The Evolving Landscape of Polycythemia Vera Treatment

Polycythemia vera (PV) is a rare and chronic blood cancer that is classified as a myeloproliferative neoplasm (MPN). The 3 classical Philadelphia chromosome-negative MPNs, consisting of PV, essential thrombocythemia (ET) and myelofibrosis (MF) originate in the hematopoietic stem cells of the bone marrow and are characterized by increased proliferation of the myeloid lineages owing to an overactive JAK-STAT pathway.¹

Bone marrow study of a myeloproliferative disorder. Image Credit: © MdBabul - stock.adobe.com

MPNs were once considered disorders rather than cancers and were largely ignored.⁹ This identification changed in 2008 once it was understood that these diseases involve all types of myeloid cells and are clonally driven by specific driver mutations.^1,2 The recognition of MPNs as blood cancers in 2008 brought long-overdue attention and research investment.² PV is the most common MPN and the only MPN in which erythrocytosis occurs.³

Acquired somatic gain of function mutations of JAK2, primarily JAK2V617F and less commonly exon 12, are present in virtually all patients with. These mutations lead to an overactive JAK-STAT signaling pathway, which is responsible for transmitting signals from growth factors, cytokines and other ligands outside of a stem cell to its nucleus. This leads to excessive erythropoiesis and a subsequent increase in red blood cell (RBC) mass, which may lead to clinically significant thrombotic and hemorrhagic complications. Because pluripotent stem cells are involved, PV is considered to be a tri-lineage disease and can overproduce white blood cells and platelets as well.

PV is estimated to affect 44 to 57 per 100,000 people, equating to an estimated 150,000 to 190,000 patients in the US.⁴ PV is usually diagnosed between 50 and 70 years of age and is more common in men than women. The median survival for patients with PV is approximately 14 years, with those diagnosed at an earlier age more likely to survive longer.⁵ These patients have a 1.6-fold higher mortality.⁶ Despite its later diagnosis and indolent course, PV is still expected to shorten survival by approximately 5 to 10 years.

PV symptoms are often non-specific but can greatly impact qualify of life (QOL). Fatigue is often reported by patients as the most prevalent and severe symptom, with 84% of patients reporting fatigue in the international MPN Landmark survey.⁷ In addition, of patients with PV with high symptom burden, 94% had reduced QOL and 48.3% had decreased work productivity.⁷ Other symptoms include drenching sweats, weight loss, abdominal discomfort, bone pain, sexual dysfunction, headache, shortness of breath, blurry/double vision, eye pain, dizziness, brain fog, lack of concentration, and aquagenic pruritis. Many of these symptoms (ie, fatigue and pruritis) are thought to be caused by pro-inflammatory cytokines from the JAK-STAT pathway.⁸ Clinical signs may include hypertension and splenomegaly.

It is important to note that patients with PV may not always exhibit obvious signs of illness but often feel “sick” as these non-specific symptoms compound and impact QOL. This may make their experience difficult to understand for others.

The complications of PV can be serious and lead to significant morbidity and mortality. The increased blood viscosity caused by erythrocytosis, qualitative abnormalities of RBCs, and leukocytosis has been associated with an increased risk of thromboses and other microcirculatory abnormalities.⁹ Thromboses can be either venous or arterial and may occur in any area of the body. The incidence range of arterial and venous thrombosis is 12% to 39% in PV.¹⁰ Arterial thrombosis, including acute myocardial infarction, cerebrovascular ischemic episodes, and peripheral arterial occlusion, represent 60% to 70% of all cardiovascular events in PV.¹¹ Deep vein thrombosis and pulmonary embolism may also occur in these patients. Additionally, patients with PV show a high prevalence of rare forms of thrombosis, such as abdominal vein thrombosis, including extrahepatic portal vein occlusion, Budd-Chiari syndrome, and mesenteric vein thrombosis.¹² These events tend to occur most frequently shortly before or after diagnosis and decrease over time, likely due to PV treatment. Cardiovascular mortality accounts for 41% of deaths (1.5 death events per 100 persons per year), with an incidence of non-fatal thrombosis of 3.8 events per 100 patient-years.¹³

Another serious complication of PV is the risk of progression to MF or transformation to acute myeloid leukemia (AML). Approximately 20% of patients with PV progress to MF or an aggressive form of AML known as MPN blast phase (MPN-BP).¹⁴

Elevated hematocrit (HCT) is a hallmark of PV, indicating overproduction of RBCs and high blood viscosity. Other lab abnormalities include increased hemoglobin (HGB), abnormal red cell morphology (mean corpuscular volume, mean corpuscular hemoglobin), increased lactate dehydrogenase, decreased erythropoietin, and iron deficiency.

