REVEAL trial | Updates from the EHA 2022 Congress

Polycythemia vera (PV) is a myeloproliferative neoplasia characterized by clonal hematopoiesis, resulting in elevated peripheral blood counts and increased likelihood of thrombotic events (TEs).¹ The conventional risk model uses age and TE history to determine the TE risk and treatment strategy. While the connection between increased risk of TE and elevated hematocrit (HCT) levels has been established, the association between TEs and white blood cell (WBC) or platelet (PLT) counts has not been consistently assessed.¹

A prospective observational study of patients with PV in the US clinical practices, entitled REVEAL study (NCT02252159), is currently evaluating patients with PV treated in community or academic centers in the real-world settings. During the European Hematology Association (EHA) 2022 Congress, Gerds, et al.¹ reported an evaluation of the association between elevated blood counts and the occurrence of TEs, based on data from the REVEAL study. We summarize the key points below.

Study design

REVEAL is a multicenter, non-interventional, prospective, observational study. Key inclusion criteria are as follows:

• ≥18 years old.
• Clinical diagnosis of PV.
• Under supervision by the healthcare professional for management of PV.

Patients included in this analysis had ≥3 blood counts in the post-enrollment period. Patients were excluded if they had a post-enrollment TE but did not have a blood count value <6 months before that TE. The main thresholds used in the analysis for blood counts were as follows:

• HCT >45%
• WBC count >11 × 10⁹/L
• PLT count >400 × 10⁹/L

Alternative thresholds were also investigated:

• WBC count: <7 × 10⁹/L, ≥7 to <8.5 × 10⁹/L, ≥8.5 to <11 × 10⁹/L, and ≥11 × 10⁹/L
• PLT count: >600 × 10⁹/L

A separate analysis of the association between elevated WBC count and TEs at HCT ≤45% was conducted to evaluate whether the risk could be reduced by controlling the WBC count alone.

Results

Of the 2,510 patients enrolled, 2,271 were included in the analysis. The patient characteristics are summarized in Table 1. About 20% of patients had a TE history, and ~60% of patients were on cytoreductive therapy (hydroxyurea, 52.6%).

Table 1. Patient characteristics*

HCT, hematocrit; PLT, platelet; WBC, white blood cell. *Adapted from Gerds, et al.1 †Risk status was assessed based on the National Comprehensive Cancer Network (NCCN) guidelines. ‡Other treatments: ruxolitinib (4.4%), anagrelide (2.2%), interferon (1.5%), busulfan (0.2%), chlorambucil (0%).
Characteristic	Patients (N = 2,271)
Median age, years (range)	67 (22–95)
Male, %	54.1
Median disease duration, years (range)	4.1 (0–56.3)
History of thrombosis, %	20.1
Risk status,† %
Low	22.1
High	77.9
Cytoreductive therapy, %
None	40.5
Hydroxyurea	52.6
Other‡	8.0
HCT level, %
≤45%	52.5
>45%	47.5
WBC count, %
≤11 × 109/L	69.2
>11 × 109/L	30.8
PLT count, %
≤400 × 109/L	63.7
>400 × 109/L	36.3

After enrollment, 106 patients had any TE: arterial TEs occurred in 30 patients, mostly transient ischemic attack (0.7%); and venous TEs were recorded in 76 patients, mostly deep vein thrombosis (1.6%).

• Among those with a TE history at enrollment, 38 patients (8.3%) had a TE during the follow-up, including 10 arterial TE events, and 28 venous TE events.

Association between blood count and TEs

Table 2 shows the covariates associated with TE risk. As expected, age, male sex, and history of TEs were significant. Elevated HCT, WBC count, and PLT count were also significantly associated with TE risk. The significance was less for WBC count.

Table 2. Association between blood count and TE (main threshold)*

CI, confidence interval; HCT, hematocrit; HR, hazard ratio; HU, hydroxyurea; PLT, platelet; TE, thrombotic event; WBC, white blood cell. *Adapted from Gerds, et al.1
Analysis	HR (95% CI)	p value
Association between elevated HCT and TEs
Age, years	1.03 (1.010–1.046)	0.0026
Male sex (male vs female)	0.54 (0.362–0.799)	0.0021
History of TE (yes vs no)	2.49 (1.667–3.717)	<0.0001
HCT (>45% vs ≤45%)	1.84 (1.234–2.749)	0.0028
Association between elevated WBC count and TEs
Age, years	1.02 (1.007–1.042)	0.0068
Male sex (male vs female)	0.58 (0.393–0.858)	0.0063
History of TE (yes vs no)	2.42 (1.623–3.619)	<0.0001
WBC count (>11 × 109/L vs ≤11 × 109/L)	2.35 (1.598–3.465)	<0.0001
Association between elevated PLT count (>400 × 109/L) and TEs
Age, years	1.03 (1.010–1.046)	0.0022
Male sex (male vs female)	0.62 (0.416–0.914)	0.0162
History of TE (yes vs no)	2.45 (1.640–3.654)	<0.0001
PLT count (>400 × 109/L vs ≤400 × 109/L)	1.60 (1.088–2.359)	0.0170

In terms of alternative thresholds, for WBC count, only the ≥11 × 10⁹/L versus <7 × 10⁹/L threshold was significantly associated with increased TE risk. There was no significant association between PLT count >600 × 10⁹/L and TE risk.

When the HCT was controlled at ≤45%, an elevated WBC count (>12 × 10⁹/L) was significantly associated with increased risk of TE (hazard ratio, 1.95; 95% CI, 1.066–3.554; p = 0.03).

Conclusion

This analysis of the REVEAL study has shown statistically significant associations between elevated HCT levels, elevated WBC count, and elevated PTC count and increased TE risk in patients with PV. A WBC count of >12 is significantly associated with increased TE risk when the HCT is controlled, which suggests that TE risk may be reduced by controlling the WBC count and HCT level. This analysis supports the incorporation of blood cell counts into risk assessments and treatment plans for patients with PV. The causal relationship between blood counts and TEs needs to be explored further.