by David Wallace
Transcript | Can Polycythemia Vera (PV) Patients Live a Normal Lifespan?
David Wallace:
So you had several important abstracts and one that our listeners with PV will be excited about. So tell us about the potential for normal life expectancy in PV.
Dr. Abu-Zeinah:
So this a project was inspired by our last paper, I guess our paper published in leukemia back in March of 2021 where we found that treatment of polycythemia Vera with interferon alpha was associated with an improved myelofibrosis free and overall survival that inspired us to look and see, well, you know, if there are different outcomes we see with different treatments and outcomes, particularly long-term outcomes. So survival outcomes can be so heavily affected by treatment and many different variables. We were actually curious to know if it is possible that if everything was done right can a patient with PV live a normal life without, you know, major disease complications or issues that, you know, affect their lifespan. And so it was also inspired by several other studies published in the past by other groups that show that patients with PV have a shortened lifespan or, or PV shortened survival.
Dr. Abu-Zeinah:
So, you know, there’s no doubt that when PV was first discovered it, it was a very highly morbid disease because patients often presented late with very high hematocrits and had major cardiovascular events that led to death. And so thrombosis and cardiovascular events have always been a major cause of death in polycythemia Vera, but a lot has changed since the early 19 hundreds and the 1950s. And even from when the PVSG clinical trials were run in the 1960s to the, to the 1980s. So a lot us changed since then. And you know, the question that really came up in, in our minds is if we can prevent major thrombotic events by being vigilant and being, you know, very careful with controlling hematocrits, you know, optimally at an academic center and we have a drug and we have a treatment approach that can reduce the risk of disease progression to myelofibrosis.
Dr. Abu-Zeinah:
If we target these two major causes of morbidity and death, could we potentially achieve normal life, could patients with PV have a normal life expectancy. So that kind of inspired this study. And we went on to do you know, more analysis and data collection or I should say data collection first and then analysis. So what we did is we got data from two sources. One is from the national cancer Institute, SEER database, which is the cancer registry in the United States. It covers about 27 to 35% of the United States cases of really any cancer and MPN have been included in that definition since the early two thousands. So there’s data available from about 2001 till 2017 when, when we first collected the data. And so we looked at what the survival was for PV patients reported in this registry.
Dr. Abu-Zeinah:
And we did in, we indeed found that it is consistent with the prior data, that it is life expectancy is shortened. And how we determine that is we compare the overall survival of the PV patients in this database to a considered controls. So these are age matched sex matched and race matched general US population. So those who don’t necessarily have PV, but, you know, they’re, they’re out in the community. So when we make this comparison, we find that PV indeed shortens survival. And so our next step was to try to understand if at our center being an academic center, specialized in treating these diseases if the outcome is better than what has been anticipated and to do this analysis, we really had to try our best to make sure that the groups are matched. You know, we don’t wanna be comparing a, a group of 55 year old patients to 65 year old patients.
Dr. Abu-Zeinah:
You know, the median age of PV diagnosis in the country is in the early sixties whereas in our center, it’s in the early fifties. So what we actually did is we looked at our PV patients at Cornell median age of about 54 and then found a group of PV patients matching our population of patients by age sex and race. After we did the matching, we looked to see, well, what does the survival look like? How is it different? So, you know, the good news is actually our survival when we compared these groups was on average 10 years longer than what is reported in the cancer registry. So that actually provided us with a lot of hope. I mean, that made us of course, very happy to learn that our center has really been treating these MPS for a long time expertly and appropriately.
Dr. Abu-Zeinah:
But the next step, you know, after looking at this remarkable achievement is to understand what went right and what went wrong. And so, and to see if we can really tease out the data to, or tease out information from the data we have to tell us what are the practices that should be emphasized in the treatment of PV in order for us to get the survival, to be significantly better than how it is right now, out in the community. So when we looked at it in more detail closely, it, it did appear that early excess mortality in PV, which particularly comes from cardiovascular events was essentially eliminated at at our center. So there was no difference between PV patients at Cornell and the general community in the first 10 to 12 years, as far as survival goes. So that was encouraging and, and the PR what’s presumed to be the cause of that is really trying to prevent clots from happening by being vigilant about controlling the hematocrit and really introducing CUC treatments early on in the disease course.
