MDS updates from iwMDS-iwMPN 2024 | New directions and governmental progress in MDS: insights into MyeloMATCH & CTEP

Elizabeth Griffiths:

Hello. Today we’re going to talk to you a little bit about our session about new directions and governmental progress in management of patients with MDS. We’re coming to you from the International Working Group on Myelodysplastic Syndrome. Today I’m with Dr. Gore, Dr. Odenike and Dr. Stahl. And I’m Elizabeth Griffiths, and I’m so happy to have been able to share this excellent session. I think one of the things that was really exciting is these opportunities to really organize the structure of our investigation in the United States around new therapies for patients with MDS. I think your work with MyeloMATCH is really driving this, and it’s really an exciting time for us in MDS.

Olatoyosi Odenike:

Yeah, we are so pleased. This is the kind of effort that’s never been undertaken before in MDS and myeloid malignancies broadly, including acute myeloid leukemia. We are super excited that the initiative is now launched as of last month, and we already have some patients registered on this broad effort. The idea is to rapidly profile patient samples as they enter through various centers involved in research in MDS in the United States. And to then, based on the knowledge of the mutations that their disease harbors, to be able to assign them onto a specific treatment. We also have patient advocates who are involved in this effort and we hope it will move the needle forward in this field.

Steven Gore:

Yeah, it’s also Canada. It’s North America. I think it’s going to be transformative in the way drug development and myeloid malignancies, at least in North America, is done assuming we’re successful. And maybe that will influence elsewhere as well. But these are, for the most part, small, randomized Phase II trials with very discrete endpoints that are signal finding. So they’re not meant to answer the ultimate question of this versus that. But to say, wow, there’s a really important signal, that adding this drug to whatever it is in this particular genomic subset gives you deeper remissions or more remissions or longer remissions depending on which kind of MDS or AML we’re talking about. And then for the most part, we would expect the companies or the cooperative groups to proceed with a more definitive kind of Phase III approach when appropriate.

Elizabeth Griffiths:

I think what’s really exciting to me about this program particularly is the idea of being able to follow patients over time and to re-enroll them within the same protocol in a different arm. And I think that’s really going to change how we view patients. I think it’s one of the things that we’ve lost from clinical trials in relatively recent time and that we need to really regain. That was part of the original clinical trial drug development program, really to start on one drug, try a different drug, demonstrate the lack of cross-resistance and the potential for synergy.

Steven Gore:

Yeah, and I think it’s sometimes hard for me to really conceive of how patients are going to be tracked, because you’re right, they’re going to be tracked from their first therapy-

Low-dose luspatercept, low-

Steven Gore:

Right. And then if they achieve a remission with detectable residual disease, they’ll be eligible for something else, another randomized study. And then some people will go on to transplant, for another study some people won’t. So you can follow one patient like this. So how are you going to follow all the patients? It’s a little multi-dimensional for me, but I think we’re going to learn a lot.

Olatoyosi Odenika:

I am very sure that we will. The other thing that I find particularly great about MyeloMATCH is that it’s designed to bring as many investigators as possible together to try to solve this problem. And that includes early career investigators, people who are younger than me like Max, who’s been quite involved in this effort as well.

Steven Gore:

Yeah, that’s been remarkable. The senior investigators who have built this over the last seven or eight years are people who they were… I think we were always all friends, but there was quite a bit of competition between the various cooperative groups in this space. And I have to say, it’s been just an unbelievable kumbaya cooperative synergistic approach. Max, what’s been your experience as a, not so much baby investigator but you’re still pretty much a junior investigator?

Max Stahl:

No, it’s been very good. I think MyeloMATCH, but also I think in generally CTEP, and I think you talked a lot about CTEP small brought up portfolio today, Steve. It has been very good for junior investigators, me personally, but also a bunch of other investigators I think. Usually junior investigators don’t really get leadership in, I would say company sponsored trials. They usually go with who’s most well known in the field and has been around the longest. And I think that has been a really wonderful opportunity. The other thing I want to say is for even outside of MyeloMATCH, I think after you got to CTEP Steve, I think really it became really very open for junior investigators proposals. And I think the rigor by how they are reviewed, not only based on the clinical value but also what qualitative studies are done and how are they done. And I think that was a very, very good experience for me.

It really felt like that the CTEP investigators, but also all the associated labs that you mentioned that are associated with CTEP really care about doing assays the right way. And I sometimes feel like that it’s lost in some trials where correlative studies are the afterthought.

Steven Gore:

Yeah. I was a customer of CTEP all my investigative career, and I didn’t really get everything that CTEP does. To me, they were kind almost like a hurdle. You had to get your proposal accepted by CTEP, and it is just the opposite. We are so eager to help people develop stuff, and it’s so positive. And for everything that I may be the medical monitor for say [inaudible 00:06:55] which you’re working on, but your LOIs and your protocols are being reviewed by 12 or 15 different people, pharmacists, patient advocates, biomarker people, disease people, drug people. So it’s such an informed consent specialists, statisticians of course. It’s such a high level of view, and they’re all really smart people who could be making a lot of money doing stuff in the private sector but who really have this great feeling of mission. I’m so privileged to work there. I really love that.

