A session with experts Claire Harrison, Ruben Mesa, and Jean-Jacques Kiladjian who discuss the latest updates in myeloproliferative neoplasms (MPNs) from the 2022 EHA Annual Meeting.

Welcome to The MPN Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Claire Harrison, Ruben Mesa, & Jean-Jacques Kiladjian, who debate key updates in the treatment and management of myeloproliferative neoplasms (MPNs), including myelofibrosis, polycythemia vera, and essential thrombocytopenia, following the 27th Congress of the European Hematology Association (EHA) 2022.

Working group for MPNs: potential role of digital pathology and machine learning in MPNs

“I think a key take home for me was reproducibility and then this looking and tracking patients and maybe being able to predict patients who may be heading towards progression. And we’ve been using some of our very long studies in the UK and their carefully curated samples to look at that, and I can see that’s a way forward we might be looking at in the future.”

– Claire Harrison

Calreticulin-directed vaccine trials

“They even have a small clinical trial of vaccination showing that in the patients who receive these sequential injections of the vaccine, they could induce some immune response but unfortunately until now, no clinical response. ”

– Jean-Jacques Kiladjian

“Well certainly the technological challenges, I think more to come. I know there’s calreticulin antibodies that are in development as well as multiple different vaccine trials. Hopefully we’ll overcome some of this technical difficulty.”

– Ruben Mesa

Clinical trial updates at EHA 2022

“We haven’t had a new treatment for ET, have we, for a long time? And some drugs are being developed in that setting. There’s a study with ropeg… there’s also some very exciting data with the LSD1 inhibitor IMG-7289 or bomedemstat, showing very good patient responses and good tolerability.”

– Claire Harrison

“It’s an exciting drug. We have an investigator initiated study at our center with bomedemstat, clearly has activity so looking forward to the Phase III. Nice shoutout for ropeg.”

– Ruben Mesa

Key updates in the treatment of MF & the importance of combination approaches

“I think many of us recognize that JAK inhibitors really do improve the lives of our patients, but there are issues with tolerability, durability of response, and actually whether there’s really disease modification. And we know this is an aggressive hematological malignancy and these are diseases we rarely treat with one therapy, so clearly an interest in combination”

– Claire Harrison

“I’m pretty sure that we will not achieve disease modification with only one drug but probably a more targeted, specific, patient specific combination of drugs will probably help us to achieve this improvement again, beyond the one we already had.”

– Jean-Jacques Kiladjian

Watch the full session
Full Transcript

Ruben Mesa:

Hello, I’m Ruben Mesa. I’m the executive director of the Mays Cancer Center at UT Health, San Antonio MD Anderson and I’m here at the 2022 European Hematology Association meeting with wonderful friends and world MPN experts, Professor Claire Harrison and Professor Jean-Jacques Kiladjian and we’re going to share with you a little bit about the discussions here of MPNs at EHA 2022. Claire, why don’t we start with yourself, both yourself and Jean-Jacques lead the working group for MPNs and that was a really well-attended session. There were some interesting things. One of them was a potential role of digital pathology, potentially helping us better assess MPNs, track it over time. What are some key takeaways?

Claire Harrison:

The special working groups are a really important part of EHA and Jean-Jacques and I have been chairing the MPN one for a while. And so it was our pleasure to host the session entitled ‘Seeing MPNs Through a New Lens’ and the lens in this case referred to the use of digital pathology and machine learning.

Claire Harrison:

For a long time, we’ve known that obviously pathological features are a key aspect of MPN diagnostics, where we’ve really argued a lot about whether features are reproducible or not. Dan Royston really, he did a fantastic talk about machine learning, how we might be assessing [inaudible] biopsies in the future. And then looking, I think a key take home for me was reproducibility and then this looking and tracking patients and maybe being able to predict patients who may be heading towards progression. And we’ve been using some of our very long studies in the UK and their carefully curated samples to look at that and I can see that’s a way forward we might be looking at in the future. And we’ve seen in fact, some digital pathology, we might talk about that, I guess in a minute from some of the clinical trials. I was really super excited to see that presentation.

Ruben Mesa:

I think it’ll be very impactful as we clearly see potential bone marrow histologic changes being endpoints in clinical trials. Being able to really capture that, having more granularity is key. Now, shifting gears a little bit, Jean-Jacques, we heard, so really some of the first time we’ve heard data regarding a calreticulin-directed vaccine trial from our colleagues in Denmark. What are some key takeaway for folks?

