This podcast episode was recorded live by Oncology Data Advisor and ConveyMED at the 2022 ASH Annual Meeting in New Orleans.

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're here at the ASH Annual Meeting and I'm here with Dr. Ira Zackon. Thanks so much for joining today.

Ira Zackon, MD: It's a pleasure, thank you for having me.

Oncology Data Advisor: Would you like to tell us a little bit about yourself and about what you do?

Dr. Zackon: Sure. I've been a practicing Hematologist/Oncologist for well over 30 years. I've been a subspecialist in hematologic malignancies and benign hematology for well over a decade, and I am currently a Senior Medical Director with Ontada, which is where we do real-world and database research.

Oncology Data Advisor Great. So, I know you have your retrospective study here on myelodysplastic syndromes. Would you like to tell us a little bit about this?

Dr. Zackon: Sure. Myelodysplastic syndromes, or MDS, have been a challenging disease to treat. It occurs primarily in the elderly. Outside of low-risk disease, the outcomes have been less than optimal, and there are limited treatments. This retrospective study is using the database of the US Oncology Network. It's a large network in terms of community-based practice, so it really reflects real-world patients. This is a descriptive study of patterns of care and outcomes.

Oncology Data Advisor: What were the results that your study found?

Dr. Zackon: First of all, to our knowledge, this is the largest population analyzed in retrospective data. There were over 2,700 patients, and the study covered a decade from 2011 to 2021. We have to be mindful that this reflects that time of therapy, although it hasn't changed a lot, but we can talk about that as we go along. As I mentioned, we were primarily looking at patterns of care, as well as overall survival outcomes.

In this population of the 2,700 patients, about one-third were in the low-risk category according to the revised International Prognostic Scoring System (IPSS). This is how we can kind of classify, at least prognostically, the different groups of patients. One-third of patients were in the low-risk category, and the remainder were in what we might aggregate as high-risk, which is intermediate, high-, or very high–risk in the system. These patients have either more advanced low blood counts or adverse cytogenetic gene mutations picked up by classical cytogenetics in this classification system.

One of the most important things from our data is that when we look at the proportion of patients who have what we might call high-risk MDS, the primary therapies we've had over that decade are the hypomethylating agents (HMAs) such as azacitidine or decitabine. About 75% of the patients, three-quarters of them, went on to receive a first-line therapy with a hypomethylating agent. Well, that leaves a gap. What about the 25% who did not get treated?

So, when we're working with retrospective data, we have to understand some of the limits of that. In this patient population, the median age was 75; 40% were female and 60% were male. At least this is reflective of the patient population that we deal with, which is primarily a disease in the elderly. Among the quarter of patients who weren't documented to have received therapy, it doesn't absolutely mean that they did not receive therapy. It is possible that they received therapy outside of the US Oncology Network or went into a clinical trial outside of the US Oncology Network.

Also, 10% of this patient population went to allogeneic transplant. You have to be fit in that age group or a bit on the younger side of that median to likely be eligible to go to transplant. That's a small minority of the overall patient population, which I think does reflect the real world. But in the real world, many patients may not be treated for a whole variety of reasons, whether it's their other health status and individual circumstances that might preclude therapy.

So, moving on to the patients who were treated—that's the 75% of patients. What was important that we saw was that first of all, in terms of pattern of care, the vast majority received azacitidine compared with decitabine, which would be common in terms of, again, the choices of therapy during that time. When we looked at the median duration of being on treatment with these therapies, we know we have to treat for at least four monthly cycles before we evaluate efficacy. Well, the median was just under five months, so the majority of these patients are not on therapy long in aggregate, generally less than a year. It's really showing the limitations of the impact in the real world of hypomethylation therapy.

The other aspect was that over 80% of patients never went on to a second-line therapy that we identified in our database. That's probably means that most don't get onto a second-line therapy. Again, some may have gone to transplant; it's a small minority. Some may have gone to a clinical trial or outside therapy, but the majority probably don't get onto second-line therapy. Again, this is reflective of the limited options that we've had, as well as other individual factors in the elderly population that might mitigate against going on therapy.

Oncology Data Advisor: How do you propose that these findings can be used to impact treatment decisions in the future?

