Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian

Evolving Therapeutic Options for Polycythemia Vera: Perspectives of the Canadian Myeloproliferative Neoplasms (MPN) Group

Shireen Sirhan1, Lambert Busque2, Lynda Foltz3, Kuljit Grewal4, Caroline Hamm5, Nicole Laferriere6, Pierre Laneuville7, Brian Leber8, Elena Liew9,Harold J. Olney10, Jaroslav Prchal7, Anna Porwit11, Vikas Gupta12

Institution Affiliations:1Division of Hematology, Jewish General Hospital, Montreal, Quebec; 2Hematopoiesis and Aging Research Unit, Hôpital Maisonneuve-Rosemont, Montreal, Quebec; 3Division of Hematology, St. Paul’s Hospital, University of British Columbia, Vancouver, British Columbia; 4Faculty of Medicine, Memorial University, St. John’s, Newfoundland; 5Western University, Department of Oncology, Windsor site;, Windsor, Ontario6Thunder Bay Regional Health Sciences, Department of Oncology, Lakehead University, Thunder Bay, Ontario;7Department of Oncology, McGill University, Montreal, Quebec; 8Department of Medicine, Hematology and Thromboembolism, McMaster University, Hamilton, Ontario;9Division of Hematology, University of Alberta, Edmonton, Alberta;10Department of Hematology and Transfusional Medicine, Centre Hospitalier de l'Université de Montréal, Montreal, Quebec;11Department of Pathology, University Health Network, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario,12 Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario

Short Title: Treatment Options for PV

Word count:

Abstract:243Main Manuscript:~ 5430References: 90

Tables:4Figures:3

Corresponding author: Vikas Gupta, MD,FRCP, FRCPath;The Elizabeth and Tony Comper MPN Program, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G2M9, Canada; Phone: 416-946-4521; Fax: 416-946-6546; E-mail:

Conflicts of Interest

Vikas Gupta: Received research funding from Incyte and Novartis; received honorarium from Novartis/Incyte; and served on advisory board panel of Novartis.

Pierre Laneuville: Served on advisory board panel and as a speaker for Novartis.

Brian Leber: Received honorarium form Novartis and membership in medical advisory board.

Elena Liew:Received honorarium from Novartis and served on advisory board panel of Novartis.

Anna Porwit: Received honorarium from Novartis and served on advisory board panel of Novartis.

Shireen Sirhan: Received honorarium from Novartis and served on advisory board panel of Novartis.

Other authors declare no relevant conflict of interests.

Abstract

Polycythemia vera (PV) is a clonal stem cell disorder characterized by erythrocytosis and associated with burdensome symptoms, reduced quality of life, risk of thrombohemorrhagic complications, and risk of transformation to myelofibrosis (MF) and acute myeloid leukemia (AML). The discovery of the JAK2V617 mutation marked asignificant milestone in understanding the pathophysiology of the disease and, subsequently,the diagnostic and therapeutic approaches. The current diagnostic criteria for PV are based on hemoglobin leveland presence of the JAK2 V617mutation. The treatment is geared toward prevention of thrombotic events, normalization of blood counts, control of disease-related symptoms, and potentially prolonging survival. Cytoreductive therapy is indicated in patients at increased risk of thrombosis. Hydroxyurea (HU) remains the most commonly used first-line cytoreductive therapyand is superior to phlebotomy in reducing risk of arterial and venous thrombosis. Interferon (IFN) is used either at failure of HU or in selected patients as first-line therapy. The results of pegylated IFN in phase 2 studies appear encouraging,with molecular responses occurring in some patients. Ongoing phase 3 studies of HU vs. pegylated IFN will define the optimal first-line cytoreductive therapy for PV. A recent phase 3 trial has shown the superiority of JAK1/2 inhibitor,ruxolitinib in comparison to best available treatment (BAT) in HU-intolerant or resistant patients. The therapeutic landscape of PV is likely to change in the near future. In this report, we assess the potential impact of the changing landscape of PV management on daily practice.

Key words: Polycythemia vera,JAK2 mutation, hydroxyurea, interferon, ruxolitinib

Introduction

Polycythemia vera (PV) is a clonal stem cell disordercharacterized by overproduction of red blood cells, often accompanied by leukocytosis and/or thrombocytosis.1In 1951, Dameshek speculated that the manifestations of proliferative activity of bone marrow cells was due to an undiscovered myelostimulatory factor,1 which later was discovered to be the JAK2V617Fmutation. Overactivity of JAK signaling caused by the unique V617F mutation within exon 14 (~95% of PV)2 and by different mutations within exon 12 of the JAK2 gene (~4% of PV)3 has been implicated in the pathogenesis of PV. Erythrocytosisisthe most prominent clinical feature of PV and distinguishesit from other myeloproliferative neoplasms (MPNs). Similar to other MPNs, individuals with PV oftenhave splenomegaly and significant burden of disease-related symptoms, including pruritus, night sweats, fatigue, and bone pain. Patients arealso at risk of thrombotic complicationsandtransformation to secondary myelofibrosis also known as post-polycythemia vera myelofibrosis (PPV-MF) or acute myeloid leukemia (AML).