Jean-Jacques Kiladjian:

This was really also an exciting presentation by Morten Holmström from Denmark, where in fact as you know, calreticulin mutations are very heterogeneous, there are more than 15 that have been described but they all result in the same change in the protein with a sequence that is in fact immunogenic. And the idea was to design a vaccine that could recognize the CALR mutation, which is expressed at the surface of the cells, the hematopoietic stem cells, megakaryocytes, et cetera, to induce an immunity against the malignant cells that have this mutation.

Jean-Jacques Kiladjian:

And Morten showed indeed very nice in vitro results, showing that you could induce an activation of T-cells against CALR-mutant cells in patients. And they even have a small clinical trial of vaccination showing that in the patients who receive these sequential injections of the vaccine, they could induce some immune response but unfortunately until now, no clinical response. And in fact, what they found as maybe one of the reason is that the T-cells that are activated against the CALR mutant cannot go back in the bone marrow. And when they looked for them in the bone marrow, they couldn’t find any of them. They’re in the blood, maybe in the spleen, but for the moment this homing in the bone marrow was not seen. Maybe there’s improvement to find there.

Ruben Mesa:

Interesting. Well certainly the technological challenges, I think more to come. I know there’s calreticulin antibodies that are in development as well as multiple different vaccine trials. Hopefully we’ll overcome some of this technical difficulty. Now Claire, let’s shift a bit to some of the therapy trials that were presented here at EHA. First, let’s build that on ET=PV and then finally MF, but ET splanchnic vein thrombosis, both recovered to a little bit of a degree. Some take away in each of those challenging situations?

Claire Harrison:

Well, maybe let’s start with splanchnic vein thrombosis. In the UK, we have this so called HaemSTAR Network, which is doctors, postgraduate doctors in training across all of the hospitals who are powered to collate real-world data. And I think it’s such a powerful group. Big call out to HaemSTAR for the listeners. And they collected data on over 200 patients with splanchnic vein thrombosis in different hospitals. These are very challenging patients, often as we know, needing multidisciplinary management. What they showed was this was almost exclusively a JAK2-driven event. That’s a really important message. And also that there was a very high rate of re-thrombosis. Now this was a little bit surprising to me, I would say, and I think we need to lean in and learn a bit more about the data. Either I’m missing that in my patients, could be, but often frequently shunts, thrombosis, et cetera. Powerful network, good idea, maybe for the listeners to recapitulate that and important data in a challenging field. And then I wanted to give a call out to ET. We haven’t had a new treatment for ET, have we, for a long time? And some drugs are being developed in that setting. There’s a study with ropeg, which I’m guessing we’re going to come along to talk about ropeg in a moment but there’s also some very exciting data with the LSD1 inhibitor IMG-7289 or bomedemstat, showing very good patient responses and good tolerability. And I understand that’s going to be taken forward in a randomized trial so that’s definitely one to watch.

Ruben Mesa:

It’s an exciting drug. We have an investigator initiated study at our center with bomedemstat. Clearly has activity so looking forward to the Phase III. Nice shout out for ropeg. Dr Verstovsek and I were leading the global SURPASS ET study, as second line in ET. If you have patients out there, just want to consider that important trial. Now here, we also had a very nice update regarding long-term data that you’ve been intimately involved with from the beginning on ropeg in PV. What are some updates, really takeaways from some of these truly long-term experience now with ropeg in PV?

Jean-Jacques Kiladjian:

In fact, Heinz Gisslinger presented the final results because the study now is closed after six years actively treated in the trial. And a total of about more than seven years of follow up in the patients and the key messages, I think are the superiority of ropeginterferon compared to standard therapy to achieve and maintain complete hematological response on the long term. The second is a huge difference in terms of molecular response since the ropeg treated patients experienced a very important decrease in their JAK2-mutant variant burden. And we have now after six years of active treatment, 21% of the patients who are achieved a burden of JAK2 below 1%, almost undetectable in several of these patients. That is not the case in any of the standard treatment treated patients. And lastly, what we could see in this final analysis is a better event-free survival, including death, transformation, thrombosis or hemorrhage in patients treated with ropeginterferon compared to standard treatment. Three key points, complete response maintained on the time, molecular response, much deeper and even free survival, hopefully better outcome for our patients.