The 2016 World Health Organization diagnostic criteria for PV requires the presence of either all 3 major criteria or the first 2 major criteria and the minor criterion.¹⁵ The major WHO criteria are:

1. HGB >16.5 g/dL in men and >16 g/dL in women, or HCT >49% in men and >48% in women, or red cell mass >25% above mean normal predicted value.
2. Bone marrow biopsy showing hypercellularity for age with trilineage growth, and
3. Presence of a JAK2 V617F or exon 12 mutation.¹⁵

The minor criterion is a subnormal erythropoietin level.¹⁵A workup for PV typically includes a bone marrow biopsy to detect the JAK2 mutation and look for the presence of fibrosis, which may indicate progression to MF.

Risk stratification per National Comprehensive Cancer Network (NCCN) classifies patients with PV under 60 years of age and no history of thrombosis as low risk and those over 60 years of age and/or with a prior history of thrombosis as high risk.¹⁶ The main goals of treatment are to reduce the risk of thrombosis, which is the most common cause of mortality, prevent transformation to MF or MPN-BP, and to treat symptoms.¹⁴ At this time, no drug therapy has been shown to prolong life or prevent transformation to MF or AML.¹⁷

The mainstays of PV treatment are low-dose aspirin and therapeutic phlebotomy (bloodletting) to mitigate thrombotic risk. The purpose of phlebotomy is to reduce the red cell mass and subsequent hyperviscosity, which can directly lead to thrombosis.¹² Current guidelines recommend that patients with PV maintain a target HCT under 45%.¹⁶ This cutoff is based on the 2013 CYTO-PV study, which randomized 365 patients with PV treated with phlebotomy and/or hydroxyurea to either a HCT target of less than 45% or 45% to 50%.¹⁸ After a median follow-up of 31 months, death from cardiovascular causes or major thrombotic events was recorded in 3% of patients (5 of 182 patients) with a HCT level of less than 45% compared to 10% (18 of 183 patients) of patients with a HCT level of 45% to 50% (P = .007).¹⁸ Some physicians use a HCT target of 42% in women or in those with symptoms.

An argument can be made that because men have higher testosterone levels, which boost RBC production, and a higher normal red cell mass than women, women should have lower HCT targets. While there is no data to support this practice, HCT targets can be individualized for those who may feel better at lower HCTs.

Phlebotomy is not a benign intervention as it can exacerbate disease-related iron-deficiency. Recurrent phlebotomy may lead to or worsened iron-associated symptoms, such as fatigue, lack of concentration, shortness of breath, depression, paresthesia, and restless legs syndrome.¹⁹ It also results in volume shifts which can lead to hypotension, lightheadedness and dizziness. Phlebotomies are also time-consuming and resource-intensive, and access may be difficult for patients living in more rural areas.²⁰

The treatment of PV is driven by the patient’s risk stratification. Low-risk patients are managed with phlebotomy and low-dose aspirin. Cytoreductive therapy may be added in the case of frequent phlebotomies, phlebotomy intolerance, disease-related symptoms, progressive thrombocytosis and/or leukocytosis, or splenomegaly.¹⁶ Cytoreductive agents used in PV include hydroxyurea (HU), pegylated interferon-alpha (INF-α) and ruxolitinib.

