ASH 2022 | Key highlights in MPNs: novel agents, combinations, and the potential role of immunotherapy

Aaron Gerds:

Hi, my name is Aaron Gerds and I’m here with my good friend Lucia Masarova from MD Anderson. And here on behalf of VJHemOnc to discuss the latest and greatest here at the ASH annual meeting for MPNs. Welcome.

Lucia Masarova:

Hey, thank you very much for having us around.

Aaron Gerds:

So a lot’s been presented at this meeting, a lot of clinical trial results, preclinical data even, some new therapeutics. Did anything jump at out you as super exciting in this meeting that you have not heard before?

Lucia Masarova:

That’s a fantastic question because there’s so many I haven’t heard before.

Aaron Gerds:

It’s hard to keep up with everything.

Lucia Masarova:

Yeah, it’s hard to keep up with everything. Of course, we were awaiting more updates of the Phase III randomized trials with the add-on or combined JAK inhibitors. A lot of good preclinical data, which I’m excited about. Interferon data. You’ve presented a great update on the MOMENTUM study, right? We’ll talk about that one.

Aaron Gerds:

Yeah, yeah. Well thank you for asking. So yeah, the MOMENTUM study. So the MOMENTUM study is a randomized prospective Phase III trial comparing momelotinib versus danazol in patients who had previous JAK inhibitor, who are also anemic and who are symptomatic with their myelofibrosis disease. And so the week 24 data where the primary outcome was assessed was already reported at prior congress, but here we reported the next 24 weeks of therapy on study, the open-label, the post crossover phase. So patients who were on momelotinib for the first 24 weeks or on danazol, at that point were allowed to go on open-label momelotinib.

And the key take homes from the presentation were the responses that we saw at week 24 with the blinded portion of the study were maintained through week 48, whether we’re talking transfusion-independence, spleen volume response, symptom burden response. Additionally, kind of a curious thing, a few of the patients who were on momelotinib, who weren’t responders at week 24, ultimately became responders by week 48 in terms of symptom burden improvement. So that’s kind of an intriguing thing because maybe we need to hang on to treatment a little bit longer before we can see the full effects. But most importantly with the updated data is, we didn’t see any new safety signals and that’s really key at assessing any new therapy.

Lucia Masarova:

I think that is a very important point with having more of the combinations in the frontline setting where people will be doubting whether to choose upfront combination or more of the novel JAK inhibitors, they are not myelosuppressive such as momelotinib. Right?

Aaron Gerds:

Yeah, clearly that’s going to be the key thing is we’re going to take a look at single agents JAK inhibitor side effect profile versus how bad are the side effects with combination therapy and do the added side effects from combination therapy, are they outweighed or outstrip the positive results that we’ll see in terms of swing volume response and symptom burden improvement. I think ultimately at the end of the day, for the combination therapies that are coming along, things like pelabresib and ruxolitinib, navitoclax and ruxolitinib and many others, can we see more than just spleen volume responses? Can we see more than just symptom burden improvement? We got to do better by our patients. And I think that’s what these really highly anticipated trials are going to hopefully show us.

Lucia Masarova:

I think that was a fantastic point to definition of [inaudible] markers of these studies are really going to be the next work for us in the field because we will have more and more drugs and we will have to answer the question, how do we sequence them and how do we choose for what patient what’s going to be the benefiting? And then to that point, I think interesting data are surprising to me where the JAK2 allele burden with, for example, ruxolitinib. That was not something I honestly expected. What do you think about that?

Aaron Gerds:

Yeah, I mean that’s always a tricky one because you can measure JAK2 allele burden in patients and it goes up and down without changes in therapy sometimes in some patients and so it’s always tough to say. Likewise, the bone marrow fibrosis abstract was truly interesting to me too, where there was no association between measured clinical outcome and changes in bone marrow fibrosis. So with all these kind of biomarkers, whether we’re talking about allele burden, whether we’re talking about bone marrow fibrosis, you wonder why do we check these things? Because if they’re not fully correlating with clinical outcomes, what’s the value? Sometimes I cynically think that we just check these things because we can, they’re easy to measure, we know how to do it. But I think we need to, like you said, do further work, dig deeper and get to whatever the true biomarkers are in order to get these early reads. Ultimately, we want to see people live longer and live better, but if we can predict that using a biomarker of some variety early on, I think that is key.

