Sustained erythrocytosis (hematocrit > 49% in men and > 48% in women) in the presence of JAK2 V617F or JAK2 exon 12 mutations is the hallmark sign of polycythemia vera.1 Evidence of trilineage proliferation in the bone marrow in patients with polycythemia vera, pointing to the systemic nature of the disease, was moved from a minor to a major diagnostic criteria in the 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia2; this was maintained in the 2022 publication of the International Consensus Classification of Myeloid Neoplasms and Acute Leukemia diagnostic criteria (Figure 1).1 Ruben Mesa, MD, Executive Director of Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center, in San Antonio, Texas, explained, “In the bone marrow, polycythemia vera leads to the overproduction of red blood cells, white blood cells, and platelets, all of which can play a role in thromboembolic events as well as hemorrhagic events.” For patients with polycythemia vera, the goals of care include reducing the risk of thrombotic or hemorrhagic complications and improving the patients’ symptoms that impact their quality of life.3
As demonstrated in the MPN Landmark survey, most patients with polycythemia vera (88%) are symptomatic at diagnosis, and two-thirds of patients report that these symptoms reduce their quality of life.4 Thrombosis is a driver of impaired quality of life and decreased overall survival in patients with polycythemia vera.5 In an analysis of 50,405 Medicare beneficiaries diagnosed with high-risk polycythemia vera, 28% of patients experienced a thrombotic event, most commonly ischemic stroke.6 Patients with polycythemia vera who experienced a thrombotic event within 1 year had a shorter median overall survival (5.1 years vs not reached; adjusted hazard ratio [aHR] = 18.6; 95% confidence interval [CI] = 16.1–21.6; P < .001).6 Thrombotic events comprise a significant proportion of mortality in polycythemia vera; thus, treatment of polycythemia vera is focused on minimizing the risk for thrombosis.
The mutation-enhanced international prognostic system for polycythemia vera (MIPSS-PV)7 is included in the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for myeloproliferative neoplasms as a predictor of overall survival for patients with polycythemia vera.3 The MIPSS-PV score is based on thrombosis history (1 point), leukocyte count greater than or equal to 15 × 109/L (1 point), age greater than 67 years (2 points), and presence of the adverse genetic mutation SRSF2 (3 points).7 Patients with high-risk polycythemia vera (> 4 points) have a median overall survival of 3.2 years compared with a median overall survival of 24 years in patients with low-risk (0–1 points) MIPSS-PV score (hazard ratio [HR] = 76.9; 95% CI = 36–162.8). Although the MIPSS-PV is predictive of overall survival in polycythemia vera, it is not used to guide therapy decisions; rather, it is the risk of thrombosis that is used to guide treatment in polycythemia vera, with patients 60 years of age or older and/or a history of thrombosis considered high-risk.
Low-dose aspirin, management of cardiovascular risk factors, and maintenance of hematocrit less than 45% are recommended for all patients with polycythemia vera.3,8 The NCCN and European LeukemiaNet (ELN) guidelines recommend that patients with polycythemia vera age 60 years or older and/or with a history of thrombosis should start cytoreductive drug therapy with hydroxyurea, peginterferon alfa-2a, or ropeginterferon alfa-2b-njft.8 Patients younger than 60 years of age, who have not had a previous thrombotic event, should begin cytoreductive therapy only if they fulfill criteria outlined in Figure 2.5
Dr. Mesa provided context, noting, “Our prior management of polycythemia vera in the era of hydroxyurea was very conservative, based on concerns regarding the safety of hydroxyurea. We focused on the reasons not to use hydroxyurea, and that's where the whole issue of age over 60 and prior vascular events arose as a discriminating factor. I think this led many patients to be symptomatic and to not feel well on phlebotomy and aspirin. Going forward, I think the inclusion of more patients under medical therapy will be appropriate, and the number of individuals we manage with phlebotomy and aspirin alone will continue to become a smaller and smaller minority.”
