Hypomethylating Agents Impacting MDS Treatment Landscape


Salman Fazal, MD, shares opinions regarding the role of hypomethylating agents (HMAs) in treatment for patients with MDS.

Ryan Haumschild, PharmD, MS, MBA:As we discuss some of the treatments, one thing you brought up was hypomethylating agents [HMAs]. We’ve brought that up a lot. Dr Fazal, I want you to chime in because I’m curious about your thoughts. With hypomethylating agents, what does the treatment landscape look like for myelodysplastic syndrome [MDS]? When are they are used? Which agents are available? There are some IV [intravenous] therapies, and we’ve even mentioned some oral therapies when we think about transportation vulnerabilities. If you could, give us an overview of these agents that you’re able to utilize.

Salman Fazal, MD: As Dr Zeidan mentioned, when we see a patient with myelodysplastic syndrome, we risk stratify them. The major reason we like to risk stratify is because we like to see what treatment options we can offer the patient. In the initial clinical trial, hypomethylating agents were studied in patients with high-risk myelodysplastic syndrome, where it showed that it improved hematologic parameters, reduced risk of transformation to acute myeloid leukemia, and improved the overall survival. We offer patients who have high-risk disease IV [intravenous] azacitidine, a 7-day treatment, and then there’s IV decitabine, which is given over 5 days.

There are challenges in giving hypomethylating agents for high-risk myelodysplastic syndrome. One major problem in treating with a hypomethylating agent is that there’s usually a drop in the blood cell count in the first and second cycles, and it usually takes up to 6 cycles for them to respond before we could call them a nonresponder to therapy.

There are challenges in treating these patients with a hypomethylating agent. Fortunately, since 2020, we have the availability of the oral decitabine-cedazuridine combination. It was compared with IV decitabine-cedazuridine in the ASCERTAIN trial and met its primary end point, which led to FDA approval. For high-risk myelodysplastic syndrome, we’re able to offer the oral decitabine-cedazuridine combination for these patients. Having an option of oral therapy is great. Having treated patients with myelodysplastic syndrome for years, one of the frequently asked questions by my patients was: “Do we have any oral therapy?” I appreciate that we now have an oral option for these patients with oral decitabine-cedazuridine.

Ryan Haumschild, PharmD, MS, MBA: It’s nice having both. A lot of times, these patients were used to IV therapies, and the same question came up with us: “Is there any oral agent I can take?” If they can get an oral agent and adhere to it and get good proportion-based cover, that’s something you want to consider. It’s great to have those options for a patient. That’s so patient centric.

Dr Zeidan, I didn’t hear Dr Fazal talk about it, but some people ask me, “What’s the role of oral azacitidine in MDS? Can we use that for treatment?” I don’t see it used a lot. There might be a reason for that. Do you recommend oral azacitidine for treatment in MDS? If you don’t, what role can payers play to help make sure people aren’t using medications inappropriately?

Amer Zeidan, MBBS, MHS:That’s a great question. Some of the confusion around this issue has probably come from the fact that despite availability of both IV azacitidine and IV decitabine, for a long time—until 2020—we didn’t have an oral equivalent of those approved drugs in the market. Within a couple of years, we had both an oral version of decitabine and an oral version of azacitidine. However, these are very different in terms of pharmacokinetics. As we just heard from Dr Fazal with cedazuridine, oral decitabine has been established to have very similar biokinetics and a similar profile in terms of its bioavailability. In most facets, it’s very similar to intravenous decitabine. That’s why the FDA approved it for the treatment of patients who have MDS for the same indication as intravenous decitabine, which is intermediate 1 and higher by the IPSS [International Prognostic Scoring System].

On the other hand, oral azacitidine is very different in its pharmacokinetic profile compared with intravenous azacitidine. It’s given differently. It’s given over a prolonged period of time, over 2 to 3 weeks. It has been approved for older patients who have acute myeloid leukemia and have received intensive chemotherapy as a maintenance strategy. It isn’t approved for MDS. However, I have occasionally seen physicians use it in the community, which clearly isn’t the FDA label. I strongly discourage against that, because we have a phase 3 trial that looked at specifically lower-risk MDS, and there was an increased early mortality with oral azacitidine due to increased risk of infection. The issue is more related to the dosing and how you do it the best way. Until we understand how the dosing of oral azacitidine should be in MDS, I don’t think it should be used for this indication.

I also like to focus on the importance of oral HMAs. Because as we discussed earlier, these treatments are usually continued as long as the patient is responding. One of the biggest problems that we hear from many patients, especially those who are responding, is the difficulty to come for 5 or 7 days every month—especially if they live far from the center—to get IV or subcutaneous azacitidine or decitabine. Especially in the Medicare-age patient population, where many times they’re [a widow] or their spouse can’t drive them. Their children are out of state. It isn’t that easy to come over, especially if you’re only coming to get the injection.

The availability of an oral equivalent has been a significant advancement for many patients, especially those who are responding. But at the same time, it’s important to remember that they’re still considered chemotherapies, which means that you still have to monitor the patient. You still have to get the blood cell counts. People shouldn’t underestimate the use of those agents just because it comes in a pill vs an IV formulation, because it can cause infections and problems, and the patients should be monitored the same way you would monitor someone who’s getting the injectable formulation.

Ryan Haumschild, PharmD, MS, MBA: Great points. I like how you talked about the benefits of these oral hypomethylating agents, the importance of safety, and that the same things that we see applied with the IV formulations extend to the orals. A big takeaway I had is that we don’t want to use oral azacitidine in patients with MDS because that isn’t its indication. There’s different bioavailability, pharmacokinetics, and pharmacodynamics, and we want to make sure we preserve the most appropriate therapies for these patients.

Transcript edited for clarity.

Related Videos
dr meredith mckean
dr erin gillaspie
Related Content
© 2023 MJH Life Sciences
All rights reserved.