During a presentation at the Society of Hematological Oncology (SOHO) Annual Meeting 2021, Carole B. Miller, MD stated, “Although the median survival for PV is estimated to be approximately 20 years, survival in patients with PV has not been retrospectively assessed. There is often a lack of granularity in terms of causes of death and patient comorbidities. “
REVEAL is a multicenter, non-interventional, non-randomized, prospective phase 4 observational study. Patients with PV who are treated in both academic and public practices will be enrolled in the study. All patients were 18 years of age or older with PV. Individuals with a life expectancy of less than 6 months or a diagnosis of myelofibrosis, acute myeloid leukemia, or myelodysplastic syndrome were excluded from the study. Patients with a history or an active plan to have an 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 of the REVEAL study and how the findings can be used for future research.
TARGETED ONCOLOGY ™: What previous research led to your study and what were the main objectives of this study?
Müller: Polycythemia vera is a long-lived disease and there are not many prospective longitudinal studies, especially in the modern era with additional targeted therapies. So we hoped to get a feel for the real-life experience of patients with polycythemia.
Can you explain the study design?
REVEAL is a prospective study in which 270 study centers in the USA from both academia and the public agreed to participate in this prospective database. The study enrolled patients seen at their general clinic visits, conducted prospective quality of life measurements using the MPN symptom scale, and collected clinical details about their disease and its treatment and outcomes. However, patients were enrolled for a period of 2 years and followed up to 36 months from the date of last patient enrollment.
In general, all patients had a follow-up period of at least 3 years and some of the patients had a follow-up period of up to 5 years. As soon as we have collected all the data, the database will be locked. And now we look at the patient data and the actual number of patients was 2,510 total. There are many different types of data that need to be collected. When we finished with this dataset, this particular study focused on the 244 patients who died during the study. The aim was to examine the predictors of death as well as the causes of death and clinical information that was available in the year or so prior to their death.
What were the characteristics of the patients included in this analysis?
The patients were divided into high-risk and low-risk patients based on the inclusion criteria. High-risk patients were those older than 60 years with a history of thromboembolic history or both. So there were basically 3 risk categories. Then the patients are categorized according to whether they have died or stayed alive.
At the time the study was completed, 2,510 patients were included, of which 244 patients died during this time. The study population had more men than women and the polycythemia demographics were similar.
What notable factors have you observed that may have been correlated with survival?
The mean age at diagnosis of the deceased patients compared to those still alive was 68 years. The mean age at diagnosis was 60 years. The median age at death was 77 years and the median time for patients who died from their diagnosis was 8.6 years. Again, this is a group of patients who have the disease and die within less than 9 years of being diagnosed. So this really shows that there is a group of patients who are not getting as good a result on polycythemia vera as we think they are.
Significantly more patients who died in one study were classified as high-risk patients at the time of diagnosis. That makes sense. But it was primarily age-related; there was no clear difference between the patients who had died at the time and those who were still alive whether they had thromboembolic events prior to enrollment in the study. Deceased patients had higher symptom scores at all different times. The patients were screened every 3 months.
If you look at all of the points, the patients who died had worse symptoms than the patients who were still alive, but I think that’s to be expected. The patients who died in the 6 to 9 months with a longer follow-up period had significantly worse quality of life symptoms than the patients who remained alive throughout the study. And the things that are driving the increase in symptoms in general have been fatigue, feeling satiated early, difficulty concentrating, and unintentional weight loss. These were specific complaints related to polycythemia vera.
As expected, we then looked at comorbidities. The deceased patients had major comorbidities both on admission and during the follow-up examination, with the majority of the patients exhibiting vascular diseases, respiratory diseases, gastrointestinal diseases in both the dead and the living group. but a higher proportion among the deceased patients. History of thromboembolic events prior to enrollment and thromboembolic events occurring during the study period were both significantly associated with reduced OS. We also found that about a third of patients who died had more than 1 or more elevated liver frites within the 6 months prior to their death, and almost 60% of patients had raised white blood cells again in the 6 months, suggesting that that patients who died from the disease also had uncontrolled myeloproliferation. The highest risk of death was in patients who were 60 years old at the time of diagnosis and who had a thromboembolic embolism before death.
What were the general results of your analysis?
This survival in patients classified as low risk was excellent at 97% in the lowest patient versus 86% in the high risk patient. But interestingly, the survival of the patients who were considered high-risk at admission was very similar to the low-risk patients during the study at 94%.
The worst group of patients, classified in the high risk group at admission, by both age and thromboembolic events, with a 2% survival rate at a median follow-up of 4 years, which is somewhat surprising. Given that the average age at admission was only about 66 years and we followed the patients for a total of about 5 years, an overall mortality of more than 10% at 4 years was quite surprising. Compared to living patients who completed the degree, deceased patients had a higher comorbidity rate. We were also able to investigate the causes of death. The leading cause of death was vascular complications and 33%. hematological malignancies.
Overall, this study showed that there was a surprisingly high 4-year death rate, greater than 10%. In the patients at higher versus lower risk, about one-third of deaths with vascular complications, and in the 6 months before death, 90 of the patients had elevated hematocrit or uncontrolled myeloproliferative. Even today we still have leeway in the treatment of polycythemia vera.
Was information collected from this study that could generate hypotheses for clinical studies?
I think it is a little tentative to be able to make recommendations based on this largely descriptive study. And I think, as authors, we need to look at the data and do some comparisons before we can make recommendations that could change clinical care. I think it is important to see that polycytopenia vera still has significant mortality, this event in patients treated at a grid and 4 year mortality rate greater than 10% for the past eight years.
I hope we will use this data to design further studies. If we use this data in another study, we may be able to examine 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 drugs.
What other key polycythemia clinical issues do you hope to see explored in clinical trials?
We still have many questions about polycythemia vera. I think one of the most important questions is, can you reduce our risk of death by introducing some of the newer active ingredients such as JAK inhibitors earlier? And number 2, how do we make patients really have consistent hematocrit control?
Prospective observational study of patients with polycythemia vera in US clinical practices (REVEAL). Clinicaltrials.gov. Retrieved on September 20, 2021.