iwMDS 2022 | Key highlights from iwMDS 2022

Amer Zeidan:

Hi, my name is Amer Zeidan. I’m joined today by Dr Valeria Santini and Dr Rena Buckstein. We are going to talk today about the first International Workshop in MDS that took place in Miami and included two days of intensive talks about MDS and how to improve drug testing and delivery of new medications that are safe and effective to patients with MDS. We had more than 40 speakers, excellent workshop. So I’ll start with you, Valeria. What are your main take-home messages from the proceedings in the last couple of days?

Valeria Santini:

As you just mentioned, there were two intense discussion days in which I would say the physician, the clinical researchers who are more involved in MDS research were presenting not only their observations and their results but also were commenting on the hot topics and the subjects that we would like to cover for MDS. With that, I want to say that this gathering was extremely important because there were many critical lectures, so we had to think of what we were doing, of the results we are discussing every day, just taking it for granted. This is something that is resulting in a very important time for reflection, time for planning new studies with different point of views and with different design. And of course, exchanging in person the impression and the ideas and trying to find a way to collaborate in different countries builds up, I’m sure, great hope for patients and for ourselves. There are still areas in MDS in which we do not have success in treatment, and this is what we would really like to cover. The more we are, the easier it is to find a way to design the ideal study and find the ideal therapy for different MDS subtypes.

Amer Zeidan:

Yeah, that makes a lot of sense. Rena, you talked about the importance of quality of life and assessment of frailty in MDS patients who are much older than some of the other cancer patients who go in clinical trials. This is a big issue in clinical trial design, so what are your thoughts on how we can improve clinical trial design from that perspective?

Rena Buckstein:

So thank you, Amer. Yes, I think it’s critical that we going forward try to understand the patients that are unable to remain on our therapies and evaluate whether or not some of their patient-related factors we say, which include quality of life metrics but also frailty and comorbidity and see whether or not they are impacting their ability to stay on drug because many of the drugs that we’re testing require prolonged administration to see efficacy. So, we want to minimize the futility of putting a patient on a trial and exposing them to toxic therapies if some of these factors identify these patients as high failure rates. At the same time, it gives us the opportunity to perhaps design our trials or customize our trials for these patients who are not going to be able to stay on drug on the traditional dosing, but maybe on different schedules and doses may be able to tolerate these medications so that we can reach all MDS patients with these novel therapies. I also think that it will maybe better clarify why some patients respond better because it’s entirely possible that having frailty or increased comorbidity may correlate with maybe a more complex genotype or disease biology, and that’s part of the reason why they’re not doing well. It’s not just from toxicity purposes, so lots of research opportunities. The major thing is that these are really easy metrics to embed in our studies. They take literally two minutes, but they’re not captured prospectively in our trials. I do think we can learn a lot from some simple assessments that the physicians can do, the clinical research assistants can do. I think it’ll add a lot to the depth of our understanding in their clinical trials.

Amer Zeidan:

Yeah, thank you for that answer. Valeria, there have been several disappointments in large phase trials in MDS in the last couple of years. However, there is a lot of excitement still present in the field because there are several drugs that are in advanced clinical testing. Maybe you can tell us about some of those drugs and what are the type of data that we are waiting for in the next couple of years in high-risk. I’ll ask the same question to Rena in lower-risk MDS.

Valeria Santini:

Sure. So you want me to say something about the high-risk MDS?

Amer Zeidan:

Correct.

Valeria Santini:

You know, what I appreciated in these two days was also the confluence of interest of basic science and clinical research because we should speak even more than what we do. Having said that, I really want to point out that we are waiting for the results of a very interesting combination. So azacitidine that is the standard of care, it’s always present in the therapy in the new and the novel design studies. Azacitidine plus venetoclax has been evaluated in high-risk MDS, and the results of the so-called VERONA study should be available in a short time. We are very eager to understand whether this treatment that is approved for elderly AML since some time would be available for our MDS patients as well, so this is the first trial that we are really looking forward to.

Valeria Santini:

Another very interesting kind of approach is that using immune modulation and immune therapy in high-risk MDS. We heard a lot about the combination of anti-CD47 antibodies, especially magrolimab with azacitidine. The results of this study that is still ongoing are very interesting. The evaluation of the, let’s say, efficacy and safety will require still some months, I suppose, to complete the enrollment, but the results we have seen until now are very interesting with very high response rate and a prolongation of response from duration of response that is really significant. This would be a complete different approach from what we have seen in the last couple of years. As I mentioned in my talk, we are taking an empirical approach, but the more we know the biology of MDS, the better we could really target these cases. There are other studies ongoing using other agents like eltanexor or the RARA [inaudible 00:07:56].

