In an interview with Targeted Oncology™ during the SOHO Annual Meeting, Carole Miller, MD, discussed results from the REVEAL study and how the findings can be used to aid future research.
Overall survival (OS) for patients with polycythemia vera (PV) is estimated to be 20 years; however, uncertainty about what factors impact mortality in these patients still exists. This clinical question led to an analysis of mortality and causes of death in patients with PV.
During a presentation at the Society of Hematologic Oncology (SOHO) 2021 Annual Meeting, Carole B. Miller, MD, stated: “Although the median survival for PV is estimated to be about 20 years, survival in patients with PV has not been evaluated retrospectively. Granularity with respect to causes of death and patient comorbidities is often lacking.”
REVEAL is a phase 4, multicenter, non-interventional, non-randomized, prospective, observational study. Patients with PV treated at both academic and community practices are enrolled in the study. All patients were aged 18 years or older with PV. Those with a life expectancy below 6 months, or a diagnosis of myelofibrosis, acute myeloid leukemia, or myelodysplastic syndrome were excluded from the study. Patients with a history of or an active plan to proceed to allogeneic hematopoietic stem cell transplant within 3 months and those who had a splenectomy were also included.
In an interview with Targeted Oncology™ during the SOHO Annual Meeting, Carole Miller, MD, director of the Cancer Institute at Ascension Saint Agnes, discussed results from the REVEAL study and how the findings can be used to aid future research.
TARGETED ONCOLOGY ™: What previous research led to your study and what were the key goals with this study?
Miller: Polycythemia vera is a disease where people live with for a long time, and there have not been many prospective longitudinal studies, especially in the modern era with additional targeted therapies. So, what we were hoping to do was to sort of get a feel of the real-world experience for patients with polycythemia vera.
Can you explain the study design?
REVEAL is a prospective trial where 270 sites in the US both academic and in the community agreed to participate in this prospective database. The study enrolled patients who were seen at their general clinic visits, they had quality of life measures using the MPN symptom scale done prospectively, and clinical details about their disease and its treatment and outcomes were collected. But the patients were enrolled in over a 2-year period and were followed until 36 months from the date of the last patient enrollment.
Generally, all patients had at least 3 years of follow-up, and some of the patients had up to 5 years of follow-up. Once we collected all the data, the database will be locked. And now we're looking at the data from the patients and the actual number of patients was a total of 2,510 patients. There's lots of different data to collect, so when we are done with this data set, this particular study focused on the 244 patients who died during the course of the study. The goal was to try and look at predictors of death, as well as the causes of death, and the clinical information that was available around them in the previous 1 year or so prior to their death.
What were the characteristics of the patients included in this analysis?
Patients were characterized into high-risk and low risk based on the inclusion criteria. Patients were considered high-risk if they were greater than 60 years of age, and or had a thromboembolic history, or had both. So, there were basically 3 risk categories. Then, patients are categorized as to whether they had died or remained alive.
At the time of study completion, 2,510 patients were enrolled, of which 244 patients died during the time. The study population had more men than women, and polycythemia vera demographics were similar.
What notable factors did you observe that may have correlated with survival?
For the patients who died, the mean age at diagnosis was 68 compared with those who are alive. The mean age of diagnosis was 60. The mean age of death was 77 years, and the median time for patients who died from their diagnosis was 8.6 years. So again, this is a group of patients who have the disease and die within the median of less than 9 years from diagnosis. So, this is really showing that there's a group of patients who don't have as good of an outcome as we seem to think, in polycythemia vera.
Significantly more patients who died in a study were characterized as high-risk at diagnosis. That makes sense. But it was primarily due to age, there wasn't a clear difference between the patients who died and were alive at the time about whether they had thromboembolic events prior to enrollment. Patients who died had higher symptom scores at all the different time points patients were screened every 3 months.
When you look at all points, the patients who died had worse symptoms than the patients who lived, but I guess that is expected. The patients who died in the 6 to 9 months with a longer follow up, the patients who died had significantly worse quality of life symptoms than the patients who remained alive during the course of the study. And the things that push the increase in symptoms were generally fatigue, early satiety, difficulty concentrating, and unintentional weight loss. These were specific complaints related to polycythemia vera.
We then looked at comorbidities as you'd expect, the patients who died had greater comorbidities both at enrollment, and during follow-up with the majority of the patients having vascular disorders, respiratory disorders, gastrointestinal disorders in both the dead and alive group, but a higher proportion in the patients who died. History of thromboembolic events prior to enrollment, and thromboembolic events occurring during the study period, were both significantly associated with reduced OS. What we also found, was that about a third of the patients who died had more than 1 or more elevated hepatic frit value within the 6 months before their death, and almost 60% of the patients had elevated white count during the 6 months, again, suggesting that patients who were dying of the disease also had uncontrolled myeloproliferation. The highest risk of death was in patients who were both 60 years of age at diagnosis and had thromboembolic embolism before death.
What were the overall findings of your analysis?
This survival in patients who are considered low risk was excellent at 97% in the lowest patient versus 86% in the high-risk patients. But interestingly enough, the patients who had were considered high-risk at enrollment, during the study, their survival was very similar to the low-risk patients at 94%.
The worst group of patients that were put into the high-risk group at enrollment both by age and thromboembolic events where their survival was at 2% at a median of 4 years of follow-up, which is somewhat surprising. Given that the mean age at enrollment was only about 66 years, and we followed the patients for about 5 years overall, seeing greater than 10% mortality rate overall at 4 years was quite surprising. Compared to patients who are alive who study completion, patients who died had higher rates of comorbid disease. We also were able to look at causes of death. The most common cause of death was vascular complications and 33%. hematologic malignancies.
Overall, this study showed that there was a surprisingly high 4-year mortality rate of greater than 10% greater. In the higher versus the lower-risk patients, about a third of the deaths with vascular complications, and the 6 months before death, 90 of the patients had an elevated hematocrit or uncontrolled myeloproliferative. So, even in the contemporary period, we have room to go in the treatment of polycythemia vera.
Was there any information gathered from this study that is hypothesis generating for clinical trials?
I think it's a little preliminary, to be able to make recommendations based on this mainly descriptive study. And I think as authors, we're going to have to look deeper into the data and do some comparisons before we can make recommendations that could that that may change clinical care. I think what's important to see is that poly cytopenia Vera still has significant mortality, this event in patients treated within the last eight years with a grid and 4-year mortality rate of greater than 10%.
My hope is that we will use this data to design more studies. Using this data in another study, we may be able to look at outcomes based on different interventions. There were 2510 patients that we can look at. Our next steps will be to see if we can look at subgroups and different medications.
What other important clinical questions in the polycythemia vera space do you hope to see investigated in clinical trials?
We still have lots of questions about polycythemia vera. I think 1 of the important questions is can you decrease our risk of death with earlier institution of some of the newer agents such as JAK inhibitors? And number 2, how do we get patients to really be managed to have consistent hematocrit control?
Prospective observational study of patients with polycythemia vera in us clinical practices (REVEAL). Clinicaltrials.gov. Accessed September 20, 2021.