Thrombosis is a primary contributor to morbidity and mortality in patients with polycythemia vera (PV), a rare hematologic disorder seen primarily in adults aged 60 years and older, with a higher prevalence in men. A clinical history of thrombosis increases the risk of PV.1 Characterized by a mutation in the Janus kinase 2 (JAK2) gene and overproduction of functionally normal blood cells, PV is also the most common Philadelphia chromosome-negative myeloproliferative neoplasm (MPN).
Common and serious clinical complications of PV include arterial and venous thrombosis, transient ischemic attacks, and, in some patients, transformation to bone marrow failure, myelofibrosis, and acute leukemia. The varied clinical symptoms, including migraine headache, visual disturbance, itching, and burning pain in the extremities, often result in a poor quality of life.2-5 In the United States, the Leukemia & Lymphoma Society estimated that the incidence of PV is approximately 2.8 and 1.3 per 100,000 population among men and women, respectively. The prevalence of PV is about 22 cases per 100,000 people.1
The optimal management of PV requires differential diagnosis, patient risk stratification for the optimal treatment strategy, and control of modifiable risk factors. Despite decades of research, PV remains a diagnosis of exclusion. “Some patients are asymptomatic, with no presenting clinical symptoms, and diagnosis may be made as part of routine blood work or a medical incident such as a blood clot,” said Aaron T. Gerds, MD, assistant professor at Case Comprehensive Cancer Center in Cleveland, Ohio.
The differential diagnosis of PV is complicated by expanded plasma volume masking erythrocytosis, an essential clinical presentation for differential PV diagnosis.3 Currently there is no cure for PV and treatment is focused on reducing hematocrit and platelet concentrations, controlling symptoms, and reducing the risks of thrombotic events and leukemic transformation. There remains a lack of clarity on therapeutic strategy with current treatment options, including treating low-risk and high-risk PV and how to treat patients who have PV that is intolerant, resistant, or refractory to treatment.3 Treatment recommendations for PV were added to the National Comprehensive Cancer Network (NCCN) guidelines in 2017 and required physicians to be familiar with the recommendations for uniformity in the diagnosis and treatment of PV.6
Given the potential for misdiagnosis and the need for individualized disease management based on risk level, this review summarizes the current approach to risk stratification, differential diagnosis, and the optimal use of current treatment options with a discussion of emerging investigational agents.
PV Risk Stratification and Differential Diagnosis
Patient risk stratification by age and history of thrombosis provides the basis of risk-adapted therapeutic intervention. Patients with PV are categorized as high risk or low risk: high risk generally refers to those who are 60 years of age and older, who have a history of thrombosis, or with a hematocrit ≥45%. In the absence of these risk factors, patients are considered low risk. 4,7,9 Other risk factors also considered for patient stratification include white blood cell count ≥11×109/L, the burden of mutant JAK2 allele, and traditional cardiovascular risk factors including diabetes, high cholesterol, and increased systolic blood pressure.8
PV Differential Diagnosis
In the absence of molecular markers specific for PV, diagnosis is made clinically and often by exclusion; however, the differential diagnosis is challenged by the similarity of the symptoms and pathophysiology between PV, essential thrombocythemia, and primary myelofibrosis. In addition, several conditions can mimic PV.10 These include the following:
- Erythrocytosis resulting from various clinical conditions, including hypoxia; renal disease; tumors; congenital disorders such as Chuvash polycythemia and erythropoietin receptor mutations; and certain drugs such as androgenic steroids and recombinant erythropoietin
- Conditions that promote plasma volume contraction, including hypertension; diuretics; tobacco use; and androgenic steroids
