At this year's EHA meeting, we presented an abstract from the REVEAL study. Really focusing in on thrombosis risk in patients with polycythemia vera, with respect to their blood counts outside of the adequate the REVEAL study is a very large prospective observational study of patients with polycythemia vera treated in both.
Community practices as well as academic practices. And it is a cross-sectional study where we enrolled 2,500 patients, again, four observations. So, there was no therapeutic intervention there. And they were followed for a minimum of 36 months after enrollment. So, we got a pretty good broad swipe of data before they enrolled on this observational study, as well as afterward.
And again, the focus of this abstract was looking at thrombotic event. The reason we focus on thrombotic events is we have a really old way of looking to identifying patients who have high risk for thrombosis and low risk for thrombosis. Basically, anybody who is older, or who has had a history of a blood clot is considered to be high risk for thrombosis.
And then everybody else is considered to be low risk. So very antiquated. And the thought is that perhaps we can look at other parameters to refine our ability to identify clot risk in these folks. Cause thrombosis is the major complication of PV and there have been prior studies that have been published that show that yeah, perhaps an elevated white count or elevated platelet counts might be associated with thrombosis risk, but it's not a certainty.
And moreover, when you control the hematocrit, do these factors still hold. So, we took the REVEAL database and we looked for patients who had at least enough blood counts in order to make a judgment on things. And from the 2,500 patients that were enrolled wet things down to about 2100 patients but still a very large database.
In fact, the largest database of polycythemia vera ever made, we looked at a couple of different cutoffs, white counts that were above normal, above 11, or below 11, as well as platelet counts with a cutoff of four, 400 to see if these markers had any prediction for thrombosis in these populations.
And what we saw is yes, as the white count increases, we do see increased risk of thrombosis. Additionally, we see. Platelet counts above 400 were associated with thrombosis risk. But oddly enough, when we looked at platelet counts above 600, it wasn't associated with thrombosis risk, and we're not in quite sure why we saw that.
Probably a couple of different reasons. One is the interaction between thrombosis risk, and platelet count may not be that strong. And secondarily, there were a few patients with platelet counts above 600 enrolled in the study. So, the numbers may not be big enough really to appreciate that increased risk of thrombosis.
Secondly, we took all the patients who had controlled hematocrits, so hematocrits less than 45, and look to see in those patients to see. Increasing white blood cell count or platelet counts was associated with thrombosis risk. And it looked like there was a trend when the white count was over 11 for increased thrombosis risk.
But certainly, when the white count became over 12, there was an association between that elevated white blood cell count or leukocytosis and future blood clot risk. We also confirmed in this study that classic markers of thrombosis risks such as age and history of blood clots were also predictors.
So, in the end. The important take-home points from this study were that we should really be starting to think more broadly about risk stratifying patients for thrombosis who have PV and moving beyond the classic thrombo hemorrhagic model and including things like white count and potentially platelet count during discussions it was also brought up that JAK2 allele burden can predict thrombosis and perhaps that could be included as well.
And in fact, these are analyses that we are undertaking with this database.
Aaron T. Gerds, MD, MS, Associate Professor of Medicine, Deputy Director for Clinical Research at the Cleveland Clinic Taussig Cancer Institute and Medical Director of the Case Comprehensive Cancer Center Clinical Research Office at Cleveland Clinic. In this video, he speaks about the EHA 2022 abstract A Real-World Evaluation of the Association Between Elevated Blood Counts and Thrombotic Events in Polycythemia Vera: An Analysis of Data from the REVEAL Study.
PV is characterized by clonal hematopoiesis, which results in higher peripheral blood counts and an increased risk of thrombotic events (TEs). The standard risk model used to predict TE risk/treatment strategy includes advanced age and TE history. Although there are connections between TEs and higher hematocrit (HCT) levels, relationships with white blood cell (WBC) or platelet (PLT) counts have not been systematically examined. The large, prospective Observational Study of Patients with Polycythemia Vera in US Clinical Practices (REVEAL; NCT02252159) monitored patients with PV treated in community or academic facilities.
Using REVEAL data, this study looked at the links between high blood counts and TEs in patients with PV.
Eligible patients had three lab values (blood counts) after enrollment; patients having a post-enrollment TE but no lab value six months earlier were excluded. A time-dependent covariate Cox proportional hazards model was used to examine the relationship between blood counts and TEs. Time to first post-enrollment TE was modeled, with time censored at last known visit for patients who did not have TE. Each lab parameter was modeled with gender, age, disease duration, and TE history as baseline factors and therapy as a time-dependent covariate. Blood counts were included as binary time–dependent covariates if HCT was greater than 45 percent, WBC was greater than 11109/L, and PLT was greater than 400109/L. To determine lab values between observed lab values, linear interpolation was applied. Alternative WBC thresholds (7, 7 to 8.5; 8.5 to 11, and 11109/L, and >12109/L with HCT regulated at 45%) and PLT counts (>600109/L) were tested. P0.05 was used to determine statistical significance.
There were 2271/2510 eligible points (median age, 66 years [range, 22–95]; male, 54.1 percent). The median disease duration was 4.1 years (range, 0–56.3), 456 patients (20.1 percent) had a history of TE, and 52.6 percent got hydroxyurea. Thirty patients experienced arterial TEs (the most common being transient ischemic attack [n=15]) and 76 had venous TEs (the most common being deep vein thrombosis [n=37]).
Elevated HCT levels (>45 percent, HR=1.84 [95 percent CI, 1.234–2.749], P=0.0028), WBC (>11109/L, HR=2.35 [1.598–3.465], P=0.0001), and PLT counts (>400109/L, HR=1.60 [1.088–2.359], P=0.0170) were all linked to an elevated risk of TE (Table 1). When compared to WBC count 7109/L, WBC count 11109/L is related with the highest TE risk (HR=2.61 [95 percent CI, 1.594–4.262], P0.0001). With HCT managed at 45 percent, elevated WBC >12109/L was strongly related with higher risk of TE. PLT count greater than 600109/L increased TE risk (HR=1.37 [95 percent CI, 0.763–2.468]) compared to PLT count less than 600109/L, however this was not statistically significant (P>0.05). Advanced age, female sex, and TE history were all linked with higher TE risk in all models.
This study of REVEAL, the largest real-world cohort of PV patients to date, found that higher HCT levels (>45 percent), WBC counts (>11109/L), and PLT counts (>400109/L) were related with an increased risk of TE. When HCT was decreased, a relationship of raised WBC >12109/L with increased risk of TE was also detected, demonstrating that TE risk may be lowered by controlling WBC as well as HCT. These findings suggest the necessity to incorporate blood count into risk categorization and treatment methods for patients with PV in clinical practice, as well as to go beyond the traditional risk model. More research is needed to understand the link between high blood counts and TEs.