The estimated incidence of PV worldwide is about 0.84 per 100,000,with slightly higher reported rates in Europe than in North America.4,5 Recent data from two large health plans in the United States indicatethe prevalence rates of 44 to 57 cases per 100,000.5However, there is a wide variation in both prevalence and incidence estimates observed across data sources. The median age at presentation is in the sixth decade and approximately 10% of patients are under 40 years, with an equitablegender distribution.6

The clinical presentation of PV usually involvesthe following three common scenarios:1) an incidental discovery of elevated hemoglobin or hematocrit (Hct); 2) diagnosis after athrombotic event;and 3) diagnosisafter investigating disease-related symptoms.7These may be nonspecific complaints, such as headache, weakness, dizziness, and excessive sweating, whichare present in 30% to 50% of PV patients; acute gouty arthritis has been described in 5% to 20%. Symptoms more specific to PV include pruritus,especially after warm baths or showers(aquagenic pruritus; reported by 70% of patients),8and erythromelalgia, or a burning pain in the feet or hands accompanied by erythema (seen in 28% of patients).9

The most commonabnormal findings on physical examination in PV include splenomegaly (present in about 30% to40% of patients), facialplethora (67% of patients), and hepatomegaly (40% of patients). Laboratory findings includean elevated hemoglobin/Hct in most patients, platelet count >450x109/L,and a white blood cell (WBC) count >10.5x109/L in about 50% of patients.6

Diagnostic Approaches

Current diagnosis of PV is based onthe 2008 World Health Organization (WHO)criteria and requires the composite assessment of clinicaland laboratory features, as summarized in Table 1A.10Although the WHO criteria are widely applied in clinical practice, consensus for the optimal diagnostic criteria for PV has not yet been achieved.11Furthermore, the current WHO criteria are undergoing revisionsproposed changes are also outlined in Table 1A.12

The rational for the proposed changes is based on recent observations that some JAK2 V617F-positive PV patients present with hemoglobin levels lower than the current WHO criteria of 185 g/L for men and 165 g/L for women.13,14Compared to other PV patients, masked PV (mPV) patients have increased risk of thrombosis, perhaps resulting from late diagnosis, and inadequate disease control. As mPV patients are missed by current WHO criteria, a retrospective analysis of a large cohort of MPN patients has suggested that lowering the hemoglobin threshold to 165g/L for men and160g/L for women would capturemost of these mPV cases.14

The Canadian MPN group acknowledges the necessity of appropriately diagnosing mPV, but has concerns about potential misuse of these criteria for screening for PV, as large numbers of individuals would be subjected to unnecessary further testing to rule out mPV. To that end, two large Montreal hospitals (Centre Hospitalier de l'Université de Montréal and Maisonneuve-Rosemont Hospital) performed an analysis (unpublished results, manuscript in preparation)that showed that close to 4.4% of all complete blood count (CBC) analyses from unselected male (non-hematology-oncology clinic)patients had hemoglobin levels higher than 165g/L vs.only 0.29% that meet current criteria (hemoglobin higher than 185g/L). This indicates that close to 15 times more males will be suspected as having PV and will be subjected to further investigation. The proposed change to the WHO criteria has less impact in females, as only 0.39% had hemoglobin levels greater than 160 g/L. This is only fivetimes more frequent than the current cut-off of 165g/L, which accounts for 0.07% of unselected females. Therefore, it is important that the cost-effectiveness of the new proposed criteria be carefully evaluated before theyareadapted in routine clinical practice. In addition, hemoglobin levels above the suggested threshold should not be taken in isolation, but rather in the context of other potential signs and symptoms indicative of PV. It is important to emphasize that the intent of lowering the thresholds is to more accurately differentiate between JAK2-positiveessential thrombocythemia(ET) and mPV rather than to serve as a base for population screening.