An increase in the volume of red blood cells, white blood cells, and platelets, accompanied by increased spleen size in some patients, is clinically consistent with PV but does not differentially confirm a diagnosis. Increases in blood cell types, increased spleen size, and JAK2 mutation are also seen in essential thrombocythemia and primary myelofibrosis. Consequently, misclassification and misdiagnosis of PV are not uncommon and can lead to inappropriate and suboptimal treatment. A positive test for JAK2 mutation establishes an MPN with a high suspicion of PV, as PV is the most common MPN.11 As PV, essential thrombocythemia, and primary myelofibrosis share the same JAK2 mutation and other clinical features, a JAK2 mutation in the presence of elevated hematocrit, hemoglobin level, or red cell count in conjunction with neutrophilic leukocytosis and thrombocytosis, with or without splenomegaly, establishes a diagnosis of PV.11 However, many patients with PV will present with only erythrocytosis and thrombocytosis, while fewer will present with erythrocytosis and leukocytosis.12
The World Health Organization identified 3 major criteria and 1 minor criterion for PV. A diagnosis of PV requires either all 3 major criteria to be met or 2 major criteria plus the minor criterion.14-16 Major criteria include 1. Hemoglobin >16.5 g/dL in men and >16.0 g/dL in women OR hematocrit >49% in men and >48% in women OR increased red cell mass >25% above mean normal predicted value; 2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size); and 3. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size). The minor criterion is a subnormal serum erythropoietin level.14-16
Risk-Adapted PV Treatment
Bone marrow transplantation (BMT) theoretically offers the only curative therapy. Given the lack of clinical studies, the uncertainty of the conditioning regimen, and transplantation-related mortality, the real benefit of BMT is unclear. However, BMT may be considered in patients with PV who have transformed to a primary myelofibrosis phenotype.2,13 In the absence of a well-established curative therapy, the clinical management of PV is focused on aggressive control of the hematocrit, minimizing the risk of thrombotic and hemorrhagic complications, reducing the risk of transformation to myelofibrosis, and control of modifiable risk factors.15
The current standard of care for low-risk PV is phlebotomy combined with once-daily or twice-daily low-dose (81 mg) aspirin therapy to maintain a target hematocrit below 45%. There is currently a lack of clinical data to categorically address a potential correlation between phlebotomy frequency and the risk of thrombosis. Available data are inconclusive; an increased risk of thrombosis with more frequent phlebotomy, reported in one study, was not confirmed in another.17,18 Cytoreductive therapy is recommended for high-risk patients to directly reduce counts of red cells, white cells, and platelets. Observational studies suggest the benefit of systemic anticoagulation, aspirin therapy, and cytoreduction in preventing venous thrombosis, cerebral events, and coronary events, respectively.19 The current treatment options include hydroxyurea, pegylated interferon alfa-2a, busulfan (also used in combination with pegylated interferon alfa-2a), and ruxolitinib.20-23
In general, the first-line treatment of choice for cytoreductive therapy for PV is hydroxyurea in conjunction with therapeutic phlebotomy to maintain a goal hematocrit of < 45% based on the CYTO-PV study, which demonstrated a reduced rate of cardiovascular events as compared to less-stringent hematocrit control (45%-50%).21 Pegylated interferon alfa-2a and busulfan are second-line and third-line treatment options, respectively, and may also be considered for patients who cannot tolerate hydroxyurea.4 Ruxolitinib, a JAK1/JAK2 inhibitor, is approved as second-line therapy for patients with PV resistant to or intolerant of hydroxyurea complicated by severe and protracted pruritus or marked splenomegaly that is not responding to treatment.4,21 “The RESPONSE trial that led to the approval of ruxolitinib was designed to prove its superiority to hydroxyurea in controlling hematocrit and achieving phlebotomy freedom as well as inducing spleen volume reduction,” said John Mascarenhas, MD, associate professor of medicine at the Icahn School of Medicine at Mount Sinai, New York. “Although there were numerically fewer thrombotic events in the ruxolitinib arm, the study was not powered to prove superiority in thrombotic risk reduction,” he said.
