ASH 2022 | Key highlights in MDS: treating lower-risk & higher-risk disease, trial updates, and more

David Sallman:

Hi. It’s a pleasure to be here with you today with VJHemOnc at ASH 2022. It’s really an exciting congress that is robust and the first real post-COVID ASH conference to date. It’s a pleasure to be here with my colleague, Dr Andy Brunner, from Mass General Hospital, myself, Dr David Sallman from Moffitt Cancer Center in Tampa, Florida.

So Andy, just to start out, maybe we could think about lower-risk MDS. So maybe if you could tell us what abstracts and presentations you’re excited about, where do you think we’re going in lower-risk MDS?

Andrew Brunner:

Sure. There’s actually a lot of moving pieces in lower-risk MDS. I think that we have growing data about how we utilize some of the therapies that have been recently improved, notably luspatercept, and what kind of effects that we can expect to see from there. I also think that we’re all excited in the field to see ongoing data, for instance, about imetelstat.

I think there’s some very provocative data about long-term responders on imetelstat, and also this curious phenomenon of a drop in VAF during treatment, which I find to be increasingly something that I’m interested in as we evaluate MDS therapeutics. And so I think both of those spaces have changed quite a bit. I also think that one of the more perhaps controversial studies out there that we’re all trying to wrap our heads around, I’m certainly trying to wrap my head around for clinical practice, is the SINTRA-REV trial.

So administering lenalidomide for about two years to patients who have not yet developed transfusion dependence, who have MDS with del(5q). I think it raises a lot of questions, and challenges some of our practices in typical management of lower-risk MDS. Usually, we would wait for the disease to present enough immediate risks to the patient before we would initiate therapy. Suddenly, we have a lot of provocative data about preemptive therapy almost. And so I think that that’s something where each congress seeing some updates from that. I’m still trying to figure out how I will integrate that into practice.

David Sallman:

Yeah, I agree. I think it was one of the more controversial abstracts. I think the data today were quite impressive as far as time to transfusion dependence, although clearly no difference in overall survival, at least at the current data cutoff. To me, I thought what was very fascinating is there’s a growing concern that we shouldn’t use lenalidomide in patients that have P53 mutation with deletion 5q. There’s a nice study out of MD Anderson that clearly shows that that clone can expand under lenalidomide pressure. I think that being said, they actually did enroll patients with P53 mutation. Those patients, although small subsets, I think was around six, did relatively equally well. And at least one of the questions it seemed that these patients were not acquiring, which is actually quite surprising. So could we be changing the natural history? I think we all struggle, but it is provocative and it’s only two years so kind of a “fixed duration.”

But I think I will think about it. I think there are those patients that are borderline requiring treatment. And to me, I think maybe a more highly support initiation of LEN over, let’s say, ESA and those patients that do have symptomatic anemia and require therapy. I agree. I think the duration of transfusion independence on the imetelstat data are quite interesting, some of the most durable responses we’ve seen. So we hope the IMerge trial may read out positive in the not-distant future.

I think maybe piggybacking off, can we have disease modification in lower-risk myelodysplastic syndrome? I think that’s one of our major goals. I think how do we define that, is quite tricky. So what level of VAF reduction? Is there some reduction? 50% reduction? Clearance to less than 5%? Ideally, the deeper is better, but I think we don’t really have those answers. But I do think disease modification, lower-risk MDS is really a goal. There’ll be an abstract presented by Dr. Garcia-Manero on canakinumab, which is an interleukin-1 beta inhibitor. We similarly have an investigator initiate a trial. It seems to be safe, although activity is low. But potentially, as you’re targeting this in inflammasome microenvironment, you may need novel combinations. So I think could a single drug be enough or could we think about combinations in order to change the natural history for this patient group? I think, additionally, maybe lastly, hypomethylating agents, which I think we’re trying to avoid for the most part. Can we use lower schedules? Can we use oral therapy? Another presentation? I think it’s provocative. But again, how we move that forward, I think, is an important question. Maybe switching now to higher-risk MDS. We still only have azacitidine, but is there a hope for the future? Again, maybe what data you think is most intriguing at this congress?

Andrew Brunner:

I think we’re all eagerly awaiting. There’s now four large Phase III randomized trials that we’re all eagerly awaiting for a readout of. My hope is that we have a lot of new agents that we can utilize in higher-risk MDS. It remains a very challenging disease group. I think also, maybe one of the biggest stories that came out of this ASH is just how we are redefining higher-risk disease.

And a number of abstracts, looking at new classification systems, trying to identify patients who have the highest risk disease, who have the worst courses, either with or without treatment. And also, realizing how molecular diagnostics really change our understanding of the course of patients. So interesting study that was comparing IPSS, IPSS-R and IPSS-M classifications. And you can just see how we have pulled out these higher and higher-risk patients by incorporating mutation from a typical NGS panel.

Now, where does that lead us? And do we understand how to interpret our old trials in light of now moving a bunch of people into higher-risk disease? Should we be treating everybody still as if they have higher-risk disease? Or will we have another shift in our treatment where maybe MDS with excess blasts is one entity, MDS with poor risk mutations is a second entity approach? And then we have a different way of approaching lower-risk disease given that we think that they’re going to be stable for some time.