For diagnostic purposes, a CBC is of particular relevance, as an increase in all three lineages (erythrocytosis with leukocytosis and/orthrombocytosis) is more indicative of PV than isolated erythrocytosis.15In patients with isolated erythrocytosis, causes ofsecondary polycythemia should be considered. The investigations for PV in suspected cases should begin with peripheralblood screening for JAK2V617Fmutation (Figure 1 provides a proposed diagnostic algorithm).16The laboratorydetection of JAK2V617F is highly sensitive (97% sensitivity)and almost 100% specific for distinguishing PV from othercauses of increased Hct.17The finding of theJAK2 V617F mutation, however, is not specific for PV, since it is also present in a substantial proportion of patients with ET, as well as primary myelofibrosis(PMF).18The possibility ofa false positive or false negative mutation test result can be addressed by the concomitant testing ofserum erythropoietin(EPO)level, as more than 85% of patients with PV have low serum EPO concentrations.19Furthermore, EPO levels above normal are unusual for PV and suggest secondary erythrocytosis, with a specificity of 98%.20Low serum EPO levels in the absence of JAK2V617Frequire additional mutational analysis for JAK2 exon 12mutations. 3,21

Bone marrow (BM) evaluation in JAK2V617F-positive patients with erythrocytosis provides limited additional value for diagnostic purpose and currently is not routinely required.15,22However, the proposed changes to the WHO criteria for the diagnosis of PV mandates aBMbiopsy with typical PV histology as one of three major criteria (Table 1B).12Information regarding age-adjusted bone marrow cellularity and grade of fibrosis may have prognostic value and, as such, help in optimizing therapeutic approaches.22In addition, a baseline BM biopsy might be essential in cases where the diagnosis is unclear.

Approximately 11% of PV patients have cytogenetic abnormalities,6 including trisomy 8, trisomy 9, 13q-, and 20q-.23These abnormalities are not specific toPV,are more common in older PV patients (>60 years of age)23, and increase in frequency with disease progression and transformation.24Earlier studies suggest that some of the cytogenetic abnormalities may have prognostic value.25To our knowledge, cytogenetic studies are not routinely performed in PV patients in Canada.

Presently, there is no indication to test forgenetic mutations other than thoseinvolving the JAK-STAT pathway in the routine clinical management of PV. However, with the wider availability of next-generation sequencing (NGS), there is an increasing interest to investigate additional mutations in PV patients.26

Prognosis and Risk Assessment

Polycythemia vera is associated with a shortened life expectancy compared with the general population.4,6,27According to a large population-based study conducted in Sweden,the relative survival rate for PV at 10 years is about 60%.27 Thrombosis,which is much more commonin PV than in the general population, is one of the major causes of death.28At PV diagnosis,arterial thrombosis is present in 16% to 27% and venous thrombosis in 7% to 12% of patients, and the rate of thrombosis is 2% to 4% per year over the course of the disease.28-31 Thus, because of the high prevalence and incidence of this complication, risk-stratification of PV patients is typically based onthe likelihood of thrombotic risk rather than survival or risk of transformation to PPV-MF or AML.32The data indicate that individuals with a history of thrombosis or those who are 60 years of age are considered at higher risk of thrombotic events.32,33Table 2provides an overview of risk factors associated with thrombosis,28overall survival,6 transformation to PPV-MF,28,34 and AML.6,35Arisk-stratification model, based on a retrospective analysis of 1,545 PV patients, clearly delineated threedistinctcategories, with median survival ranging from 10.9 years to 27.8 years.6

Goals of Therapy

The goals of therapy in PV are prevention ofoccurrence orrecurrence of thrombosis, control of Hct and normalization of other blood counts,and mitigationof disease-related symptoms.By decreasing the risk of thrombosis survival is extended. Given the long natural history of the disease, it is important to manage certain high-risk situations, such as pregnancy and surgery, effectively. Patients should be counseled that current approaches are aimed at maximizingbenefits while minimizing potential risks, and are non-curative.

Therapeutic Approaches

The European LeukemiaNet(ELN) guidelines for Philadelphia-Negative Classical MPNs recommend that all patients with PV be managed with phlebotomy to maintain the Hct below 45%, and low-dose Aspirin®to reduce risk of cardiovascular events.32Although phlebotomy has the advantage of immediately reducing the Hct, it does not decrease the platelet or leukocyte count due to the short half-life of these cells. Thus, cytoreduction is recommended in patients at high risk for thrombosis. Figure 2provides a suggested algorithm for the frontline management of PV based on patient risks and symptoms.

Control of Cardiovascular Risk Factors

Currently, there are no data informing lipid or blood pressure target ranges specifically for individuals with PV. However, with the increased risk of arterial thrombosis, it is prudent to manage atherosclerotic risk factors (including hypertension, hyperlipidemia, diabetes)and encourage smoking cessation. Clinicians should refer to the Framingham Heart Study and the risk assessment tool incorporated into Canadian guidelines for general prevention of cardiovascular disease(Figure 3).36

Phlebotomy

Phlebotomy, recommended by Osler at the beginning of the 20th century,37 has remained the mainstay of the treatment for PV for the past 100 years. A randomized trial conducted by the Polycythemia Vera Study Group (PVSG) in 1967 compared phlebotomy alone with phlebotomy combined with myelosuppressive therapy (chlorambucil or P-32).38Although the incidence of thrombosis in the first three years was higher in the phlebotomy-only arm, these patients had a significant overall survival advantage.The difference in survival was attributed to an increased incidence of AML in patients treated with chlorambucil or P-32 compared to those treated with phlebotomy alone.