Olatoyosi Odenike:

No, that’s so wonderful. I really truly agree that CTEP and for our audience, otherwise known as the-

Steven Gore:

Cancer Therapy Evaluation Program of the National Cancer Institute.

Olatoyosi Odenike:

Yeah, it’s been instrumental in moving many careers forward, mine included, having put through a number of concepts along the way. I also think that the other thing that’s so important about those trials is that we really try to learn from every patient enrolled, whether the drug really worked or not by doing this ancillary or correlative studies. So that we can kind of use that to move forward and build upon what we’ve just done to make the next thing that we embark on better, all for the benefit, hopefully, of our patients.

Steven Gore:

And it’s going to be so important to the various investigators who may be listening to this, that really all potential participating centers, including NCORP and community-based centers and academic centers open up as much of MyeloMATCH as possible. A huge amount of citizens tax money has gone into this thing and continues. It’s an extremely expensive endeavor that would never be done by pharma. And if it’s going to be self-sustaining, we’ve got to show that it works.

Elizabeth Griffiths:

Very exciting. I think we’d be remiss if we didn’t touch briefly on some of the VALIDATE database data that Max presented so eloquently. And I really think one of the things that’s very exciting about some of these larger group databases that I think that really have been spurred by the iwMDS Collaborative, are starting to get at real-world assessments of activity of these drugs and validation of our response assessment criteria. And then finally, making us question the paradigm of whether or not really additional upfront therapeutics for our patients are really substantively better than upfront allogeneic transplant. And one of the questions that I didn’t get an opportunity to ask you is really analogous to what Lisa Pleyer asked you. And really the question in my mind is, should we be replacing our upfront therapeutics in these patients with allotransplant and then following our patients with post-transplant therapeutics as a standard of care, instead of trying to do it the other way around?

And maybe that would result in an improved outcome for our patients and better graft versus leukemia, graft versus MDS effect and get a larger number of patients to transplant. I think that’s a provocative question. I don’t know that there is an answer at the moment, but I really am starting to work on that. I think the issue of course as you raised, is this issue of timing for transplant in this country which remains a little bit of a barrier.

Max Stahl:

Right. Yeah, I love provocative questions with no answers. The best questions. So just a couple of thoughts. I think there’s I would say rationale for both approaches. I think a lot of our reduce disease burden as much as we can comes from the AML literature, where we try to get even MRD erased before transplant and try to get people with the lowest disease burden to transplant, a priori would not be the same for MDS, period. And I think to your point, it’s like maybe we should think about post-transplant approaches in patients who have residual disease or are high risk. But I would say, I think the key point of our analysis was try to say is that we see in some centers that people are not being taken for transplant because they haven’t achieved a response. It’s almost like a paradigm.

You need to achieve a complete remission, otherwise you cannot go for transplant. And I would say in the highest risk population, this is even more prevalent. In TP53, there are a lot of people who say, if you don’t achieve a response for TP53 mutated disease, you shouldn’t be transplanted. And there’s our data, but also data recently from the BMT CTN trial that was reanalyzed by Coleman Lindsley that looked at TP53 mutations. And really there was no impact of outcomes between patients who cleared TP53 or did not clear with our current detection techniques. So those patients should be transplanted and should not be a priori excluded just because they haven’t achieved the response.

Steven Gore:

The other way I look at your data, and I’ve really been thinking about it a lot since you gave it, not necessarily clearly but trying to think about it, is that the patients who are most likely to not respond to DNA methyltransferase inhibitors are also the patients who are least likely to benefit from transplant. And I realize you did this across the risk groups and everything. And so I think it’s a little hard to say that, well, all these patients say with TP53 mutations should be transplanted because I think the reluctance to transplant them is it’s so well publicized by your group and others, at how terrible the outcome is with transplant as currently promulgated. And I do remember, it has a feel to me of the old paradigm in large cell lymphoma that’s relapsed to give people a couple of cycles of CHOP and not take the non-responders. You’re basically selecting those with response. Clearly this situation is a little different.

And one of the other speakers in our session, Alain Mina, thank you from NCI, I should know better, is his group is developing an ETCTN trial that’s going to be including the radioactive lintuzumab anti-CD33 antibody in non-ablative transplants. And I think that if that works out, that could be a great thing to study in patients who haven’t been cytoreduced, because it may just be with that anti CD33 thing, that’s the ticket to get it low enough. I don’t know, I’m speculative.

Max Stahl:

Yeah, but I agree. And I think the other thing that we showed was maybe a minor point of this is that even within the very high-risk patients, there’s a significant difference between very high-risk patients that are not biallelic TP53 and those patients who are biallelic TP53. Actually the very high-risk patients, probably arguably, that are not TP53 mutated benefit the most from transplant. But the biallelic TP53 mutation, they still benefit from transplant versus no transplant but the delta is very small, as Steve mentions.

Elizabeth Griffiths:

All right. Well, thank you so much for your attention. We had really a scintillating session and excellent discussion here. It’s been really a pleasure to come to you from the International Working Group for Myelodysplastic Syndromes. Thank you.