Going forward, I think….the number of individuals [with polycythemia vera whom] we manage with phlebotomy and aspirin alone will continue to become a smaller and smaller minority. Ruben Mesa, MD
The ELN and NCCN guidelines recommend maintaining a hematocrit less than 45% in patients with polycythemia vera.3,5 The randomized CYTO-PV study established a goal hematocrit level below 45% as standard of care after finding a 3.9-fold higher rate of vascular events and death in patients with a hematocrit of 45% to 50%, compared to those with a hematocrit of less than 45%.9 Recent publication of the REVEAL study confirmed this finding in 2,510 patients diagnosed with polycythemia vera and managed in community or academic practices in the United States.10,11 An increased thrombotic risk was noted in a subgroup of 2,271 patients with a hematocrit above 45% (HR = 1.84; 95% CI = 1.234–2.749; P = .0028), a white blood cell (WBC) count of less than 11 × 109/L (HR = 2.35; 95% CI = 1.598–3.465; P < .0001), and platelet count greater than or equal to 400 × 109/L (HR = 1.60; 95% CI = 1.088–2.359; P = .0170).10
Prithviraj Bose, MD, Associate Professor, Department of Leukemia, Division of Cancer Medicine of The University of Texas MD Anderson Cancer Center in Houston, Texas explained that some patient symptoms correlate with hematocrit levels, so much so that “patients will call and say ‘I need a phlebotomy’” based on their symptoms alone. In the MPN Landmark survey, two-thirds of patients with polycythemia vera reported stress and/or anxiety related to managing their hematocrit to a goal of less than 45%.4 While phlebotomy is central to the management of polycythemia vera, fluctuations in hematocrit are observed in patients managed with a phlebotomy-only strategy. Both Dr. Bose and Dr. Mesa agreed that a major limitation of phlebotomy is the inconsistent control of the hematocrit. Approximately 30% to 50% of patients managed with a phlebotomy-only strategy maintain a therapeutic hematocrit value.5,11,12 Dr. Mesa asserted, “Medical therapy provides a much more even control that probably leads to better and more even control of symptoms, and undoubtably also has a greater net benefit in terms of risk of vascular events.”
Medical therapy provides a much more even [hematocrit] control that probably leads to better… control of symptoms, and undoubtably also has a greater net benefit in terms of risk of vascular events. Ruben Mesa, MD
Dr. Bose explained, “In general, patients do tolerate phlebotomy; however, there could be situations where it's just too frequent because the disease is too proliferative.” He cited an observational study from the Spanish Registry of Polycythemia Vera that found that receipt of three or more phlebotomies per year in patients with polycythemia vera concurrently receiving hydroxyurea was associated with a significantly higher rate of thrombosis (21% at 3 years compared to 5% at 3 years for those receiving two or fewer phlebotomies per year; P < .0001).13 Data from the ECLAP and CYTO-PV studies did not confirm these findings, and it was postulated that the higher risk of thrombosis might be related to a hematocrit value above goal range, rather than the use of phlebotomies per se.14 Dr. Bose viewed the need for phlebotomy more than three times per year while taking hydroxyurea as a signal to change therapy, “If I'm seeing that happening, then I'm thinking about switching them to ruxolitinib.”
