In an interview with Targeted Oncology, Ghaith Abu-Zeinah, discussed the factors contributing to overall survival in patients with polycythemia vera and what is expected of future research.
Ongoing studies are focusing on the development of drugs that can lower blood counts and help maintain a stable hematocrit in patients with polycythemia vera (PV). Still, physicians are unaware as to whether or not the agents being examined can prevent disease progression.
According to Ghaith Abu-Zeinah, MD, a hematologist/oncologist at Weill Cornell Medicine, several studies have set focus on understanding how survival has changed over decades with newly available treatments. Another question constantly brought up is whether or not patients with PV can have a normal life expectancy if adequately treated.
In a study conducted by Abu-Zeinah et al, the median survival was on average 10 years longer at Weill Cornell Medicine compared to data from the National Cancer Institute. Ultimately, raising awareness and understanding about PV can significantly improve outcomes for all patients, regardless of age, sex, and race.
One type of therapy which works to improve progression-free survival and overall survival (OS), is interferon as it has shown significant benefit when used in the treatment of PV, according to Abu-Zeinah. Ropeginterferon alfa-2b (Besremi) was recently approved by the FDA as a first-line treatment of adults patients with PV and was added to the NCCN Clinical Practice Guidelines in March 2022. Approval was based on the PROUD/CONTINUATION-PV clinical trial (NCT01949805; NCT02218047) in which ropeginterferon alfa-2b showed superiority to phlebotomy alone, and many physicians hope this will encourage the utility of interferon for treating all PV patients, according to Abu-Zeinah.
In an interview with Targeted OncologyTM, Abu-Zeinah, discussed the factors contributing to OS in patients with PV and what is expected for the future of PV research.
TARGETED ONCOLOGY: Can you discuss overall survival outcomes in patients with PV?
Abu-Zeinah: PV is a blood cancer, it's a chronic hematologic malignancy, that does shorten survival. Several studies have shown that what we were particularly interested in is to understand how survival has changed over the past few decades with available treatment, and whether our patients could have a normal life expectancy while living with PV if it's adequately treated.
We first looked at the National Cancer Institute data, the SEER database, and did find that these overall survival of PV patients was shorter than what is expected of age, sex and race matched controls, the general population who don't have PV. We found that there was a significant reduction in overall survival in comparison to controls. Then we looked at our center asking the question, at an academic medical center, here at the silver MPN center of Weill Cornell medicine, could certain practices in terms of close follow-up monitoring of patient or an introduction of cytoreductive therapy early in the course of disease, could some of these interventions improve overall survival to the degree that it restores a normal life expectancy?
What factors are contributing to what we're seeing right now with overall survival?
What was very interesting is at our center, introduction of cytoreductive therapy was done at a median time of less than 5 years. Patients were followed, about 70% percent of that total followed was done at our center. Given that we are an academic center with experts in this field, we looked at these factors as potentially being beneficial improving outcomes of PV patients and therefore improving survival. What we did find is that particularly early in the course of PV, there really was no excess mortality from having this diagnosis. Compared to age and other demographic controls, the PV patients had normal life expectancy in the early course, but later on in the disease, it did appear that PV patients were having excess mortality.
When we tried to understand why that is, we looked at some of the most common causes of morbidity and PV particularly thrombotic events and also myelofibrosis progression. What it appeared to be is that myelofibrosis progression was the leading cause of morbidity and mortality, with about 50% of the patient’s developing myelofibrosis by the end of the follow up period of 30 years of further study. So 50% by 30 years is quite a significant number of patients who develop myelofibrosis from this disease, and therefore the excess mortality seen, particularly in the later stage of this disease even at our center, was primarily attributed to myelofibrosis progression.
To better understand that and what we can do about it, 1 of the things we were interested in is looking to see how age of diagnosis factored into the risk of progression and also how certain treatments may have reduced the risk of progression. It turns out that age, whether it's patients over the age of 60 or under the age of 60, was not a distinguishing risk factor for those who later on develop myelofibrosis. In fact, the risk of myelofibrosis or the cumulative incidence was almost the same between both age groups. That suggests that the current risk for modification is sub optimal in identifying patients at high risk of progression and actually treating those patients appropriately in a way that prevents disease progression to myelofibrosis.
