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Polycythemia Vera
Proceedings from a Multidisciplinary Roundtable
By Lisa A. Raedler, PhD, RPh
A
multidisciplinary roundtable was convened on mately 2.8 per 100,000 men and approximately 1.3 per
May 29, 2014, to gain insight and guidance from 100,000 women.3 Based on several small studies, the prev-
experts on the diagnosis and management of alence of PV is approximately 22 cases per 100,000 popu-
polycythemia vera (PV), including practical strategies, lation.3 PV is typically diagnosed in persons 60 to 65 years
recent advances, and the emerging science. The round of age, and the disorder is relatively uncommon among
table was comprised of 10 experts in relevant fields: he- individuals younger than 30 years. The condition is ob-
matology, oncology, managed care, specialty pharmacy, served more often among Jews of Eastern European de-
translational research, and oncology nursing/nurse navi- scent than among other European populations and Asians.3
gation. This supplement highlights the discussions and Approximately 96% of patients with PV have a muta-
recommendations of the experts who participated in this tion of the Janus kinase 2 (JAK2) gene.9 JAK2 is involved
meeting, with the overarching goal being to improve directly in intracellular signaling in PV progenitor cells,
outcomes by enhancing the quality, delivery, and contin- a process that occurs after exposure to cytokines to which
uum of care for patients with PV. these cells are hypersensitive.10
The course of PV is variable. Some patients exhibit few
Clinical Aspects of Polycythemia Vera symptoms, such that the condition is discovered only after
Natural history and presentation blood work is performed during a routine medical exam-
Like myelofibrosis (MF) and essential thrombocythe- ination. In other patients, signs, symptoms, and complica-
mia (ET), PV is a Philadelphia chromosome–negative tions of PV arise from the high number of RBCs and
myeloproliferative neoplasm (MPN).1 PV is characterized platelets in the blood.3 In patients with milder symptoms,
by clonal stem-cell proliferation of red blood cells (RBCs), PV can persist for many years without distinct stages or
white blood cells (WBCs), and platelets.2,3 Increased RBC clear progression.5 Other patients will evolve to post-PV
mass results in hyperviscosity of the blood, increased risk MF, which occurs at a rate of up to 10% of patients every
for thrombosis, and a shortened life expectancy.4 Effective 10 years.11 Transformation to AML has been observed at
management of PV is essential, given the risk for morbid- a rate of up to 15% of patients with PV every 10 years.12
ity and mortality, complexity associated with diagnosis Symptoms of PV stem primarily from high RBC counts,
and treatment, and overall impact on patients’ quality of which result in increased blood viscosity, and from high
life (QOL). platelet counts, which can contribute to the formation of
According to the World Health Organization (WHO) thrombi. Along with underlying vascular disease, which is
classification scheme for myeloid neoplasms, PV is a common among older persons with PV, the risk for such
BCR-ABL1–negative MPN.5 MPNs share several com- clotting complications as stroke, heart attack, deep vein
mon features6-8: thrombosis, and pulmonary embolism is enhanced among
• Clonal involvement of a multipotent hematopoietic persons with the disorder. Blood clots occur in about 30%
progenitor cell of patients before a PV diagnosis is made.3 During the first
• Marrow hypercellularity with effective hematopoiesis 10 years after diagnosis, 40% to 60% of patients with
(compared with ineffective hematopoiesis, as in mye untreated PV may develop blood clots.3
lodysplastic syndrome) Thrombotic complications can be divided into 2 cate
• Extramedullary hematopoiesis; enlarged spleen and/or gories—microvascular and macrovascular. Microvascular
liver complications, or microcirculatory disturbances, are
• Thrombotic and hemorrhagic diathesis caused by the formation of thrombi in small blood vessels
• Potential evolution to MF, as well as to acute myeloid and can result in the signs and symptoms shown in Table