Lucia Masarova:

I think that’s great. And you touched really well on the topic of the bone marrow fibrosis where we have heard very intriguing abstract from Stephen Oh actually from MD Anderson and [inaudible] Srdan Verstovsek about that the bone marrow changes do not matter but then at the same time we have a hard update of the pelabresib combination with ruxolitinib showing that well, okay, we have up to 20% of the patients that actually achieved complete resolution of the fibrosis. I think that is something interesting for us to be looking for and waiting for, although we have a little bit contradictory results with that from interferons. Once we stop, the disease could still come back.

Aaron Gerds:

Truly interferons are a biologic agent. So Intron is no longer on the market, but we still have pegylated interferon and we have ropeginterferon and all those studies showing molecular remissions. I mean, intuition will tell you that that’s not a bad thing. That is probably truly meaningful.

The part that really compliments that is the French data on treatment interruption with interferons where people can go and stay in remission, hematologic remission without even treatment in those cases. And so I think it is biologically active in disease-modifying and every time we hear these abstracts and the new data comes out, it just kind of reconfirms that. The trick is, it doesn’t happen for everybody. There are still plenty of patients who have persistent disease or allele burdens don’t go down or these amazing remissions. And who are those people that really do and how can we select for them and really apply this incredibly valuable therapy?

Lucia Masarova:

I think that’s a fantastic point. We actually also have from our institution an update on 15 years of pegylated interferon in ET/PV, and we have seen some patients being technically cured, the JAK2 allele burden went away. Although when we use more sensitive assays, it was still detectable or zero point something percent, but we have patients who stop and never came back. But on the other hand, we have patients who have not achieved such a control and just rebounded right away. So what are those predictive tools that we can pick and choose and tell, “Hey, we can do a couple of years of interferon, you’re going to be cured and that’s it for you.” Or those patients where we, “Hey, this is not the case, this is going to come back right away,” and then we’ll need to come up with something better like the combination Ruxopeg study.

Aaron Gerds:

Yeah. I mean the big knock with interferons has always been toxicity. Patients can’t tolerate interferons. And that’s true to a certain degree with the older versions of interferon and the intense dosing that used to be done. But the way we can handle nimbly interferons now, especially with the newer things like Ropeginterferon, that has a potentially better side effect profile. I’m glad that we’re revisiting this. And then case in point, every ASH we come here, we hear more interferon studies that kind of reconfirm that idea. And Ruxopeg is a great example. You’d say, “Okay, we take Rux, we combine it with interferon, which is pretty toxic. People aren’t going to do well on it.” But they actually did. And to me the responses are of course intriguing and I really like to see those. But the tolerability of the combination really stood out to me as well.

Lucia Masarova:

I think that was impressive. Interferon 135 mcg per week, is a dose I would never use as a single-agent because it would be quite toxic.

Aaron Gerds:

It’s pretty toxic.

Lucia Masarova:

And with the ruxolitinib there was pretty much almost no discontinuation, like 2%.

Aaron Gerds:

I was pretty surprised to see that. If you would’ve had me guess before the study was done, I would say most people would’ve been on say 45 micrograms-

Lucia Masarova:

Yeah. That was my bet as well.

Aaron Gerds:

Or maybe a couple patients will get up to 90. But I was pretty impressed with how big the doses could get because I think they think that’s going to only deepen your biologic response, I think if you can get more in folks safely.

Lucia Masarova:

Yeah. What about some of the novel agents that you’re interested in?

Aaron Gerds:

Certainly. The way I organize them in my mind is we had the last wave, which are all the new JAK inhibitors, the pacritinib, the fedratinib and the momelotinib. The next big wave are going to be these combination therapies. So like I mentioned, pelabresib, navitoclax, parsaclisib, and all the other combination therapies. And the next wave after that is going to be stuff that’s truly innovative. We heard the plenary abstract this year on monoclonal antibodies directed against calreticulin-mutated disease.

Lucia Masarova:

That was fascinating.