PV is not a monolithic disease, and as such, response to treatment may vary. Consequently, risk stratification is essential, including stratifying patients according to sex as sex differences exist in PV.24 “Risk stratification is absolutely key to treatment decision-making,” said Prithviraj Bose, MD, associate professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center, in Houston. “Pegylated interferon alfa is a reasonable first-line alternative to hydroxyurea and may be preferred in very young patients. It is definitely the cytoreductive drug of choice in pregnancy. Low-risk patients may need cytoreductive therapy under certain circumstances,” he said. In special populations such as young patients and pregnant women with PV, there are concerns over the long-term risk of cancer with hydroxyurea, which is a category D drug in pregnancy with evidence of risk to the fetus. Ruxolitinib is contradicted in pregnancy. In these special populations, pegylated interferon alfa-2a is a reasonable safer PV treatment option.22 In general, irrespective of the patient population, chlorambucil, radiophosphorus, or pipobroman should be avoided for PV treatment as they have been shown to accelerate clonal degeneration into acute myeloid leukemia or myelofibrosis.25,26
Evidence-based treatment strategies are recommended to maximize life expectancy. A schematic illustration of the treatment algorithm for PV is shown in the Figure. The NCCN Clinical Practice Guidelines in Oncology for myeloproliferative neoplasms provide a more comprehensive treatment algorithm for low-risk and high-risk PV.7
Figure. Current treatment algorithm in PV.14 From the American Journal of Hematology. 2018;94(1):133-143.
Symptoms experienced by patients while on treatment can be tracked over time using the Myeloproliferative Neoplasm Symptom Assessment Form. The shortened version is a 10-question survey that provides a useful tool to identify new or worsening trends in PV-related symptoms.27
On the Horizon: The Promise of Novel Therapies
Despite the efficacy of the current cytoreductive treatment options in controlling hematocrit, they do not induce morphologic or cytogenetic remission or alter the disease’s natural course. There remains an unmet need for therapy with antitumor activity in addition to symptomatic relief. Furthermore, the adverse effects associated with some of the current treatments can limit their use. Several new therapies are being investigated with novel mechanisms of action, as summarized in the Table.
Table. Emerging Treatment Options
Novel agent Mechanism of Aaction Clinical Phase Ropeginterferon28 Long-acting pegylated-IFN alpha-2b 3, FDA BLA accepted June 2020 Givinostat29 Histone deacetylase inhibitor 3 Idasanutlin30 MDM2 inhibitor 2 KRT-23231 MDM2 inhibitor 2 PTG-30032 Hepcidin mimetic 2
HDM2 = Human double minute 2
Ropeginterferon alfa-2b is an investigational, long-acting pegylated-IFNα-2b administered every 2 weeks and over time administered less frequently. “Ropeginterferon alfa-2b is already approved in Europe and submitted for regulatory approval in the United States,” said Dr Gerds. “Studies found that ropeginterferon alfa-2b is better than hydroxyurea and with long-term improvements.” PROUD-PV, and its extension study CONTINUATION-PV, were multicenter, open-label, active-controlled, phase 3 trials involving 307 patients with PV that compared ropeginterferon alfa-2b with hydroxyurea. The investigators found high and durable hematologic and molecular responses with good tolerability. The research suggests that ropeginterferon alfa-2b can be considered first-line cytoreductive therapy instead of hydroxyurea and may be an attractive option for many patients given the favorable dosing schedule and promising long-term efficacy and safety data.20,33
“The use of MDM2 inhibitors is a very exciting way to target the TP53 pathway and selectively induce death in the PB stem and progenitor cell population. The first study to explore this approach in PV was published last year in Blood,”34 said Dr Mascarenhas. “Idasanutlin, either alone or in combination, was effective in normalizing counts and improving PV-related symptoms and reducing the JAK2-mutant allele burden and even normalizing bone marrow cellularity and fibrosis.”