Dr. Mesa noted, “One of the problems with phlebotomy is that it's really just targeting the red cells, not the white cells or the platelets—and certainly not the underlying disease.” Several studies have linked an elevated WBC count with an increased risk of thrombosis. An analysis of the ECLAP observational database found an increased risk of thrombosis (HR = 1.71; 95% CI = 1.10–2.65; P = .017) in patients with a WBC count above 15 × 109/L, compared with those with a WBC count below 10 × 109/L.15 A post hoc, time-dependent, multivariable analysis of the randomized CYTO-PV study found that a WBC count greater than or equal to 11 × 109/L at the last clinical visit was associated with a fourfold increase in risk for a thrombotic event (HR = 3.9; 95% CI = 1.24–12.3; P = .02) relative to a WBC count less than 7 × 109/L.16 Most recently, the REVEAL study linked a WBC count greater than or equal to 11 × 109/L with thrombotic event risk (HR = 2.61; 95% CI = 1.594–4.262; P < .0001) compared with WBC count less than 7 × 109/L.10 Lastly, as originally demonstrated in a large, international study,17 publication of the MIPSS-PV confirms leukocytosis of greater than or equal to 15 × 109/L is an independent predictor of overall survival in polycythemia vera (HR = 2.8; 95% CI = 1.8–4.2).7 According to Dr. Bose, “elevated WBC count is associated with increased leukemic transformation, worse survival, as well as thrombotic risk. While there aren’t clear data that reducing the white count will change those outcomes, I think it's just a logical thing to do.”
Elevated WBC count is associated with increased leukemic transformation, worse survival, as well as thrombotic risk. Prithviraj Bose, MD
Dr. Bose explained, “We know that inflammation and thrombosis are inextricably linked. What is really interesting is something called neutrophil extracellular trap (NET) formation. These NETs have a role to play in the pathophysiology of thrombosis.” Normal neutrophils expel extracellular strands of decondensed DNA coupled with histones and other neutrophil granular proteins termed NETs.18 Neutrophils from patients with myeloproliferative neoplasms (MPNs) have increased NET formation relative to patients with myelodysplastic syndromes or age-matched controls.18 Increased NET formation in response to neutrophil stimulation is associated with JAK2 V617F expression in patients with MPNs and in Jak2 V617F mouse models.18 A NET-rich, prothrombotic phenotype has been demonstrated in Jak2 V617F–driven MPN.18 In addition, ruxolitinib reduced NET formation in a murine model and was associated with reduced thrombosis.18 Together, these data support NET formation linked to JAK2 V617F expression as a driver of thrombosis in MPN. Dr. Bose added, “Generally speaking, we regard the hematocrit and the white cells as being much more important to the risk of thrombosis than elevated platelets.”
The NCCN and ELN guidelines both recommend managing cardiovascular risk factors, aspirin at 81–100 mg/day, and targeting a hematocrit of less than 45% for all patients with polycythemia vera.3,5,8 Patients age 60 years or older and/or those with a history of thrombosis should also receive cytoreductive therapy. Translated to clinical practice, Dr. Mesa explained, “Our goals in polycythemia vera are 1) to keep the hematocrit under 45%; 2) if we're using cytoreduction to have a white [blood] cell count under 10 × 109/L and a platelet count of under 400 × 109/L; and 3) improvement in splenomegaly or symptoms if they are present.” A phlebotomy-only strategy may not provide optimal care, even for low-risk patients with polycythemia vera, due to fluctuations in hematocrit and associated symptoms. Managing patients to a target hematocrit under 45% is associated with a reduced risk of thrombosis and while prospective data hasn’t proven the same for targeting a specific WBC count, experts do view this as an important data point to factor in decision-making for patients with polycythemia vera.
Dr. Mesa has served in a consulting or advisory role for Novartis, Sienna Oncology, La Jolla Pharma, and Constellation Pharmaceuticals; and has received research funding from Incyte, Genentech, CTI, Promedior, Celgene, AbbVie, Samus, Constellation Pharmaceuticals, Mays Cancer Center, and P30 Cancer Center Support Grant.
Dr. Bose has received honoraria from Incyte, CTI Biopharma Corp, Blueprint Medicines, Bristol Myers Squibb, Novartis, Karyopharm Therapeutics, Pharma Essentia, AbbVie, and MorphoSys; has served in a consulting or advisory role for Sierra Oncology; and has received research funding from Celgene, CTI Biopharma Corp, Incyte, Blueprint Medicines, NS Pharma, Promedior, Constellation Pharmaceuticals, Kartos Therapeutic, Cogent Biosciences, Bristol Myers Squibb, Ionis Pharmaceuticals, Astellas, and Pfizer.
