Title

Phlebotomy versus Pharmacological Agents in the Treatment of Polycythemia Vera: A Systematic Review of Existing Literature

Authors

Ishita Gupta 1*, Manognya Chekragari 2*, Hema Hotchandani 3, Oluwaseun Azeez 4, Shreeya Pradhan 5, Maya Magdy Abdelwahab 6, Nafisa Turabi 7 1 - St. Bernards Medical Center, Jonesboro, Arkansas, USA 2 - University of Florida, Gainesville, Florida, USA 3 - Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, Maharashtra, India 4 - Lagos State Health Service Commission, Lagos, Nigeria 5 - Lokmanya Tilak Municipal Medical College and General Hospital, Mumbai, Maharashtra, India 6 - Helwan University, Cairo, Egypt 7 - Innores International, Madhya Pradesh, India * - Co first authors

Introduction

Polycythemia Vera (PV) is a myeloproliferative neoplasm characterized by clonal proliferation of myeloid precursors, predominantly increased erythroid precursors, and red cell mass production. The majority of complications arise due to hyperviscosity, making it a major determinant of morbidity and mortality (1). Guidelines recommend maintaining hematocrit below 45% in patients with PV based on the CYTO-PV study which demonstrated significantly lower rates of thrombotic complications and cardiovascular deaths compared to those with hematocrit in the range of 45-50% (2). Phlebotomy, a well-established first-line therapy, directly reduces the blood volume and hematocrit, remaining the mainstay of therapeutic approaches (3). Hydroxyurea, the first-line treatment in the US and European LeukemiaNet (ELN) guidelines, is widely used due to its efficacy in decreasing the thrombotic risk by lowering hematocrit (4). However, it does not prevent complications like Myelofibrosis (5,6). Interferon alpha (INF-a) helps reduce leukocyte and platelet counts, offering broader symptom control, but is limited by adverse effects like cytopenias and neuropsychiatric disturbances. Despite the widespread use of these treatment modalities, to our knowledge, there is limited evidence on how the different interventions compare in terms of efficacy and long-term outcomes. We conducted a systematic review to evaluate the impact of phlebotomy versus pharmacological agents, focusing on clinical outcomes like hematocrit levels, spleen size, and thrombotic events.

Methods

We performed a comprehensive search across PubMed, Scopus, and Web of Science (WOS) databases to include studies published on or before September, 2024. We used MeSH terms, Boolean operators, and keywords to further refine data. Our inclusion criteria was adults with a confirmed diagnosis of PV being treated with hydroxyurea, busulfan, INF-a and phlebotomy. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines (7). We registered the study protocol prospectively on PROSPERO with the registration number: CRD42024546809. The primary outcomes of interest included a decrease in hematocrit, a reduction in spleen size, and incidence of thromboembolic events. Secondary outcomes included quality of life, morbidity and mortality, and adverse effects associated with the different treatment modalities. We conducted the risk of bias assessment using the critical appraisal tools by the Joanna Briggs Institute (JBI) (8).

Results

Our systematic review included 14 full text studies and a total of 6,949 patients with Polycythemia Vera. Phlebotomy effectively reduced hematocrit but required frequent interventions and showed limited efficacy in long-term disease control, particularly in reducing thrombotic events and spleen size. Hydroxyurea demonstrated superior control over hematocrit levels, significantly reduced thrombotic risks, and was associated with better survival outcomes than phlebotomy alone. INF-a outperformed phlebotomy in normalizing hematocrit, reducing spleen size, and controlling myeloproliferative symptoms, although it was associated with a higher incidence of adverse effects.

Conclusion

While phlebotomy remains an essential component of PV management, the addition of pharmacological agents can significantly improve patient outcomes by reducing thrombotic risks and more effectively controlling symptoms. Moving forward, research should focus on addressing these gaps through well-structured clinical trials that evaluate long-term outcomes and the comparative safety profiles of these treatments, ultimately enhancing the care provided to patients with PV.

References

1 - Barbui T, Finazzi G, Falanga A. Myeloproliferative neoplasms and thrombosis. Blood. 2013;122(13):2176-2184. doi:10.1182/blood-2013-03-460154 2 - Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22-33. doi:10.1056/NEJMoa1208500 3 - Assi TB, Baz E. Current applications of therapeutic phlebotomy. Blood Transfus. 2014;12 Suppl 1(Suppl 1):s75-s83. doi:10.2450/2013.0299-12 4 - Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770. doi:10.1200/JCO.2010.31.8436 5 - Gisslinger H, Klade C, Georgiev P, et al. Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study [published correction appears in Lancet Haematol. 2020 Apr;7(4):e279. doi: 10.1016/S2352-3026(20)30069-7]. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4 6 - Podoltsev NA, Zhu M, Zeidan AM, et al. The impact of phlebotomy and hydroxyurea on survival and risk of thrombosis among older patients with polycythemia vera. Blood Adv. 2018;2(20):2681-2690. doi:10.1182/bloodadvances.2018021436 7 - Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. Published 2021 Mar 29. doi:10.1136/bmj.n71 8 - https://jbi.global/critical-appraisal-tools