Aaron Gerds:

I mean, it’s fascinating. So if you have a monoclonal that can affect change, it’s really well tolerated, has a great side effect profile. Then as oncologists, we like to put things together, so we’re going to do it in combination and then building off that, if it truly does target that, could we do bispecific antibodies and use the immune system to kill these things? Can we come up with some sort of engineer T-cells or BiTEs? And so really I think that’s the future. So that’s going to be the next wave after the next wave. And that was really exciting for me to see.

Lucia Masarova:

I think that was exciting because here we are actually going after the clone. We are not only doing something for spleen and symptoms as you elaborated at the beginning, we have to do better, go after the disease. So they show that actually it does deplete the malignant clone. So probably next thing would be to go after JAK2 mutated cells.

Aaron Gerds:

Yeah. Simple next step.

Lucia Masarova:

Yeah.

Aaron Gerds:

And likewise, we’re opening up a study at our center looking at a vaccine trial. And so the protein for the vaccine does include JAK2, calreticulin, MPL, the three mutations, and then the given an ipilumumab boost to enhance the immune response. So yeah, I mean if we can harness immunotherapies, even antibody therapies, to really go after those clones and eliminate them, to me the biggest gains are going to be in people who actually have lower risk disease. High-risk disease is so molecularly complex, it advances so quickly. I worry that some of these therapies may not be as effective, probably augmentative but not transformative. But think about someone with a high risk ET that could turn into myelofibrosis in a few years. But if you turn back the clock 15 years, that could be a real huge win for that individual. So to me, that’s really exciting because we don’t have a lot of therapies for lower-risk myelofibrosis and ET and PV because quite frankly, people do so well for so long. But if we could really turn back the clock for those folks, it could be a huge win.

Lucia Masarova:

Yeah, yeah. That’s really very exciting to me. What about the TP53? I think that’s always funny, lots of debates as emerging TP53 clone if we actually use a key negative regulators like MDM2 inhibitors, which I think there are a couple data. Even on the combination with the PPM1D which was very interesting as a first kind of foot in to see some efficacy and some safety. That was something I was really interested in. But we’ll probably have to follow more on the possible emerging TP53 clones in that setting. I’m a little bit more anxious about how it’s going to play in disease such benign as some of these diseases are.

Aaron Gerds:

Yeah. And you can think of some patients that you’ve had who’ve had P53 clones and you’re like, “Ah, I don’t know what to do,” and you kind of sit on it and nothing happens, right? It is almost like a ticking time bomb. Because if they progress, it’s just so hard to treat. Refractory to chemotherapy is more likely to relapse. Transplant outcomes are worse. They’re not zero, they’re not horrible and it’s not feudalistic, but it’s not great. And so I think likewise, therapeutic approaches that attack TP53 mutated diseases desperately needed, not just in MPNs, but I would say all malignancy. I mean TP53 mutations being bad is a universal truth in oncology medicine. And so I think going after that could not only benefit patients with myelofibrosis and MPNs, but all oncologic patients in general.

Lucia Masarova:

Yeah. Yeah. There’s been lots of data about CD47s macrophages has not translated to myeloproliferative neoplasms yet, but maybe we will see that sometimes in our lives to go after those clones and see how they’re going to play out.

Aaron Gerds:

Yeah, absolutely.

Lucia Masarova:

But I haven’t seen a lot of data about accelerated and blastic phases. Those are really the bottlenecks that we are facing that we don’t really have anything for our patients here.

Aaron Gerds:

No, nothing. I mean, we’re still doing things like ruxolitinib and [inaudible] in combination in our clinics, maybe aza-ven. And that’s about it. I mean, there’s not really anything moving forward. Starting to use targeted therapies. So the MPNRC-119 study looking at IDH2 inhibition, but that’s not really new in the AML world, if you will. So I think better ways to attack accelerated blast phase disease is certainly a critical unmet need.

Lucia Masarova:

Completely agree.

Aaron Gerds:

Well, thank you so much for spending a little time with me chatting about the updates in the MPN world here at the 2020 ASH meeting, and I look forward to seeing you again over the course of the year and reconvening in one year to talk about what else is new.

Lucia Masarova:

Oh, thanks very much. It’s been a really exciting year. We thank VJHemOnc for inviting us and for having us as part of this lovely discussion.

Aaron Gerds:

Thank you very much.

Lucia Masarova:

Thanks so much.