The final point that we addressed was treatment and to see if certain treatment practices reduce the risk. We were particularly interested in interferon because we had published a study earlier on interferon belonging, myelofibrosis-free survival and overall survival. We also looked at hydroxyurea, and these are the most common first-line cytoreductive treatments, and compared that to phlebotomy only. It did look like the interferon treated patients had an overall survival that was very similar to the matched general population.
At least in this study for patients on interferon long term, there was no excess mortality from polycythemia vera, whereas the other patients who did not receive interferon, although they did not have access early mortality, they did have access late mortality, suggesting that interferon can put patients in remission and reduce morbidity and mortality from this disease to the degree that patients can have a normal life expectancy.
What does this research mean? Are there any plans to further this research?
There are a few important points here. One important point is raising awareness about this disease, that it does shorten survival, but it is possible with available treatment to significantly improve survival of patients. In our study, the median survival was on average 10 years longer at our center than it is from the National Cancer Institute data. Raising awareness and understanding about this disease and the importance of seeking expert care can significantly improve outcomes for all patients, of all age groups, of all sex, and all essentially demographics, racial demographics, too.
This brings an important point about health disparity and access to health care and it's very important that patients have that access to optimal care in order to improve their survival. I think we can make the biggest difference by raising awareness, first of all. Second of all, I do think that when we talk about risk stratification of patients with PV, we do need to revise the current approach to risk adaptive treatment because we are also using age as a factor here to decide who gets treatment and who doesn't. I don't think there should be an age bias, I think patients should be treated appropriately once diagnosed, and ideally, have an early intervention to prevent some of these poor outcomes. Revising the risk stratification to consider early intervention is a second very important point.
Moving on from here, how do we better predict patients at risk of progression? How do we develop therapies that can improve progression-free survival and overall survival, maybe prevent progression all together and ideally cure these diseases? Interferon clearly has shown to have a significant benefit and I think this should be strongly considered in the treatment of PV. Ropeginterferon alfa or Besremi was recently FDA approved as first-line treatment and I hope this will encourage the utility of interferon alpha and treating PV patients, not just the high risk older than 60, but also younger patients as demonstrated by the low PV study showing that ropeginterferon is actually superior to phlebotomy alone.
That being said, we understand that not all patients are candidates for interferon, not all patients respond to interferon, and therefore, further research will be needed to explore additional treatment options that can potentially prevent progression, ideally, cure these diseases.
Are there any ongoing studies of interest to help with treatment in this population?
There are some ongoing studies in PV. The biggest challenge in PV is that it's a chronic disease, which in a way is a good thing. We're not talking about terminal illness, or metastatic solid tumor. It is a chronic hematologic malignancy, where the median survival can be more than 20 years. The biggest challenge is when developing new therapies is to know whether these therapies can prevent progression. That will require studies that really go on for a very long time.
That being said, the current therapies that are being developed for PV are continuing to target some of the important end points of lowering blood counts, maintaining a stable hematocrit, etc. Unfortunately, we still don't know whether some of the treatments that are being developed will prevent progression. Sometimes, time will tell but, on the other hand, it would be good to know earlier. The sooner, the better. For that reason, I do think, along with the studies that are ongoing, in PV, we need to figure out a way to be able to better predict the therapies that are going to prevent progression 10-20 years down the line, starting from today.
So, how do we do that? I think it's helpful to look into potential biomarkers for disease activity and biomarkers for disease-modifying modification scene with treatment. That's actually an area of research that we're actively working on and interested in. And we actually had an abstract looking at [a] potential biomarker called MPN fitness at predicting some of these potential outcomes. I think pairing up some of the ongoing trials and research and PV with some biomarker endpoints that can potentially predict patients who are responding and who have are experiencing disease-modifying activity, I think is an exciting area of research in PV.