try to persuade patients and physicians to support clinical trial development because it’s appropriate to say that we need to try to improve results seen with hypomethylating therapy alone.

One of the interesting aspects about the approval of oral hypomethylating therapy is how we take that into the context of the use of oral venetoclax and whether people will start combining oral venetoclax with oral hypomethylating therapy and whether we know if that’s going to lead to a superior outcome compared to oral hypomethylating therapy alone. One would prefer to have those questions answered in a clinical trial rather than people doing what they would want to do, because the oral combination therapy with hypomethylating agents and venetoclax could lead to worse outcomes or [adverse] effects. There could be issues with absorption, so it’s important that we keep that in mind.

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