Hello and welcome to today’s VJHemOnc podcast. We are a global open-access video journal bringing you the latest in hematology and hematological oncology. Today’s episode features a discussion from the 2nd International Workshop on Myelodysplastic Syndromes and Myeloproliferative Neoplasms held in Boston, Massachusetts. You will hear from Andrew Kuykendall, Lucia Masarova, and Kristen Pettit, who share insights into polycythemia vera and essential thrombocythemia. They focus on the treatment of adolescent and young patients, the challenges in designing clinical trials in essential thrombocythemia, and the importance of defining goals when treating these patients.

Andrew Kuykendall
Hi, my name is Andrew Andrew Kuykendall from Moffitt Cancer Center. I’m here with Kristen Pettit from University of Michigan, as well as Lucia Masarova from MD Anderson. And so we just had a really provocative session talking about myeloproliferative neoplasms and some of the unique features of polycythemia vera and essential thrombocythemia. So, Lucia, actually a question for you. You gave a great talk speaking about adult or adolescent and young adult populations with PV.
What’s so unique about that population of AYA with polycythemia vera and essential thrombocythemia?

Lucia Masarova
Fantastic question. I think unique is the age because the median age of these patients is 60, so they represent a minority, it’s about 8%, 11% most of all of those cohorts. The largest database that exists is about 300 patients of one disease. So we are never going to have a data that we can rely on and make really, really, really great conclusions about what the outcome really is. Because even within those cohorts, these patients are not really the same. And then the therapies, there was a fantastic discussion about pros and cons. Do we put these patients more on treatments that young, with the name they’re going to be on it for good 40, 50 years. Or we don’t, and we wait for the best therapy to come, risking the outcomes that could be quite like in, for example, one of the cohorts, the incidence of very significant major abdominal thrombosis was up till 25%, which is very, very unacceptable to me in anybody who wouldn’t have a serious life consequences to live with this. So that’s the biggest uniqueness of the young population. And then I think diagnosis challenge because people don’t usually think about young people having anything, especially something so rare as MPNs. And then when the most common symptoms was headaches, who would pay attention to it, right. And we see this in the clinics. We have lots of patients that had numerous different outcomes, including heart attacks at a young age. And nobody’s really put the puzzles together and think, oh, something is wrong with your blood work, you might have something that’s called MPNs. And then they come in and there is not much to even tell them. They read about the progression rates. I’m going to die when I’m in my 50s because this is how it comes. And that’s not always the case. But on the other hand, the therapies we can give to these patients are having lots of limitations.

Andrew Kuykendall
Interesting. Do you feel like in your practice that these patients, the young adult patients, are coming in more frequently now than they used to? Do you think it’s something that with kind of the increase in genomic testing and genetic testing and maybe our understanding around some of these myeloproliferative neoplasms and their drivers, do you feel like those are coming into your clinic more often than they used to?

Lucia Masarova
I think you hit the right spot. The diagnostic and the thinking about is more awareness that we haven’t had even a couple of years ago. So I do have quite a significant amount of young patients among my population. But that’s because we had the unique trials. We’ve been kind of like using a lot of, as we mentioned, for example, interferon for years for these patients. We’ve published on it so people look it up. It’s a large academic center. I don’t think this is more frequent. I do more attributed to the awareness and then the social media, because young people these days are more connected and there has been more and more social media power. And that’s where pretty much more of my younger referrals comes. On the contrary, with the older population, they would never even have an idea where to find the reliable information about MPNs.

Andrew Kuykendall
And maybe the one good thing about social media. So moving to Kristen. So Kristen, you gave a talk really talking about essential thrombocythemia and kind of a new agents and things in development. I think the first question to ask is, you know, given our history of using hydroxyurea, anagrelide, maybe interferon to some degree, where’s the future? What are our goals in treating ET?

Kristen Pettit
Yeah, I think that’s an excellent question and a very loaded question because I think it’s very patient dependent. I think the things.. and it’s treatment dependent, it’s dependent on what our treatments are actually able to deliver. So I think our therapeutic options that we have right now have been proven to be able to decrease the risk of thrombosis, decrease the risk of serious bleeding, control blood counts to some degree improve or control symptoms related to the disease. But in a prospective way what what our field is really lacking is prospective evidence that we can really impact the disease at its base and prevent the disease from progressing over time and improve longevity, improve survival for patients. So I think all of those should be our goals in research going forward.
But I don’t know that they have made them into prime time for our clinical practice because as has really come up in the session that we were just speaking about, I think our clinical trials so far have not been designed to necessarily answer those questions in the in the long term, unfortunately. And I think that’s something that we need to do better at trying to really get to the base of that question so it can better inform which patients we’re actually treating and when.

Andrew Kuykendall
Yeah, I guess a follow up to that, in a somewhat provocative question would be, is it possible to run a clinical trial in ET where you’re measuring short term improvements in symptoms and quality of life, but also assessing long term changes in thrombotic risk or progression of risk as well.