Ruben Mesa:

Really exciting data and very relevant as I think about US patients now that have access to ropeginterferon since it was approved in November of 2021 will be really, I think, bolstered by these results. I think they’re really positive. Now let shift finally, toward myelofibrosis, we’ve got three approved JAK inhibitors, ruxolitinib, fedratinib and now in the US, pacritinib. Srdan Verstovsek presented very nice data that we were all involved with, with the MOMENTUM study showing superiority of momelotinib versus danazol in the second line improving symptoms, which was nice to see as a primary endpoint. Splenomegaly as well as anemia clearly superior to danazol, the current standard of care for anemia of these patients. But a lot of interest as well, not only in monotherapy with JAK inhibitors but combinations. Claire, you presented both data on pelabresib. There was additional data on rux and navitoclax. Thoughts on combinations, both a nutshell around pelabresib as well, where we stand with combinations at the moment.

Claire Harrison:

I think many of us recognize that JAK inhibitors really do improve the lives of our patients, but there are issues with tolerability, durability of response and actually whether there’s really disease modification. And we know this is an aggressive hematological malignancy and these are diseases we rarely treat with one therapy. Clearly an interest in combination. And there’s been a focus in combination in second line but also now in the frontline setting. Treat your best earlier, I think that’s a mantra we all learned as we were training.

Claire Harrison:

The navitoclax data, the first data for naive patients presented here. And then I had the opportunity to present the pelabresib data, both in the second line and the naive patient population with nice mature data, more than 80 patients. And I think very reassuring data with regard to efficacy, safety and some nice translational data bringing in and circling back to the digital pathology we were talking about at the beginning of our conversation. Reduction in fibrosis, changes in megakaryocyte topography. And I think this is, we are moving towards some more exciting endpoints and some more exciting combined therapies but I’m interested to hear yours and Jean-Jacques’ opinions on this subject as well. It’s a hot topic in the field.

Ruben Mesa:

Jean-Jacques, combinations, do you think they’ll replace monotherapy or be in a subset?

Jean-Jacques Kiladjian:

That’s a very important question. We don’t have the answer yet. I think certainly by proof, scientific proof but what I discussed also in the education session is what is disease modification and how can we achieve that in MF patients in particular? And I think due to the heterogeneity or in the clinical presentation of the patients, in the molecular landscape of these patients with variety of combination of mutations in the same patients, the heterogeneity of the bone marrow findings, I’m pretty sure that we will not achieve disease modification with only one drug but probably a more targeted, specific, patient-specific combination of drugs will probably help us to achieve this improvement again, beyond the one we already had, as Claire said with JAK inhibitors.

Ruben Mesa:

Wonderful. Well, let me get my final thoughts and maybe just made a couple concluding comments. One, I strongly agree with you. We’ve got an unprecedented number of Phase III trials ongoing in MF. And I think the data is really going to be critical. How really effective and safe are the combinations? And truly are there specific subgroups? It’s a heterogeneous disease. There undoubtedly will be subpockets that we find might be better linked with one versus another. But for folks watching this, I think you hopefully take away from our discussion, a tremendous sense of hope around MPNs, tremendous progress. I think back on my career, seeing first patient now over 30 years ago with MF. First 15 years, it didn’t really make a lot of progress. We tried. Not a lot of progress. These last 15, I think we’re really accelerating. New drugs, multiple drugs, multiple approvals, combinations that are effective, better understanding of biology, better quantification of pathology. More to come but good news here from EHA 2022. Thanks, Claire and thanks, Jean-Jacques.

Jean-Jacques Kiladjian:

Thank you, Ruben.

Claire Harrison:

Thanks so much.

The MPN Channel on VJHemOnc is supported by Constellation PharmaceuticalsKartos Therapeutics, Inc. and Sierra Oncology.

These supporters have no influence over the production of the content.

Disclosures

Ruben Mesa –  Research funding: Genentech, Promedior, Samus, Gilead, Celgene, Novartis, Constellation Pharmaceuticals, CTI, Abbvie, Sierra Oncology, Incyte Corproation; Consultancy: Novartis, Sierra Oncology, Pharma, Constellation Pharmaceuticals, AOP, La Jolla Pharma, Incyte Corporation.

Claire Harrison – Research funding: Celgene, Constellation, Novartis; Advisory role: AbbVie, AOP, BMS, Celgene, CTI, Novartis, Galacteo, Geron, Gilead, Janssen, Keros, Promedior, Roche, Shire, Sierra.

Jean-Jacques Kiladjian – Advisory role: Novartis, Abbvie, BMS, AOP Orphan.

 

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