HU was first used as an antineoplastic in the 1960s and, despite not being FDA-approved for PV, it is the most commonly used cytoreductive agent. It has the dual advantages of being oral and inexpensive. Important adverse effects (AEs) that are often dose-related and may lead to discontinuation include leg ulcers and other mucocutaneous manifestations such as mouth sores, gastrointestinal symptoms, pneumonitis, and fever.²¹ There is a risk of HU-induced secondary malignancies, particularly non-melanoma skin cancers, and approximately 25% of patients with PV become intolerant or resistant to HU.²¹

Two INF-α products are used to treat PV: peginterferon alfa-2a (Pegasys; pharma& GmbH) and ropeginterferon alfa-2b (Besremi; PharmaEssentia Corporation). Peginterferon alfa-2a is not FDA-approved for PV but has been used off-label for many years. Ropeginterferon alfa-2b is a longer-acting formulation that requires less frequent dosing than peginterferon alfa-2a. Both are administered as subcutaneous injections and typically take several months to reach full therapeutic effect.

A recent update to the NCCN Guidelines for PV recommends ropeginterferon alfa-2b as a preferred cytoreductive therapy, while HU and peginterferon alfa-2a are recommended as alternatives.¹⁶ The AE profile of INF-α is extensive and includes a black box warning for neuropsychiatric, autoimmune, ischemic and infectious disorders.^22,23 Other AEs include injection site reactions, flu-like symptoms, headache, fatigue, nausea, diarrhea, musculoskeletal pain, dizziness, arthralgias, and cytopenias.^22,23

Ruxolitinib (Jakafi; Incyte Corporation) is a JAK1/2 inhibitor that is approved for use in patients with PV who are intolerant to or refractory to HU. This drug may especially be useful in those with symptoms of pruritis and splenomegaly.¹⁷ The phase 2 MAJIC-PV (ISRCTN61925716) study demonstrated that ruxolitinib had a superior complete response within 1 year compared to best available treatment (BAT) in patients who were resistant to or intolerant of HU: 40 (43%) patients on ruxolitinib vs 23 (26%) on BAT (OR 2.12; 90% CI 1.25-3.60, P=0.02).²⁴ Ruxolitinib is associated with cytopenias, particularly anemia and thrombocytopenia. Its immunosuppressive effects and propensity for weight gain can make it difficult to tolerate for many patients.

There are new developments on the horizon for PV that have the potential to alleviate phlebotomy burden, consistently maintain HCT under 45% and improve patient QOL. Rusfertide, a hepcidin mimetic, is the furthest along in development. Rusfertide binds an iron exporter on key cells involved in iron metabolism called ferroportin, reducing iron availability in the bone marrow that is needed for erythropoiesis. The ongoing phase 3 VERIFY study achieved its primary end point, showing a significantly higher proportion of clinical responders—defined as patients no longer meeting phlebotomy eligibility—among those treated with rusfertide for PV (77%) compared to those who received placebo (33%) during weeks 20 to 32 (P<0.0001).²⁵

Givinostat (Duvyzat; Italfarmaco SpA) is a histone deacetylase inhibitor specific for JAK2 V617F-mutated cells. The phase 3 GIV-IN PV trial investigating givinostat is currently in progress.

There are several other molecules currently in phase 2 development. Sapablursen (ISIS 702843; Ono Pharmaceutical) is a ligand-conjugated antisense molecule that targets the TMPRSS6 gene to modulate hepcidin production and subsequent regulation of iron metabolism.²⁰ Bomedemstat inhibits LDS1, an enzyme involved in increasing cell proliferation and hematopoietic differentiation.²⁰ Divesiran is a double-stranded small interfering RNA targeting TMPRSS6 mRNA.²⁰ Lastly, the combination of 2 frequently used cytoreductive therapies, ruxolitinib and ropeginterferon alfa-2b, are being studied in a phase 2 trial in HU-resistant patients with PV; results are expected in 2028.²⁰

Pharmacists are in a unique position to improve the care of patients with PV. They can ensure that patients are treated to guideline recommendations, ie, that all patients with PV are on low-dose aspirin and high-risk patients additionally receive cytoreductive therapy, if not contraindicated. Pharmacists can intervene in cases where HCT is not maintained at less than 45% and recommend the addition of therapy or dose adjustments as needed to achieve this goal. As many new PV diagnoses are missed, pharmacists can also help identify cases of untreated erythrocytosis for further workup. Lastly, pharmacists may serve a role in educating patients and providers on the importance of recognizing and managing PV symptoms, as well as managing HCT levels to mitigate thrombotic risk.

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