leukemia (AML). 1.13-15 Macrovascular complications, which are serious
The incidence of PV is higher among men than among events caused by the development of thrombi in large
women in all races and ethnicities, with rates of approxi- arteries or veins, are often referred to as major thrombot-
ic events.14 These major events (Table 1) are the primary Table 1 Thrombotic Complications in Polycythemia Vera
cause of mortality in patients with PV, accounting for
45% of all deaths.15 Other major causes of death among Microvascular complications Macrovascular complications
individuals with PV include solid tumors (20%) and he- Erythromelalgia Arterial thrombotic events
matologic transformation to AML (13%).15 • Myocardial infarction
Headache
During the roundtable, Dr Ruben A. Mesa discussed • Unstable angina
the availability of patient assessment tools that can pro- Dizziness • Stroke
vide hematologists with data on disease burden. One Visual disturbances • Peripheral arterial occlusion
such tool is the Myeloproliferative Neoplasm Symptom
Paresthesia Venous thrombotic events
Assessment Form (MPN-SAF) total symptom score,
Transient ischemic attack • Deep vein thrombosis
which was published in 2012.16 Because symptoms associ- • Pulmonary embolism
ated with PV are not always related to high blood counts, • Intraabdominal vein
assessing patients via the use of such tools is an important thrombosis
clinical step. Patients can experience “PV-associated” • Cerebral vein thrombosis
symptoms, which are driven by higher volumes of circu-
Sources: Michiels JJ, et al. Semin Thromb Hemost. 2006;32:
lating inflammatory cytokines, resulting from abnormal 174-207; Falanga A, Marchetti M. Hematology Am Soc Hematol
activation of JAK signaling.17 The most common such Educ Program. 2012;2012:571-581; Marchioli R, et al. J Clin
symptoms are fatigue (91%), pruritus (65%), early satiety Oncol. 2005;23:2224-2232.
(62%), concentration problems (61%), and inactivity
(58%).18 Dr Mesa noted that many patients underreport
these symptoms and generally appear much healthier Table 2 World Health Organization Diagnostic Criteria for
Polycythemia Vera
than others seen in hematology practices, such that PV-
associated symptoms often go unrecognized, specifically, PV diagnosis requires meeting either both major criteria and 1
minor criterion or the first major criterion and 2 minor criteria:
symptoms that can arise from compromised blood flow,
but that fall short of overt thrombosis, such as complex Major Criteria 1. Hb >18.5 g/dL (men)/>16.5 g/dL (women)
vascular headaches (ie, migraines with visual changes), or Hb or Hct >99th percentile of reference
challenges with concentration, and erythromelalgia.18 range for age, sex, or altitude of residence
or RBC mass >25% above mean normal
predicted or Hb >17 g/dL (men)/>15 g/dL
Establishing a diagnosis of Polycythemia Vera (women) if associated with a sustained
Diagnosis of PV is made using WHO criteria, and is increase of ≥2 g/dL from baseline that
based on a composite assessment of clinical and laboratory cannot be attributed to correction of
features, including JAK2 mutation status and serum eryth- iron deficiency
ropoietin (Epo) level.19 As shown in Table 2, the presence 2. Presence of JAK2 V617F or JAK2 exon 12
of a JAK2 mutation and a subnormal serum Epo level mutation
confirms the diagnosis of PV.20 A subnormal serum Epo Minor Criteria 1. BM trilineage myeloproliferation
level in the absence of JAK2 V617F requires additional 2. Subnormal serum Epo level
mutational analysis for JAK2 exon 12 mutation to identify 3. EEC growth
the rare patients with PV who are JAK2 V617F negative.19
BM indicates bone marrow; EEC, endogenous erythroid colony;
Bone marrow examination is not essential for a diagnosis; Epo, erythropoietin; Hct, hematocrit; Hb, hemoglobin;
however, patients who fulfill the diagnostic criteria for PV PV, polycythemia vera; RBC, red blood cell.
may exhibit substantial bone marrow fibrosis.20 Reprinted with permission from Tefferi A, et al. Blood.
2007;110:1092-1097. © Copyright 2014 by American Society of
Management of Polycythemia Vera Hematology.