Dr. Abu-Zeinah:
So our median time from diagnosis to starting cytoreductive therapy was actually less than five years. So that may not be true in other places where if a patient’s diagnosed at the age of 50, they might wait till they’re 60 or until after an event occurs. You know, if they’re being treated by the the current guidelines. So we thought that that that’s one important point to highlight is, you know, the guidelines may not necessarily work in our favor in terms of the younger population of patients. So those who are under 60, but I, you know, if you could control the hematocrit and reach all those targets by any means such as phlebotomy, then as long as they’re well controlled, you know then, then you’re meeting the treatment goals. So the, the second point from the study was I, if you look at later on beyond the first 12 to 15 years you do notice that, you know, there is an excess mortality later on, you know, even at Cornell.
Dr. Abu-Zeinah:
And so our question was what is the cause of that? And we hypothesized that most likely this is disease progression to myelofibrosis. So when we looked at the incidence of myelofibrosis over about a 30 years of follow up, we do find that towards the end of those 30 years, approximately half of a patient. So 50, roughly 50% developed myelofibrosis by 30 years, you know, patients are followed for 30 years and they’re alive and, and, you know, have this disease at 30 years, then about half of those patients have myelofibrosis. So that is quite a high, it’s a high number. And so that’s where we have to really ask ourselves, well, how could we do a better job at risk stratifying patients to know who are the patients who are more likely to have myelofibrosis and who are the 50% who do not have myelofibrosis at that point in time?
Dr. Abu-Zeinah:
And what, what can we do to prevent myelofibrosis from occurring? And so that’s where we looked more closely at treatment. And because we had the prior knowledge that the interferon treatment in our group led to a reduction of fibrosis and improvement in mild fibrosis free survival. We looked specifically at the interferon group of patients and we kind of, we did the same kind of analysis where we compared that group of patients to a matched group in the general population matched by age sex and race. And in some cases we even matched by year of birth so that’s, that’s a little challenging to do, but then when the data’s available, we try to make these groups as comparable as possible, looking at the interferon group, actually the curves really almost overlapped for the 30 years of the follow up and, you know, being these curves, being overlapping really suggests that there’s no significant difference in the survival of a PV patient successfully treated with interferon alpha versus anybody else in the, in the community who doesn’t have PV.
Dr. Abu-Zeinah:
And so by doing that, although we recognize interferon is not a curative treatment and we are yet to find a cure for PV, those who you know, are able to be treated with interferon alpha, have no tolerance issues or to the drug or any side effects that they really benefit on the long term. And it does seem, you know, from analyses that we’ve done before, that really the duration of treatment is associated with a better outcome. So the longer somebody is on interferon, generally the better but even those who are on it for some period of time will derive some benefit. We did similar analyses to other drugs, such as hydroxyurea, and, you know, there’s other drugs that were used more sparsely, but H certainly the most and, and we just didn’t see the same kind of improvement, you know, with the duration of, of these therapies.
Dr. Abu-Zeinah:
So that being sent put all together, I think it sends the message that cardiovascular events and morbidity and death from cardiovascular events can be completely prevented with available therapy and that we could currently with available therapy actually achieve a normal life expectancy in polycythemia era. But we do need to do a better job at identifying patients who are at highest risk for progression considering treatment with interferon early in their course of disease or considering alternative options. If interferon is not, is not an option for clinical trials for new drugs that could potentially do similar job in preventing myelofibrosis progression, ideally drugs that hopefully cure this disease.
David Wallace:
Okay. Excellent. That’s certainly good to hear. And as we look at the progress being made in research looks brighter ever.
