Polycythemia vera was first recognized by French physician Louis H. Vaquez in 1892 and was known then as maladie de Vaquez.1 The name poly-cyt-[h]emia originates from the Greek and Latin, and literally means many-cells-in the blood. In 1951, Dr. William Dameshek included polycythemia vera in the category of classic Philadelphia chromosome–negative myeloproliferative disorders (now classified as myeloproliferative neoplasms, MPNs; myelo refers to the bone marrow, proliferative refers to rapid growth of blood cells, and neoplasm describes abnormal and excessive growth). It is the only one among the 3 classic MPNs that exhibits erythrocytosis, the increased production of red blood cells. Polycythemia vera is a condition associated with overproduction of all blood cells, including white cells and platelets.
Polycythemia vera is a chronic, incurable disease of the hematopoietic stem cells, the primary cells that can develop into different types of blood cells and are responsible for the production of blood cells during a human’s entire life. It is a clonal disease, meaning it occurs when a mutated hematopoietic stem cell starts making clones—cells with the same genetic mutation. Most affected patients can live a relatively normal and long life.
A breakthrough discovery of a genetic “driver” of polycythemia vera was made in 2005—a mutation in the JAK2 gene was found in 95% of cases, typically JAK2V617F, a mutation that leads to the constitutive activation of the JAK-STAT protein pathway causing unregulated overproduction of hematopoietic cells. This discovery led to improved understanding of the biology, pathogenesis, and long-term behavior of the disease and initiated numerous efforts to develop novel therapies focused on the inhibition of the JAK-STAT pathway.
The abnormal function of the immune system and the subsequent increased inflammation, powerfully driven by the JAK-STAT pathway as the major regulator of inflammatory signaling, contribute to disease progression and an impaired quality of life. Despite the relatively slow progression of the disease course in most patients, the disease possesses its challenges and risks, including a lifetime risk of developing thrombosis (blood clots); the evolution into myelofibrosis, a chronic type of leukemia; or development into acute leukemia. Both blood clots and leukemia are consequences that can shorten life expectancy significantly.
The invention of JAK inhibitors and the approval of ruxolitinib in 2014 as the only JAK inhibitor for refractory patients with polycythemia vera allowed excellent control of the inflammation, symptoms, and overall outcome of the disease; however, it fell short of altering the long-term behavior of the disease. Although such evidence was gradually emerging from the study of interferons (injectable drugs used off-label in this indication since the early 1990s), it wasn’t until November 2021 that the first interferon approved specifically for MPNs, known as ropeginterferon alfa-2b, gained official approval as a promising agent to possibly alter the disease course through disease modification or prevention of the progression to myelofibrosis. Other novel approaches targeting relevant disease pathways are now undergoing various stages of clinical development and hold a promise to further enhance this model.
Notwithstanding the rapid advances in therapeutic development, the identification of all patients needing therapy and the definition of relevant treatment goals remain challenging. Until recently, therapy has most often been considered for patients with a high risk of thrombosis, or for those of low risks with special needs, such as younger age, pregnancy, or physical or intellectual limitations. However, recent emerging evidence of unacceptable rates of adverse vascular outcomes and progression to myelofibrosis in traditionally low-risk patients (those ≤60 years and without thrombosis) make it necessary to rethink current strategy. It is becoming obvious that there are no “no-risk” patients and that almost every patient has some unmet needs. All patients should be offered a chance for the best and longest life possible, free from the disease consequences and even from fear of those consequences. In this article, the reader will gain an understanding of polycythemia vera with a focus on the latest developments and ongoing challenges.
Notwithstanding the rapid advances in therapeutic development, the identification of patients needing therapy and the definition of relevant treatment goals remain challenging.
Polycythemia vera, recognized by its excessive production of blood cells, has an overall incidence in the United States of about 1.55 per 100 person-years, but due to near to normal life expectancy of these patients, cumulative prevalence remains up to 50 patients per 100,000 persons.2,3 As mentioned, despite its relatively slow and chronic development, the disease brings a lifetime risk of higher chances to suffer from blood clots or bleeding. It also comes with frequently debilitating systemic symptoms vastly impacting quality of life, and it might ultimately progress to the next stage of MPNs, myelofibrosis or acute leukemia. Acute thrombotic complications, such as heart attack, stroke, or blood clots affecting the major vasculature of the liver or spleen, overshadow the generally considered low urgency of the disease, often leading to serious consequences in up to one-third of all patients.4 Although the risk of vascular complications increases with age, the risk persists over the disease course, endangering individuals diagnosed at a younger age even more. Similarly, the disease potential to progress to myelofibrosis increases over time, putting younger patients into the worst position as they live with the disease the longest. An average age at diagnosis is between 65 and 75 years; although the group of adolescent and young adult patients diagnosed prior to age 40 years is considerable.5
The most common symptoms seen at presentation are usually associated with excessive red cells in the blood, such as pruritus (itching, especially following hot showers), burning pain in the extremities, changing color of fingers or toes, and constitutional symptoms of fatigue, night sweats, headaches, blurry vision, or early satiety. Occasionally asymptomatic patients might be diagnosed based on abnormal findings of their blood work. The latest official classification of blood disorders included bone marrow evaluation as part of the diagnostic process for polycythemia vera; however, evidence of (1) JAK2 mutation, (2) elevated red cells in blood, and (3) the low-feedback hormone called erythropoietin is sufficient for diagnosis in virtually all cases. The evaluation of bone marrow, where all blood cells originate, helps in the proper assessment of other features, such as fibrosis degree and chromosomal abnormalities, or abnormalities of other cells or structures not typical for polycythemia vera.