David Sallman:

I think defining biological cohorts, which was the pitch by Dr Haferlach, I think is intriguing. I think we know that we can better prognosticate patients. I think we’re refining classifications. I think to me, and I think this is a goal that we have and potentially others, is what does this really mean for the treatment of our patients? So a patient that is “was lower risk, is now higher risk,” do we initiate HMA right away? Do we transplant right away if we have approvals, which we’re all optimistic about? How are we going to think about those patients? So I think we have a lot of data, and now we think we have to think about refining that somewhat and really understanding the outcomes in these patients and how this should dictate treatment. I have a little bit of concerns right now, let’s say, in the community, patients “higher-risk.” Are they rapidly initiating therapy for an asymptomatic patient? And whether or not that is the right thing to do or not?

Another thing I think quite excited about or quite interested, and obviously, Dr Brunner alluded to the four pivotal trials. We had a glimpse into one of these at this congress. We have a STIMULUS randomized Phase II trial presented by Dr Zeidan. I think maybe some unfortunate data or somewhat of a setback. I think the response rates were not different, which is not necessarily unexpected. But I think they were going for this event-free survival based on the durability of outcomes, and at least in the total cohort was negative. Although, potentially, some separation in patients with intermediate-risk disease. I know you’ve done a lot of work with the sabatolimab program. What’s your thoughts on those data today?

Andrew Brunner:

Yeah, absolutely. It’s interesting working with immune-based therapies in MDS, especially because if we think that they’re going to work, a lot of it is a late outcome. And so I think it’ll be interesting as we continue to follow that cohort and to see do we get that long tail that we might hope for with an immune-based therapy. Based on the mechanism, I agree, you might not expect a difference in response rate per se. But can you maintain that response for a different period? And the challenge with that is waiting for the long readout. It’s difficult. I think what we’re learning from all of these trials is that dose density seems to matter. And so the ability to maintain a person on treatment, even if that’s just regular azacitidine, adhering to a fairly regimented treatment schedule, seems to be something that is very important that we take into consideration.

And as we come up with… Right now, we have four doublets in evaluation. If we’re looking at adding a triplet therapy, how do we think about that? Do we do that for a time-limited period? Do we plan to have different phases of treatment? What is the gain that we get from a single therapeutic intervention? And how much does that impact our old standby, azacitidine, if we’re delaying people on cycles or changing that dosing regimen?

David Sallman:

I think at least we have three double-blind placebo controlled trials that have now fully accrued, including the sabatolimab, the ENHANCE program with magrolimab and the venetoclax program with VERONA. I’m hoping that with this optimal trial design and focus cohorts on higher-risk MDS instead of mixtures, that finally we’ll have these breakthroughs and positive studies. Although we eagerly await the data readout, potentially first with the enhanced trial, ideally in the very near future, at least as far as the readout of the CR endpoint. The only ongoing trial that is accruing in Phase III is the SELECT-1 MDS trial, which is tamibarotene for RARA overexpressors. So I think, ideally, that trial may accrue faster in the setting of lack of other pivotal trials in this setting.

Maybe lastly, of course, HMA-failure MDS. These patients don’t have options. They don’t have targeted therapies given those mutations really don’t occur in MDS patients outside of rare IDH subsets. We’ve been looking at this CXCR2 inhibitor where we do see some early data across low and high-risk patients as far as blast clearance and hematologic improvement. Also, this immune potential mechanism through MDSC eradication, while targeting the leukemic stem cell. But other thoughts that you potentially have, HMA failure? Anything here that we should think about? What about venetoclax? Or are we just in a challenging space?

Andrew Brunner:

We don’t have a lot of updates on the venetoclax data, although I do think that the data presented previously, looking at adding venetoclax to therapy at the time of progression, does provide an option that often we will consider in practice. I think that some of the other targets that are further along that we may find have a niche in MDS, IRAK4 inhibition is an interesting story. It also seems to intertwine with splicing factor-mutated disease, which represents over half of MDS cases. There are a number of agents trying to, and actually some basic science presented at this ASH, looking at new ways to target altered splicing and vulnerabilities that are created by altered splicing. One of those was looking at the combination of PARP inhibition and ATR inhibition. So really stressing that DNA damage response to be able to take advantage of the vulnerability of the altered splicing leaves with DNA damage response. So we are, as has been the refrain, unfortunately, still trying to find that magic bullet for progressive MDS.

To that point, I think that several studies in the last couple years have really emphasized the importance of transplant consideration, and being able to think about referral of patients with MDS to transplant. Still a number of population-based studies showing that the referral rate to transplant is still very low, and thinking about that. And integrating transplant as a therapeutic goal really in a lot of our treatment.

David Sallman:

Yeah. No, I agree. I’m hoping one benefit in these updated classifications is people are thinking about MDS and AML more of as an overlap. So potentially, a lot of the cellular therapies that have only almost been exclusively tested in AML. Now some are starting to think about, are just enrolling their initial patients with myelodysplastic syndrome, so NK therapy, gamma-delta T-cell therapy, CAR-T therapy.

Would love to start to see some of these patients. Biologically, they’re nonproliferative, you may have more time to get these patients on study, granted it’s somewhat of a frail population at the same time. But hopefully, we can really further push these clinical trials and really give options for these patients to potentially get them to transplant or have outcomes optimal to transplant.

So thank you for listening to us today. I think it’s an exciting time and patients for myelodysplastic syndromes, highly important to try to get these patients on study because that’s really going to be our only path forward. Any closing remarks, Dr Brunner?

Andrew Brunner:

I’m leaving ASH with a lot of optimism. I’m excited for seeing some readouts of some big studies. I hope we have a lot of new agents in our space and that will give us the next project to complete.

David Sallman:

Thank you.

Andrew Brunner:

Thanks for having me.