Although PV is a chronic, incurable disease, it can be
managed effectively for long periods of time.3 Careful med- bosis are at high risk, whereas patients younger than 60
ical supervision and therapy are designed to reduce hema- years and with no history of thrombosis are typically classi-
tocrit and platelet concentrations to normal or near-normal fied as being at low risk.3,22
value, in order to control PV-related symptoms, decrease Patients with low-risk PV are usually phlebotomized
the risk for arterial and venous thrombotic events and other and receive low-dose aspirin. These patients often report
complications, and avoid leukemic transformation.21,22 an immediate improvement in their PV symptoms, in-
Patients with PV are stratified for their risk of throm cluding headaches, tinnitus, and dizziness after phleboto-
bosis based on age and history of thrombosis. Those who my.3 For many low-risk patients, phlebotomy and aspirin
are older than age 60 years or who have a history of throm- may be the only form of treatment required.3 In contrast,
events were 2.7% in the “low hematocrit” group versus Figure 3 Factors Affecting Hypercoagulability in Patients
9.8% in the “high hematocrit” group.43
Approximately two-thirds of thrombotic events expe-
rienced by patients with PV are arterial, including myo- Coagulation Factors Endothelial Factors
Activated protein C resistance Vascular injury
cardial infarction and stroke; the remaining one-third are
Plasma microparticles Thromboxane upregulation
venous, including pulmonary embolism, splanchnic vein
Increased thrombin generation Nitric oxide production?
thrombosis, and cerebral venous sinus thrombosis. Dr
Adhesion molecule overproduction
Michaelis noted that in younger patients with PV, clots
in the splanchnic, cerebral, or portal sinuses (including
Budd-Chiari syndrome) are of particular concern in light Hypercoagulable
of their potential morbidity.44,45
Strategies for the prevention of thrombotic events are State
determined after considering the multiple factors that can
influence a patient’s hypercoagulable state (Figure 3).
Phlebotomy or cytoreduction are recommended for Hgb Host Factors Hematopoietic Factors
and hematocrit control, and antiplatelet therapy is used Other thrombophilias V617F mutation
to prevent arterial events. Most patients take low-dose Age Cellular abnormalities
aspirin once daily, whereas those who are sensitive to as- Other medications Blood cell activation
pirin are given clopidogrel. Aggressive control of cardio-
vascular risk factors, including blood pressure, lipids,
smoking, weight, and physical fitness, is also relevant. data for use of hydroxyurea as a front-line cytoreductive
For patients who experience an arterial or venous are extrapolated from randomized, controlled trials in es-
thrombotic event, preventive therapy is revisited. sential thrombocythemia....Hydroxyurea is a relatively
Recommendations for patient management following a efficient way to control counts, it is easy to administer,
thrombotic event are summarized in Table 3. and, for most patients, it is tolerable. For these reasons,
In all patients who have experienced arterial or venous hydroxyurea emerges as the front-line strategy.”
thrombotic events, treatment with cytoreductive agents Long-term consequences of hydroxyurea use remain an
is appropriate. Dr Michaelis indicated that she prefers area of controversy. Dr Stein summarized the available
IFN-α relative to hydroxyurea in younger patients with data, as shown in Table 5.12,24,47,48 Twenty-year follow-up
PV, particularly those who plan to have children. Other data from a study comparing hydroxyurea and pipobro-
indications for the use of cytoreductive agents include man—an agent that is not approved for use in the United
poor tolerance to phlebotomy, rapidly increasing platelet States—show high rates of second malignancies with the
counts, and progressive leukocytosis. use of both agents. It is unclear, however, whether the
Management of PV-associated symptoms, including rate with hydroxyurea exceeds the rate of second malig-
pruritus and erythromelalgia (neurovascular pain disorder), nancies that would be observed in untreated patients
is increasingly being recognized as critical for patients. Dr with PV. Dr Stein concluded, “There are no hard data or
Michaelis observed, “Once you start listening to patients, controlled evidence to implicate hydroxyurea as an agent
even though we all think about PV as the ‘safe MPN,’ these that increases leukemia rates beyond what we see sponta-
symptoms are really life-altering. Some of them can be neously with PV....However, age plays heavily in my de-
quite severe, especially erythromelalgia.” Migraines, skin cision-making as I start a cytoreductive. I am concerned
rashes, leg swelling, and burning pain in the hands are also about prescribing hydroxyurea for long periods of time in
highly debilitating. Aspirin, cytoreduction, and gabapen- younger patients.”