For a long time, therapy goals have been directed at reducing thromboembolic risks and alleviating symptoms and spleen enlargement. Although these goals still represent the backbone of the current standard of care, they might just reflect a historical lack of therapies that could affect the natural course of the disease. Indeed, patients’ goals expressed in a landmark MPN study in 2017 clearly showed their desires to delay or slow disease progression more than anything else.6 This option, if achievable, would have already been the most important goal and surrogate marker of success. Hopefully, we have finally entered that era which could represent a major shift in how polycythemia vera is approached.
Without proper management, red cells in the blood remain elevated and lead to increased risk of vascular consequences including arterial and venous blood clots and cardiovascular deaths. Uncontrolled red cell proliferation is associated with a 60% increased risk of any thrombotic complication.7 Therefore, lessening the risk of thrombosis has been the mainstay of disease management, and for this reason, patients are stratified into 2 risk categories, high: age older than 60 years or history of thrombosis; and low: absence of both factors.
All polycythemia vera patients should receive low-dose aspirin and control their red cell volume, measured by a hematocrit test level <45%, a value associated with significantly lowered risk of major cardiovascular/thrombotic events. Therapeutic phlebotomy (removal of blood) served this goal for decades and remains suggested as an adequate approach to those with low risk. However, patients often require frequent therapeutic phlebotomies, which are often burdensome, poorly tolerated, and deepen iron deficiency (a standard condition in polycythemia vera due to the excessive iron incorporation into more “hungry” red cells), further contributing to quality-of-life decline and significant health-related economic issues. These patients require regular blood work monitoring and frequently visit and utilize hospitals or clinics for their phlebotomy needs; still, more than half of them do not attain steady control of hematocrit <45%.8
Ultimately, the low-risk patients bear significantly higher rates of all-cause mortality (death from all reasons) and vascular complications, often suffer with uncontrolled symptoms, and eventually face disease progression; the last 2 issues are not addressed by phlebotomies at all. Patients with high-risk disease require cytoreductive therapy (medications given to reduce blood cell counts) to further lessen their thrombosis risks.9 Low-risk patients might receive cytoreductive therapy in cases of frequent phlebotomies or their intolerance to them, worsening blood counts, uncontrolled symptoms, or spleen growth.
An oral chemotherapeutic agent, hydroxyurea, has been used for initial cytoreductive therapy for years, despite its lack of official approval by the FDA. Although the agent is generally well tolerated and has a yearslong history across various diseases, it is not the best option for symptomatic patients or those with large spleens, and it poses a challenge to young individuals, for example, females who desire to become pregnant (in which case, hydroxyurea is not allowed). It also does not address disease evolution over time and comes with certain specific toxicities that ought to be monitored. An injectable interferon has been used as an alternative option to hydroxyurea. The ability of interferon to control or modulate inflammation and cell growth and the evidence that, in polycythemia vera, it could specifically alter the long-term course of the disease by elimination of JAK2-mutated cells make this agent a preferred choice for certain groups of patients. Over the past 3 decades, more than 600 patients with polycythemia vera were treated with interferon in an off-label setting.10 Experiences suggest that the agent can extend the interval without transformation to myelofibrosis and prolong overall survival.11
The latest interferon form, ropeginterferon alfa-2b, was approved by the FDA in November 2021 after a large phase 3 randomized study confirmed its benefit over hydroxyurea in high-risk polycythemia vera patients.12 Control of blood counts without a need for phlebotomies, improvement of symptoms, and a decline of JAK2 burden from pretreatment were achieved in the majority of patients, who also experienced fewer cardiovascular complications and less progression to myelofibrosis or death (the final disease-modification goal). These results placed ropeginterferon at the top of therapeutic choices for polycythemia vera, including for low-risk patients, for whom subsequent studies confirmed the same observations of disease control. Longer follow-up is required to understand the deeper implications of these findings, but the possibility of altering the course of the disease and preventing its progression is getting real with the use of interferons. The greatest downside is its injectable form and array of worrisome side effects, particularly autoimmune issues, such as thyroid problems or hyperglycemia; or psychiatric effects, including depression, confusion, agitation, and thoughts of suicide. Moreover, as already mentioned, it is not the best drug for symptoms of painful spleen; for that, we have available another therapeutic agent, currently approved for patients only after hydroxyurea failure: the JAK inhibitor, ruxolitinib.13
Patients with high-risk disease require cytoreductive therapy (medications given to reduce blood cell counts) to further lessen their thrombosis risks.