Kristen Pettit
I think it’s difficult but not impossible. I think these are things that we need to do. I think certainly the short term endpoints are things that are much more feasible financially and logistically for us to be able to get answers for those long term outcomes, survival, progression, things like that. They’re so important obviously, they’re important to our patients and they’re important to us. But fortunately, many people with ET will live many decades and for for some subgroups approaching normal life expectancy. So these trials would have to go on for many, many years to be able to see a difference between different groups. So that is a logistic challenge. But I don’t think it’s an impossibility. I think it is something we should be looking at and looking for any early signs of other biomarkers that we can use to help predict that down the road to whether it’s these molecular reductions like decreases in the variant allele frequencies of the driver genes that might be able to predict for risk of progression or survival down the road. I think we need to clarify that whether or not that’s the case and if that’s the case, what should our cutoff be? You know, in CML we can get these deep 4.5 log molecular reductions and then some. Whereas in Bcr-Abl negative MPNs we’re looking at VAF reductions of 20 anywhere from, you know, 5%, 20%, 50%, 70%. You know, we’ve seen different cutoffs across the board. So I think we really need to do better to try to standardize that and see what really predicts for long term outcomes. And then maybe that can give us a shorter term answer for the longer term outcomes that we really care about.

Andrew Kuykendall
Yeah, wonderful. I mean, I think there’s certainly a natural overlap talking about AYA and ET, I mean, these are the kind of the populations, the subgroups within myeloproliferative neoplasms where there’s the most opportunity to change the natural history of the disease or to intervene early. And we talk about, you know, in an earlier session and people in just general talking about clonal hematopoiesis and trying to intervene there. Well, I think that’s challenging to design trials in clonal hematopoiesis for a variety of reasons. But certainly in ET and AYA populations, it may be kind of the area where we can start to kind of design nuanced trials, interesting trial designs that can kind of have a meaningful change on these things going forward.

Lucia Masarova
Yeah, I think the first session started the day with the MPN is not CML, where there’s not one disease or one VAF that we’re trying to reduce, and there’s multiple clones and multiple challenges. And if we eliminate or decrease one, what happens to the next? I think that’s something to learn. And then the second great point that was raised was the collaboration effort that nationwide global wise collaboration effort to put the resources to put the patients because there’s such heterogeneity where Kobe in Florida, Texas, UK and somewhere else in Europe or Africa that we could do so much more with the power if we can combine these things and have access to deep sequencing data, what’s reasonable, how to gather all of this information, because with such a rare disease to do long term studies are going to be impossible if we don’t include a lot, a lot of patients. And then [inaudible] is tons of patients in need and they have access to nothing. So that would be kind of like hitting both things at the same time. But I think you raised a fantastic point, which I really like during our provocative debate about the goals, because there has not been really much mentioned in the MPNs. It’s become kind of standard in the CML with the treatment free remissions abilities, and we are having lots of discussions about frontline therapies. As you said in your talk, hydroxyurea versus interferon, which is oral versus injectable, different side effect profiles, long term different side effect profiles. But you really raised an amazing point about the goal definition, which I particularly extremely like, because I think that has not been that well defined or mentioned in the field. And everybody is talking more about disease modifications and end points and what’s relevant, where we don’t even know what we can achieve with any of those. And you really ask the right question what’s your goal in treating your patients?

Andrew Kuykendall
I think it’s always an important thing, right? Trying to figure out, why are you leveraging a treatment for a patient who’s sitting in front of you? And I think if you can’t answer that question, then you really need to kind of maybe walk out of the room and think about it again before you come back in there. But yeah, I mean, I think when we talk about goals of therapy, I mean, you know, I talked about polycythemia vera. Certainly you have these kind of short term goals where you’re thinking about quality of life and symptoms. And, you know, we didn’t even go into reduction in phlebotomy rates and things like that. But you also have these long term goals. And I think only recently have we been able to kind of consider the idea of delaying or prevention of progression. And that’s where I think if we have the ability to do that, we need to be thinking about that in every patient. And certainly interferon is cumbersome to to give. And I think that’s one of the downsides, right. It’s hard to just the prescription sometimes hard to write to get to to explain to patients, to educate patients, the cost implications, the uncertainty of cost But that doesn’t mean that we shouldn’t kind of go back and say, is this really the right drug that we should be? Is this the right agent for this patient? And if it is, then the effort and the challenge should be overcome, right. And certainly we should be trying to think about patient first. And, you know, certainly we’re entering a new era where I think that we’re able to to at least consider outcomes that we haven’t before. So with that, I would say great session. Really fantastic talks in AYA populations, ET, PV, endpoints, early treatment, preventing progression. All the things that we like to really think about and how we can move the needle for patients. So thank you guys so much and I look forward to the rest of the conference.

Lucia Masarova
Thanks so much. I think we set up a provocative start.

Kristen Pettit
Yeah, absolutely. Thank you.

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