As the options expand with the approval of novel therapies, the treatment strategy for PV is likely to transition from primarily nontargeted cytoreductive to disease mechanism-based targeted therapy with the potential to alter the disease course. Although interferons can induce remission, not all patients respond, and side effects are frequently limiting. Combination therapy with ruxolitinib and pegylated interferon alfa-2a is being explored to control PV symptoms and prevent the development of JAK2 V617F mutation, potentially offering an opportunity for precision medicine. The phase 2 COMBI clinical trial is currently evaluating the safety of ruxolitinib combined with pegylated interferon alfa-2a in 50 patients, 46 of whom were intolerant of or refractory to pegylated interferon monotherapy.22 Current data show significant decreases in spleen size and JAK2 V617F allele burden and improvement in hematologic parameters, suggesting that combination therapy may be an effective treatment option with acceptable toxicity.22
PV is a rare hematologic disorder seen primarily in adults older than age 60 years, and thrombosis is a primary contributor to morbidity and mortality in this population. Serious clinical complications of PV include arterial and venous thrombosis, transient ischemic attacks, and, in some patients, transformation to bone marrow failure, myelofibrosis, and acute leukemia, leading to reduced life expectancy and poor quality of life. Risk-adapted therapy is the current management strategy; for low-risk PV, phlebotomy combined with once-daily or twice-daily low-dose aspirin is advised to maintain a target hematocrit below 45%. Cytoreductive therapy is recommended for patients with high-risk PV to directly reduce counts of red cells, white cells, and platelets. The current cytoreductive treatment options include hydroxyurea, pegylated interferon alfa-2a, busulfan (also used in combination with pegylated interferon alfa-2a), and ruxolitinib. New treatment options are in development to address the current unmet needs in PV, including ropeginterferon and givinostat, both in phase 3 clinical development. The potential for combination therapy with ruxolitinib and pegylated interferon alfa-2a is also being explored.
- Leukemia and Lymphoma Society. Polycythemia vera facts. April, 2015. https://www.lls.org/sites/default/files/file_assets/FS13_PolycythemiaVera_FactSheet_final5.1.15.pdf. Accessed November 12, 2020.
- Spivak JL. Myeloproliferative neoplasms. N Engl J Med. 2017;376(22):2168-2181. doi:10.1056/NEJMra1406186
- Spivak JL. How I treat polycythemia vera. Blood. 2019;134(4):341-352. doi:10.1182/blood.2018834044
- Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599-1613. doi:10.1002/ajh.26008
- Cerquozzi S, Tefferi A. Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors. Blood Cancer J. 2015;5(11):e366. doi:10.1038/bcj.2015.95
- Choi CW, Bang SM, Jang S, et al. Guidelines for the management of myeloproliferative neoplasms. Korean J Intern Med. 2015;30(6):771-788. doi:10.3904/kjim.2015.30.6.771
- Gerds AT, Dao KH. Polycythemia vera management and challenges in the community health setting. Oncology. 2017;92(4):179-189. doi:10.1159/000454953
- NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms. V2.2018. September 7, 2017. https://www2.tri-kobe.org/nccn/guideline/hematologic/english/mpn.pdf. Accessed November 12, 2020.
- Barbui T, Barosi G, Birgegard G, et al. European LeukemiaNet. 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
- Falanga A, Marchetti M. Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2012;2012:571-581. doi:10.1182/asheducation-2012.1.571
- Spivak J. Cancer Therapy Advisor. Hematology: polycythemia vera. https://www.cancertherapyadvisor.com/home/decision-support-in-medicine/hematology/polycythemia-vera/#:~:text=Importantly%2C%20conditions%20that%20promote%20plasma,steroids%20can%20mimic%20absolute%20erythrocytosis. Accessed November 12, 2020.
