Investigating Hypomethylating Agents for Myelodysplastic Syndromes With Amer Zeidan, MBBS, MHS
Recently, at the American Society of Hematology (ASH) Annual Meeting, Amer Zeidan, MBBS, MHS, the Interim Chief of Hematologic Malignancies Division at the Yale Cancer Center, presented his abstract regarding an investigation of oral decitabine and cedazuridine versus intravenous/subcutaneous hypomethylating agents (HMA) for patients with myelodysplastic syndromes (MDS). In this interview, Dr. Zeidan further delves into his research and what it could mean for the future treatment landscape of MDS.
Oncology Data Advisor: Would you like to start with introducing yourself and your research interest?
Amer Zeidan, MBBS, MHS: Yes, my name is Amer Zeidan. I'm an Associate Professor of Medicine at Yale University and the Interim Chief of Hematologic Malignancies Division at the Yale Cancer Center. I focus on myeloid malignancies—acute myeloid leukemia (AML) and MDS—and I do both, the clinical trials as well as outcomes and real-life analysis.
Oncology Data Advisor: To begin, going over the study that you presented at ASH, for background, could you tell us a little bit about hypomethylating agents and how they are used in MDS?
Dr. Zeidan: Hypomethylating agents were basically, and still continue to be, the standard of care in patients with high-risk MDS. Those historically have been injectable drugs, so they are given only intravenously (IV) or subcutaneously. There were two drugs approved, azacitidine and decitabine. Until the year 2020, we did not have any oral version. So, the year 2020 saw the approval of oral decitabine and cedazuridine based on the ASCERTAIN study, which randomized patients to IV or oral decitabine. The primary end point was looking at pharmacokinetic equivalence. So, there was a merging of the two arms after two cycles with the long-term follow-up after Cycle 3, everybody being on oral decitabine.
What we know historically is that many patients with MDS who otherwise are eligible to get HMA, only half of them get them because they require coming to the clinic seven days in a row, every month, which is very tough to do. Many of the MDS patients are in their 70s; they don't have enough social support or family support to come for frequent visits. So, less than half of patients get started on HMA from those who otherwise should be on them. And from those, less than half will stay on the drugs for more than three months, which we know is important because those drugs are slow-to-act, which means that less than 25% of all otherwise eligible patients for HMA are not persistent on HMA. We, and others, have shown that patients who are not persistent on HMAs or do not start on HMAs have much worse survival, but also, they lead to higher cost utilization from the system and health resource utilization. For all of those reasons, improving persistence on HMA is very important, and this is where I think oral decitabine could play an important part.
Oncology Data Advisor: If you wouldn't mind, could you go over some of the results that you were able to present at ASH?
Dr. Zeidan: In order to understand the impact of the oral decitabine approval on persistence on HMAs, we looked at a large insurance claims database, basically, that had the diagnosis as well as the claims for prescription of both injectable and oral hypomethylating agents. We followed those patients longitudinally on this database with a link to mortality so we could check for overall survival. The study period was from the approval of oral decitabine in the year 2020 through August 2022. The primary outcome was persistence, meaning how long can the patient stay on the drug?
We were able to find 1,600 patients on that database. Around 10% of them received oral decitabine, which is around 160 patients. Of those 160 patients, around 70% of them were new starts, meaning that the first time they get an HMA is the oral version, while the other 30% were switched from IV or oral decitabine. When we compare the baseline characteristics of those with oral and IV hypomethylating agents, they were largely similar. Most of them were older, in their 70s, which is common for MDS patients. They had a lot of comorbidities and generally the baseline characteristics were similar.
To better understand, in a more reliable fashion, we did propensity-score–match analysis, which is a way to find the patients within the injectable hypomethylating agent cohort to look the most like patients who receive oral decitabine. We also used age, comorbidity score, and a number of factors to match them, and we ended up with a matched cohort. Then we looked at the persistence. So, what we observed is that the persistence within the first few months was somewhat similar between oral and injectable hypomethylating agents, but once you go beyond six months, there was a trend for oral hypomethylating agents. This is probably consistent with the fact that many patients don't want to keep coming to get injections repeatedly, again, seven days every month.
The hope is that this longer persistence with oral hypomethylating agent, oral decitabine and cedazuridine, would translate into better outcomes, which is something we are going to study as well in this and other databases.
Oncology Data Advisor: I wanted to ask, how do you interpret how these results are affecting the treatment landscape of MDS and the future treatment landscape of MDS as a whole?
Dr. Zeidan: Yes, so this is, I believe, the largest real-life dataset looking at the use of oral decitabine, which has been relatively approved recently, only three years ago. I think trying to understand the real-life outcomes with any drug in oncology is very important, because sometimes there's a big difference due to selection bias that happens in clinical trial enrollment. So, I think the data does show that patients who will get the oral decitabine are somewhat similar in their baseline characteristics to those who get the injectable drugs, and that the persistence might be better. I think it's important to understand, because we clinically think they are very similar, the IV and the oral decitabine. But the persistence issue could be something that could make it not only more convenient for patients to get an oral hypomethylating agent, but if it helps their persistence, could improve their outcomes.
There are other important factors, like reducing the time they have to spend in the clinic, improving their quality of life. The chair availability in the clinic is very tight, and we need to use them to give chemotherapy to other patients to be used for other things. So, from a resource utilization point of view, all of this would be very important.
The next steps would be to understand the clinical effectiveness between these drugs, but also, I think this is laying the foundation for combinations with other drugs and doing what we call total-oral therapy, which I think would be very important in the future care for patients with high-risk MDS.
Oncology Data Advisor: Definitely. Final question I was going to ask was about you and your team's next steps, but you already answered that, so I would like to ask if you would want to relay any more information that you think is important for clinicians, or anyone listening, to know.
Dr. Zeidan: I think MDS has historically not seen a lot of therapeutic developments compared to other areas like AML, where many drugs have been approved in the last seven or eight years. In MDS, we're starting to see change. We have approval for luspatercept, oral decitabine, we have very promising data with imetelstat with the post-phase 3 trial. We have other drugs that are in large phase 3 trials, such as venetoclax and sacituzumab. So, I think the field is moving very quickly in a better direction where we hopefully will be able to offer patients better and more effective therapies. And I encourage all the listeners to this podcast to consider discussing and referring patients to clinical trials because this is how we move things forward.
Oncology Data Advisor: Absolutely. Thank you so much for your passion on this topic and your research, and again, your time today. We really appreciate it.
Dr. Zeidan: Thank you so much. Happy holidays and happy New Year. Good talking to you.
About Dr. Zeidan
Amer Zeidan, MBBS, MHS, is an Associate Professor of Medicine at Yale School of Medicine and the Interim Chief of Hematologic Malignancies Division at the Yale Cancer Center. Dr. Zeidan's research interest and passion revolve around myeloid malignancies and developing targeted therapies and immunotherapy-based approaches for these diseases. He is an active presenter both nationally and internationally, in which he regularly presents and reviews abstracts at the ASH Annual Meeting.
For More Information
Zeidan A, Costantino H, Modi K, et al (2023). Real-world treatment patterns among patients with myelodysplastic syndromes initiating oral decitabine and cedazuridine or intravenous/subcutaneous hypomethylating agents. Presented at: 2023 American Society of Hematology Annual Meeting. Abstract 548. Available at: https://ash.confex.com/ash/2023/webprogram/Paper188638.html
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.