Introduction: Polycythemia vera (PV) is associated with erythrocytosis (with or without thrombocytosis/leukocytosis), increased risk of thrombosis, and symptoms including fatigue, early satiety, and abdominal discomfort. Hydroxyurea (HU) is a common cytoreductive strategy used to control blood counts and splenomegaly in patients with PV. Although blood counts in many patients with PV are effectively controlled with HU, a proportion of patients fail to achieve controlled blood counts. The European LeukemiaNet (ELN) has defined response criteria for blood count control as well as HU resistance and intolerance in patients with PV; 1 criterion for HU resistance includes a lack of blood count control at a minimum dose of ≥ 2 g/day HU for ≥ 3 months.
The REVEAL observational study (ClinicalTrials.gov, NCT02252159) is being conducted to describe contemporary demographics, burden of disease, clinical management, patient-reported outcomes, and healthcare resource utilization among patients with PV in the United States. The objective of this analysis is to describe HU treatment patterns, blood count control, and HU intolerance among patients enrolled in REVEAL.
Methods: REVEAL is a multicenter, noninterventional, nonrandomized, prospective, observational study of adult patients with PV. Patients with high-risk PV were defined as being ≥ 60 years of age or having a history of thrombosis. Patients who had ever been treated with or were currently receiving HU were included in this analysis. HU treatment patterns were assessed by evaluating dose modifications and discontinuations. HU interruptions were defined as gaps of > 14 days or complete discontinuation of HU treatment. Toxicities were assessed following initiation of HU. Components of the ELN response criteria for PV (hematocrit [HCT] < 45% without phlebotomy, platelet [PLT] count ≤ 400 × 109/L, and white blood cell [WBC] count ≤ 10 × 109/L) were used to assess disease control. Data cutoff for this analysis was May 18, 2017.
Results: Among the 2510 patients enrolled in REVEAL, 1432 (57.1%) were treated with HU at some point during their course of treatment. In this cohort, the median age was 69.0 years (range, 26.0-95.0 years), median duration of disease was 4.2 years (range, 0-36.5 years), 49.7% of patients were male, 89.5% were white, and 84.1% were high risk. Median exposure to HU was 35.7 months (range, 0.1-448.6 months). The 2 most common maximum total daily HU doses were 500 mg (30.8%) and 1000 mg (30.6%). Approximately one-third of patients (34.50%) had ≥ 1 HU dose adjustment, 14.53% had both dose increases and decreases, and 16.56% interrupted treatment with HU. Patients experienced as many as 11 HU dose changes over the course of treatment. At data cutoff, 90.4% of patients exposed to HU continued on treatment. Among the 1390 patients receiving HU for ≥ 3 months, more than half (57.1% [n = 632]) of the evaluable patients (n = 1106) had an HCT value > 45% after the 3-month mark; more than one-quarter (27.4% [n = 303]) had uncontrolled myeloproliferation (44.9% with an elevated WBC count and 49.2% with an elevated PLT count). HU-related nonhematologic toxicities, including leg ulcers, were observed in 7.4% (106/1432) of patients during HU treatment. Cytopenias were observed in 15.0% (201/1342) of patients during the treatment period.
Conclusions: In REVEAL, HU is a commonly used therapy for PV, but over half (57%) of patients treated with HU for ≥ 3 months still had not achieved HCT control (HCT < 45%), suggesting that cytoreductive treatment with HU inconsistently leads to optimal blood count control in patients with PV. In addition, a proportion of patients developed HU-related toxicities or intolerance, and approximately one-third required ≥ 1 HU dose adjustment. Inadequate blood count control with HU or intolerance of HU may have an impact on symptom burden and the risk of complications. This analysis further emphasizes the need for active management of PV with appropriate HU dose titration to maintain blood count control while monitoring for signs or symptoms of HU intolerance.
Grunwald: Genentech: Research Funding; Cardinal Health: Consultancy; Pfizer: Consultancy; Janssen: Research Funding; Celgene: Consultancy; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; ARIAD: Consultancy; Forma Therapeutics: Research Funding; Alexion: Consultancy. Altomare: Incyte: Consultancy, Honoraria. Burke: Gilead: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Celgene: Consultancy; Incyte: Consultancy. Gerds: Incyte: Consultancy; CTI BioPharma: Consultancy. Savona: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Consultancy, Research Funding; Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Equity Ownership; Sunesis: Research Funding; Takeda: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Kuter: Rigel: Consultancy, Research Funding; Amgen: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Research Funding; Syntimmune: Consultancy, Research Funding; Zafgen: Consultancy; Genzyme: Consultancy; Alexion: Consultancy, Research Funding; Fujifilm: Consultancy; Argenx: Consultancy; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; ONO: Consultancy; 3SBIO: Consultancy; Shire: Consultancy, Research Funding; Protalex: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy. Stein: Incyte: Consultancy. Oh: Incyte: Honoraria. Colucci: Incyte Corporation: Employment, Equity Ownership. Naim: Incyte Corporation: Employment, Equity Ownership. Paranagama: Incyte Corporation: Employment, Equity Ownership. Mesa: Gilead Sciences, Inc.: Research Funding; Galena Biopharma, Inc.: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Celgene Corporation: Research Funding; Incyte Corporation: Research Funding; CTI BioPharma Corp.: Research Funding; Ariad: Consultancy; Promedico: Research Funding.
Asterisk with author names denotes non-ASH members.