Amer Zeidan:

Yeah, SY-1425. Yeah, very tough name.

Valeria Santini:

Yeah, tamibarotene. That is also interesting and it’s a completely new approach, so I think that these novel targets and these novel agents will bring us some good news for our patients.

Amer Zeidan:

Perfect. Rena, in lower-risk MDS, what do you think is very exciting and we are waiting for results on?

Rena Buckstein:

Valeria just spoke about them, the results with two very promising agents, imetelstat, which is a telomerase inhibitor and roxadustat, which is a HIF-alpha. It prolongs the life of HIF-alpha and simulates a hypoxic environment so that HIF-alpha can then be a gene transcriptor and upregulate things like erythropoietin and downregulate things like hepcidin and increase erythropoiesis, so those are very promising drugs. What’s really interesting about imetelstat is it works even in the most heavily transfusion-dependent patients, which is something that we don’t always see with luspatercept, and it seems to work even in very, very transfusion-dependent patients. So, I’m excited to see the results of the randomized study versus placebo. It also is very well-tolerated, so we’ll have to wait and see the results. The other low-risk drugs that are still under clinical evaluation, but if you ask me are extremely exciting are the clinical trials targeting the inflammasome and the Myddosome, which is upregulated in low-risk MDS and contributes to the ineffective hematopoiesis and leads to pyroptosis and ferroptosis and death of our cells, so that we get these cytopenias. There are a number of clinical trials ongoing targeting these aberrantly expressed pathways, but they’re still in earlier phase development. Hopefully, they’ll read out. At least the Phase I/II studies will read out next year, and then we’ll see whether or not they’re worth taking into Phase III.

Amer Zeidan:

Yeah, and my last question for both of you, this is a subject we did not get to cover because we did not have the time but it’s drug access. Both of you come from other countries, Canada and Italy, where drugs tend to get approved I think much later than they get approved in the US, even when you have positive trials, so how do you view that discrepancy? It must be frustrating to see some drugs get approved and take a long time to be accessed there. How can we improve this for our patients?

Valeria Santini:

I can speak for Europe. In Europe, as you know, it takes a long time. Drugs reach Europe later, anyway, because mainly pharmaceutical companies are leading their registration trials in the States first and then internationally, sometimes only in the States. So for us, it’s very frustrating, as you said, because patients can read about drugs, and we don’t have access to them. Let’s say less and less because we get the investigational studies. We do not get approval so quickly. That’s a big point.

Valeria Santini:

I think that we could work also with patient advocacy to express the need for having a quicker approval or anyway, easier consideration of new drugs, but as a matter of fact, we feel that we are always a step back. We need to bring all the procedures a little bit more rapid because we need them and for the sake of our patients.

Amer Zeidan:

Yeah. How about the Canadian perspective, Rena?

Rena Buckstein:

It’s very similar to the European. We’re always behind, often a year or more before drugs become available, partly because the filing by the pharmaceutical companies tends to go first in the United States, but also because it’s a socialized medical system and there’s not unlimited funds in our healthcare system, our government does a lot of pharmacoeconomic analysis to determine the additional benefit of this agent. There’s a price tag attached to it, so if it exceeds the bar that they are comfortable paying, often very successful drugs may be rejected, and that’s extremely frustrating as well. There is sometimes a middle ground and some compromise in the pricing of the drug. Certainly pricing of the drugs, that makes a difference as well and will hopefully improve accessibility to some of our patients, at least meeting the bar of our government’s requirement that they be cost-effective. It’s not just efficacy, but also is it cost-effective, especially when it’s a publicly funded healthcare system.

Valeria Santini:

Likewise in Europe, of course, because when a drug gets approved is available for all the population, so that means that the cost-effectiveness has to be evaluated carefully because of course, it’s all state-funded.

Rena Buckstein:

Yeah, there’s no unlimited funds.

Amer Zeidan:

Yeah. Hopefully this issue will improve because drug access is certainly as important as having positive clinical trials for our patients. So at the end, I’d like to thank you again for giving us your perspective and for your great work as part of the steering committee for this meeting. Hopefully we can have another great meeting next year for the 2nd International Workshop on MDS. Thank you so much.

Valeria Santini:

Thank you.

Rena Buckstein:

You too and congratulations.

Valeria Santini:

Absolutely. Thank you for chairing this.