Dr. Zackon: Well, it's certainly highlighting the experience that we've had over that decade, and it's primarily telling us that there's a real need to transform understanding of this disease and how we may treat it. The overall survival data, which was the other part of the data, reflects that when we look at the cohort that was not low-risk, the median overall survival was under two years. When you segregate out the very high–risk population, that's only about 12 months. Even in the intermediate group, which would be probably the most common amongst that, it was less than two years, about 20 months. This study really paints the picture of where we have been and where we need to go.

I think that we will be seeing changes in MDS. First of all is just an understanding of the molecular genomics profile and the mutational spectrum in these diseases. It's much more common to have a next-generation sequencing (NGS) panel, for example, done on your bone marrow diagnostics, which gives you a full spectrum of myeloid disease. As you know, MDS ultimately may evolve into an acute myeloid leukemia (AML), and that has certainly been a difficult disease with a poor prognosis in this patient population.

We are also going to see a refinement of the prognostic scoring system, looking at what's called the molecular IPSS (IPSS-M). This is integrating the data which will further refine the spectrum and our understanding. Ultimately, we hope that this is going to translate into more actionable mutations, as we're beginning to see in AML, being able to target specific mutations that may be driving the behavior of the disease more significantly to impact it more.

The other change is that we will be looking at MDS more as an AML, just in a different phase of the disease. Currently, we've had somewhat artificial distinction between MDS and AML based on former classifications of the World Health Organization (WHO), in which you have to have more than 20% blasts in your bone marrow or blood to be considered AML. If you have less than 20% blasts, it's considered MDS. But we will be moving towards understanding that regardless of the blast count, it's in a spectrum of AML. In patients with excess blasts, we would be more likely treating that like an AML.

In that subset, we know that there are some patients with true favorable genetic profiles in AML. We treat those with the kind of chemotherapy we would in younger patients, because that's a different disease subset. They're not really MDS; they're AML. But there's AML that will have MDS-like genetic profiles, and then there will be true favorable-risk AML. These have different prognoses and need different treatment approaches.

We will probably be treating more of these patients not just with an HMA, but perhaps an HMA and an anti-BCL2 inhibitor such as venetoclax. With these current paradigms of how we might treat the elderly with AML, I think that then we'd have to see the impact. And of course, there are trials in this space looking at novel therapies, both currently existing for AML and importantly, innovation in this space in terms of bringing new mechanisms of action.

Oncology Data Advisor: Great, that's exciting. Anything else you would like to share either about your research or about the other MDS research that you've seen here?

Dr. Zackon: I'll just give a plug for the importance of real-world retrospective data. We can't replace the importance of prospective randomized clinical trials that ultimately drive FDA approval and bring new therapies to our patients. But it's important to look back at existing data and to have databases, especially those that are electronic health record (EHR)–based, that are rich in data because they're primarily a vehicle for patient care and documentation of that patient care. Really, there's a lot of data that can be mined in terms of looking at these patterns of care and asking important questions concurrently.

The FDA is trying to look at how to integrate real-world data as a source in contemporaneous controlled trials. If you have a prospective trial using contemporaneous real-world data, having a timeline of both of these data sets is informative, because we know that randomized trials are more selected populations, whether by criteria or by just the ability to get into a clinical trial. We're all aware of the barriers in access to health care. Certainly, patients treated in clinical trials represent a small percentage of the overall population. I think that's where we do need to go into the real world to really see, well, what are the treatments being used? What are the outcomes? And how do those compare to the trials that led to the approval of these drugs?

Oncology Data Advisor: Great, that was very informative. Thank you much for sharing this with us.

Dr. Zackon: My pleasure.

Thank you for listening to this podcast recorded live at the 2022 ASH Annual Meeting by Oncology Data Advisor and ConveyMED. For more expert perspectives on the latest in cancer research and treatment, be sure to subscribe to the podcast at ConveyMED.io and OncData.com. Don't forget to follow us on social media for news, exclusive interviews, and more.

About Dr. Zackon

Ira Zackon, MD, is a Medical Hematologist/Oncologist at New York Oncology Hematology and a Clinical Assistant Professor at Albany Medical College. He is also the Senior Medical Director of Oncology Research and Insights for Ontada, a real-world data and research group. He specializes in the treatment of patients with hematologic malignancies and the direction of real-world research programs.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.