Based on several studies, the recommended Hct target is 45%.30,32A retrospective study demonstrated a progressive increase in the incidence of vascular complications at Hct levels higher than 44%.39This is also supported by laboratory studies showing impaired cerebral blood flow at higher Hct levels.40Some experts recommend Hct target <42% in women. The lower Hct target in women was derived from the physiological difference between genders and not from direct evidence.41TheEuropean Collaboration on Low-Dose Aspirin in Polycythemia Vera(ECLAP) trial,33 a large,double-blind, placebo-controlled, randomized study that assessed the safety and efficacy of prophylaxis with low-dose Aspirin®in518 patients with PV, did not demonstrate differences in the incidence of thrombosis across arange of Hct levels between 45% and 50%. However, a recent study conducted by the Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) Collaborative Group suggested that maintaining a Hct target of <45%, as compared with a target of 45% to 50%, was associated with a significantly lower rate of thrombotic events without an increase in serious treatment complications.30After 31 months, the composite endpoint of time until death from cardiovascular causes or a major thrombotic event was reached in 2.7% of patients in the low Hct group vs.9.8% in the high Hct group.Despite being the only randomized study assessing the effect of the intensity of Hctcontrol on thrombosis, the CYTO-PV trial has several limitations. For example, patients in the high-Hct group also had significantly higher leukocyte counts compared to those in the low-Hct group.Since it has been suggested that a higher leukocyte count maybe associated with an increased risk of thrombosis, this may confound the results. In addition, the study only accrued about 1/3 of the planned number of patients, therefore, overestimation of the effect size due to chance cannot be ruled out.

Based on available data, Hct target <45% is the widely accepted standard of care in routine clinical practice.

Although inconvenient, phlebotomies are usually well-tolerated. Some patients might experience fatigue after the procedure; thismight be managed by adequate hydration. Frequent phlebotomies lead to iron deficiency, abnormal red blood cell(RBC) morphology, and eventually reactive thrombocytosis. Rarely, phlebotomy-induced iron deficiency might lead to complications such as cognitive problems and restless leg syndrome.42,43

AntiplateletDrugs and Anticoagulants

The randomized, placebo-controlled, ECLAP study demonstrated a significant risk reduction in a combined endpoint of cardiovascular and venous thrombotic events (RR 0.40) with the use of low-dose Aspirin®(100 mg daily) over placebo, with no increased risk of bleeding.33Based on this data, dailylow-dose Aspirin®is recommended for all PV patients in the absence of contraindications.32 Patients presenting with acute arterial or venous thrombotic events should receive acute antithrombotic therapy, as per general thrombosis management recommendations.44For venous thrombosis (VTE), treatment with low-molecular-weight heparin (LMWH),followed by warfarin is favored.There is lack of clinical data on use of novel oral anticoagulants (NOACs) in patients with PV and these agents are not recommended in routine practice at this stage.Based on the Randomized Comparison of Low-Molecular-Weight Heparin vs. Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer(CLOT) study,45where the risk of VTE was almost reduced to half for patients treated with LMWH without increase in bleeding complications, general thrombosis guidelines recommend the use of LMWH over LMWH/warfarin for treatment of malignancy-associated VTE.44 However, one should keep in mind thatPV patients were not included in the CLOT study.45

Overall, there is no consensus regarding the optimal duration of anticoagulation in PV patients following an initial thrombotic event, leading to a broad diversity of clinical practices in duration and type of anticoagulation agents prescribed;46however,thrombosis in patients with PV has a high recurrence rate of about 7.6% per year.47On the other hand, the occurrence ofmajor bleeding is1% per year for warfarin or Aspirin®, but increases to 2.8% per year for combination therapy.47After the first venous thrombotic event, long-term oral anticoagulation was associated with a 63% reduction in the risk of recurrence without a significant increase of the incidence ofmajor bleeding. Given the high rate of recurrence of thrombosis, an individualized approach for long-term anticoagulation use is recommended after careful consideration of patient risk factors. This is in accordance with recently published German and Austrian consensus guidelines that recommend an individualized risk-benefit assessment after three to six months of anticoagulation therapyin patients who experience a thrombotic event.48According to these guidelines,Aspirin® isa reasonable option after three to six months of warfarin and cytoreduction in patients with VTE at initial diagnosis. Long-term anticoagulation may be favored in patients with high-risk features (recurrent, splanchnic, or life-threatening VTE) and low bleeding risk.