- Spivak JL. Polycythemia vera. Hematology. 2013;18(4):244-245. doi:10.1179/1024533213Z.000000000199
- Spivak JL. Polycythemia vera. Curr Treat Options Oncol. 2018;19(2):12. doi:10.1007/s11864-018-0529-x
- Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol. 2019;94(1):133-143. doi:10.1002/ajh.25303
- Bose P, Verstovsek S. Updates in the management of polycythemia vera and essential thrombocythemia. Ther Adv Hematol. 2019;10:2040620719870052. doi:10.1177/2040620719870052
- Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405. doi:10.1182/blood-2016-03-643544
- Barbui T, Carobbio A, Ghirardi A, Masciulli A, Rambaldi A, Vannucchi AM. No correlation of intensity of phlebotomy regimen with risk of thrombosis in polycythemia vera: evidence from European Collaboration on Low-Dose Aspirin in Polycythemia Vera and Cytoreductive Therapy in Polycythemia Vera clinical trials. Haematologica. 2017;102(6):e219-e221. doi:10.3324/haematol.2017.165126
- Alvarez-Larrán A, Pérez-Encinas M, Ferrer-Marín F, et al. Risk of thrombosis according to need of phlebotomies in patients with polycythemia vera treated with hydroxyurea. Haematologica. 2017;102(1):103-109. doi:10.3324/haematol.2016.152769
- Tefferi A, Vannucchi AM, Barbui T. Polycythemia vera treatment algorithm 2018. Blood Cancer J. 2018;8(1):3. doi:10.1038/s41408-017-0042-7
- Tremblay D, Mascarenhas J. Novel therapies in polycythemia vera. Curr Hematol Malig Rep. 2020;15(2):133-140. doi:10.1007/s11899-020-00564-7
- JAKAFI (ruxolitinib). Prescribing Information. Incyte; 2020. Accessed November 12, 2020. https://www.jakafi.com/pdf/prescribing-information.pdf.
- How J, Hobbs G. Use of interferon alfa in the treatment of myeloproliferative neoplasms: perspectives and review of the literature. Cancers (Basel). 2020;12(7):1954. doi:10.3390/cancers12071954
- IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 100A. International Agency for Research on Cancer; 2012. https://www.ncbi.nlm.nih.gov/books/NBK304325/. Accessed November 12, 2020.
- Spivak JL. Polycythaemia vera, ruxolitinib, and hydroxyurea: where do we go now? Lancet Haematol. 2020;7(3):e184-e185. doi:10.1016/S2352-3026(19)30262-5
- Kiladjian JJ, Chevret S, Dosquet C, Chomienne C, Rain JD. Treatment of polycythemia vera with hydroxyurea and pipobroman: final results of a randomized trial initiated in 1980. J Clin Oncol. 2011;29(29):3907-3913. doi:10.1200/JCO.2011.36.0792
- Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med. 1981;304(8):441-447. doi:10.1056/NEJM198102193040801
- Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. J Clin Oncol. 2012;30(33):4098-4103. doi:10.1200/JCO.2012.42.3863
- Broderick JM. FDA Accepts Application for Ropeginterferon Alfa-2b for Polycythemia Vera. Published online June 4, 2020. https://www.onclive.com/view/fda-accepts-application-for-ropeginterferon-alfa2b-for-polythycemia-vera. Accessed November 12, 2020.
- Chifotides HT, Bose P, Verstovsek S. Givinostat: an emerging treatment for polycythemia vera. Expert Opin Investig Drugs. 2020;29(6):525-536. doi:10.1080/13543784.2020.1761323
- ClinicalTrials.gov. A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of Idasanutlin Monotherapy in Participants With Hydroxyurea-Resistant/Intolerant Polycythemia Vera. NCT03287245. https://clinicaltrials.gov/ct2/show/NCT03287245. Accessed November 12, 2020.
- ClinicalTrials.gov. KRT-232 Compared to Ruxolitinib in Patients With Phlebotomy-Dependent Polycythemia Vera. NCT03669965. https://clinicaltrials.gov/ct2/show/NCT03669965. Accessed November 12, 2020.
- ClinicalTrials.gov. Hepcidin Mimetic in Patients With Polycythemia Vera. NCT04057040. https://clinicaltrials.gov/ct2/show/NCT04057040. Accessed November 12, 2020.
- 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. Lancet Haematol. 2020;7(3):e196-e208. doi:10.1016/S2352-3026(19)30236-4
- Mascarenhas J, Lu M, Kosiorek H, et al. Oral idasanutlin in patients with polycythemia vera. Blood. 2019;134(6):525-533. doi:10.1182/blood.2018893545