The year 2024 marked a decade since the approval of ruxolitinib in the United States. It has been a life-changer for patients with poor quality of life because it offers excellent control of inflammation and associated symptoms and reduction in spleen size. Like interferon, ruxolitinib prevents vascular events and disease progression. Long-term side effects, particularly nonmelanoma skin cancers, infections, and metabolic abnormalities such as weight gain, need to be closely monitored as the second decade of its standard use begins.
Beyond the aforementioned approved agents, recent years have witnessed expansion of clinical trials for patients with polycythemia vera. Lately, attention has been given to iron metabolism. Patients with polycythemia vera live with iron deficiency caused by the uncontrolled overproduction of red cells with their increased demand for iron and by the use of phlebotomies. A major negative regulator of iron metabolism in the human body is a hormone called hepcidin. In patients with polycythemia vera, hepcidin is suppressed due to the iron deficiency, which leads to enhanced availability of iron for the production of more red blood cells. Hepcidin mimetics, that is, molecules that act like hepcidin, are able to slow down or fully end the need for phlebotomies by restricting the iron availability for red blood cells. One of these molecules, named rusfertide, has already finished enrollment in late- phase clinical trials. Results from earlier investigations revealed that virtually all patients remained free from phlebotomies with excellent control of hematocrit. This type of agent might be a viable alternative or adjunct therapy for any patients needing phlebotomy.
To deliver effective care for every patient, it will be necessary to assess vascular risks promptly…and look for the best control of disease-related symptoms.
In addition, by achieving constant control of hematocrit, it might be possible to relieve symptoms, particularly those stemming from frequent phlebotomies, and to decrease vascular complications. Other recent interest focused on various molecules providing specific disease control, for example, inhibitors of murine double-minute 2, lysine-specific demethylase, or histone deacetylases. While some agents failed clinical development, others entered late-phase clinical trials, results of which might further shape our future therapeutic options.
In recent years, the approach to polycythemia vera has been transformed through the use of innovative, targeted treatments inspired by the discoveries of the fundamentals of the disease. Yet, these considerable advances in therapies continue to be challenged by limitations in addressing the nature of the behavior of the disease or even in recognizing all patients who will face its inescapable consequences.
The persistent risk of complications that are not fully understood through currently existing stratification should prompt the offer of more individualized treatment choices. To deliver effective care for every patient, it will be necessary to assess vascular risks promptly and frequently, recognize nuances of disease progression and therapy failures, and look for the best control of disease-related symptoms.
Despite the overall feeling that the disease-modifying story for polycythemia vera is quickly approaching, many obstacles and unanswered questions remain. With patients having more therapies available, defining their precise roles will be essential. Would their use really result in reduction of thrombotic complications and translate into a lower rate of progression and improved overall outcome? How can the risks and benefits of potentially lifelong therapies be balanced in younger, otherwise low-risk patients? Would it be possible to stop therapy, even intermittently, to offer treatment breaks and minimize the risks while relying on well-established, broadly available and affordable monitoring markers? What higher quality tools are lacking to best identify patients who would benefit from earlier treatments, therapy change, combinational therapies, or time-limited approaches? It is indisputable that identification of appropriate therapy goals and clinically relevant surrogate end points remains vital for success.
The focus should be on patient-centered approaches that can address individuals’ needs, including the remaining difficult ones: the residual risk of thrombosis and lack of sustained disease control; impaired—often by therapy itself—quality of life; commonly ignored nonthrombotic symptoms; and hurdles of treatment discontinuation, treatment limitations, and long-term treatment side effects.
Living with a rare disease is often coupled with stigmas and frustrations. The patient, however, is the finest advocate and not seldomly needs to “teach” the care team about the relevance of problems commonly labeled as not important. Rare is not rare to those who live with it. Communication between the medical teams and patients, as well as across medical professions, support groups, and patient advocates is an integral and essential part of polycythemia vera management, and it demands constant work and improvement. Disease awareness and diagnostic success have improved substantially over the past years, but a lot of work remains. Difficulties accessing care, time and financial burdens, and related stress contribute to the notoriously vicious cycle of chronic diseases, an exact opposite of the well-being wished for patients.
Normalization of blood counts, alleviation of symptoms, and prevention of disease-related complications should remain the cornerstones of polycythemia vera treatment, along with an individualized approach that will offer the best possible disease control for everyone. The time is eagerly awaited when it will be possible to alter the behavior of polycythemia vera.
Lucia Masarova, MD, is an assistant professor and co-leader of myeloproliferative neoplasms in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston.
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