Hydroxyurea Better Than Phlebotomy at Preventing Nonfatal Arterial Thrombosis in Polycythemia Vera

Hydroxyurea (HU) showed a significant advantage over phlebotomy (PHL) in protecting against nonfatal arterial thrombosis in patients with polycythemia vera (PV), according to research published in Blood Cancer Journal.

The researchers wrote that theirs was the first such study to document the greater antithrombotic protection of HU over PHL against arterial thrombosis. They also found that the 2 treatments lent similar protection from venous thrombosis.

Blood hyperviscosity is a major factor in vascular complications that severely impacts morbidity and mortality in patients with PV. Aggressive maintenance of a target hematocrit (HCT) level below 45% with PHL—either alone or in conjunction with cytoreductive drugs and low-dose aspirin—have been shown to reduce the rate of thrombosis in 2 important clinical trials,^2,3 and are recommended therapies in clinical practice.⁴ A small observational study in 1986 in patients with PV at high risk because of age and/or history of thrombosis suggested that HU be the recommended front-line cytoreductive drug,⁵ but the use of HU as first-line therapy has been questioned because due to the lack of definitive studies evaluating its ability to prevent thrombosis or prolong survival. Additionally, concerns have been raised with whether HU may increase the risk of leukemic transformation.⁶ Thus, PHL has remained the only first-line therapy independent of patient risk.

An earlier study by the same researchers⁷ showed an advantage of HU over PHL in a cohort of patients with PV who were included in the ECLAP trial³ that was consistently significant with respect to the proportion of fatal/nonfatal cardiovascular events and myelofibrosis transformation that was more frequent in patients treated with PHL only. The present study investigated the same patient cohort more thoroughly to determine whether cytoreduction therapy with HU vs therapeutic PHL was differently effective in preventing arterial and venous thrombosis.

The investigators selected patients who, during follow up, had received either PHL or HU to maintain HCT levels below 45%. To assure comparability, they conducted a 1:2 Propensity Score (PS) matching system; thus the 2 groups (PHL, n = 317; HU, n = 634) were well balanced for the parameters included in the PS. Over a median of 25.8 months and 24.0 months, respectively, they documented a significant advantage of HU over PHL for proportion of nonfatal arterial thrombosis: 6.3% vs 2.4% in PHL vs HU groups, respectively; P = .002. HU was not more effective than PHL in reduction of unprovoked venous thromboembolism (P = .574). The rate of arterial thrombosis was 3-fold lower in patients on HU compared with PHL (2.62 vs 0.84 per 100 person-years in PHL vs. HU groups, respectively; P = .001). The differential effects between the 2 treatments were independent of the patient’s prior history of thrombosis.

The researchers hypothesized that their findings might be explained by the fact that HU reduces the abnormalities of myeloproliferative neoplasm clone-derived cells, such as leukocytosis, and thus the interaction with platelets and the vascular endothelium that lead to an inflammatory state reduces the inflammatory state known to be involved in the genesis of thrombosis. They recommend that the latest study results be confirmed with investigations involving a larger number of venous events separately from the common deep vein thrombosis.

References

1. Barbui T, De Stefano V, Ghirardi A, et al. Different effect of hydroxyurea and phlebotomy on prevention of arterial and venous thrombosis in polycythemia vera. Blood Cancer J. 2018;8:124. doi: 10.1038/s41408-018-0161-9.
2. Marchioli R, Finazzi G, Specchia G, et al; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;268:22-23. doi: 10.1056/NEJMoa1208500.
3. Landolfi R, Marchioli R, Kutti J, et al; European Collaboration on Low-Dose Aspirin in Polycythemia Vera Investigators. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114-124.
4. Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm. Blood Cancer J. 2018;83. doi: 10.1038/s41408-017-0042-7.
5. Kaplan ME, Mack K, Goldberg JD, Donovan PB, Berk PD, Wasserman LR. Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol. 1986;23:167-171.
6. Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:1670-1671. doi: 10.1056/NEJMoa1409002.
7. Barbui T, Vannucchi AM, Finazzi G, et al. A reappraisal of the benefit-risk profile of hydroxyurea in polycythemia vera: a propensity-matched study. Am J Hematol. 2017;92:1131-1136. doi: 10.1002/ajh.24851.