tin can be offered to patients to help minimize these symp- Studies evaluating PV-associated symptom control
toms, whereas antihistamines, light therapy, aprepitant, with hydroxyurea demonstrate that this agent fares poor-
and antidepressants may help with pruritus. ly. Dr Stein summarized 2 studies that showed no signifi-
cant difference in symptom burden, as assessed using the
Cytoreductive Agents MPN-SAF, in patients treated with hydroxyurea com-
In the United States, hydroxyurea is considered the pared with untreated individuals.49,50 A third study of a
standard of care for initial treatment of PV with a cytore- large cohort of German patients with PV revealed that
ductive agent, despite the fact that this drug is “lacking an pruritus is a significant problem that is not improved by
evidence base.” After reviewing the efficacy and safety PV-directed treatment. Among 301 of 441 (68%) pa-
data from clinical trials of hydroxyurea for the treatment tients who experienced pruritus, 44 (15%) characterized
of PV (Table 4),24,46,47 Dr. Brady Lee Stein noted, “Most the condition as “unbearable.”51 Patients with pruritus
Table 4 Studies on the Efficacy of Hydroxyurea for the Treatment of Patients with Polycythemia Vera
Number of patients, Rate of thrombotic
Investigator/year follow-up Intervention Comparator events
Fruchtman SM et al, 199724 51 patients, 795 weeks Hydroxyurea Phlebotomy (134 9.8% vs 32.8%,
(prospective) historical controls) respectively
Najean Y et al, 199746 292 patients under Hydroxyurea Pipobroman NSD
65 years of age, 17 years (randomized)
Kiladjian J-J et al, 201147 285 patients under Hydroxyurea Pipobroman NSD
65 years of age, 16.3 years (randomized)
NSD indicates no significant difference.
Table 5 Studies on Potential Long-Term Consequences of Hydroxyurea Use in Patients with Polycythemia Vera
Number of patients,
Investigator/year follow-up Intervention Comparator Rate of AML and MDS transformation
Fruchtman SM 51 patients, Hydroxyurea Phlebotomy 6.0% vs 1.5%a
et al, 199724 795 weeks (prospective)
Finazzi G et al, 1638 patients, Retrospective No association with the use of single-agent
200512 2.8 years hydroxyurea
(4393 person-years)
Kiladjian J-J 285 patients under Hydroxyurea Pipobroman 10 years: 6.6% vs 13%
et al, 201147 65 years of age, (randomized) 15 years: 16.5% vs 34.1%
16.3 years 20 years: 24.2% vs 52.1%
(P = .004)
“Pipobroman is leukemogenic and is
unsuitable for first-line therapy [in PV].”
Tefferi A et al, 1545 patients, Retrospective No association with single-agent
201348 6.9 years hydroxyurea
No significant difference.
a
AML indicates acute myeloid leukemia; MDS, myelodysplastic syndromes; PV, polycythemia vera.
strated that ruxolitinib has long-term clinical activity, open-label, multicenter phase 3 study of Efficacy and
including durable response rates.61 Among 34 patients Safety in POlycythemia vera subjects who are resistant to
in this phase 2 trial, 97% achieved a response (defined or intolerant of hydroxyurea: JAK iNhibitor INC424
as hematocrit <45% without phlebotomy) by week 24. tablets verSus bEst available care), compared ruxolitinib
Ruxolitinib use was also associated with rapid and sus- with best available therapy (BAT) in approximately 200
tained improvements in PV-associated symptoms, in- patients with advanced PV. Study findings were present-
cluding pruritus, night sweats, and bone pain. Research ed during the annual meeting of the American Society of
ers in this trial observed spleen size reduction, phlebotomy Clinical Oncology in June 2014.62
independence, and improvements in blood counts and In this phase 3 study, patients with phlebotomy-
PV-related symptoms over a median follow-up of 21 dependent PV and splenomegaly (spleen volume of ≥450
months. Treatment with ruxolitinib also reduced ele- cm) who were resistant to, or intolerant of, hydroxyurea
vated levels of inflammatory cytokines and granulocyte were randomized to ruxolitinib (n = 110) or BAT (n =
activation. Thrombocytopenia and anemia were the 112). The primary end point of the study was a composite
most common adverse events. Grade 3 thrombocytope- that included achievement of both hematocrit control
nia and grade 3 anemia, which occurred in 3 patients (<45%) and spleen response (≥ 35% reduction from base-
each (9%; 1 patient experienced both), were managed line in spleen volume by magnetic resonance imaging) at
with dose modification.61 week 32. After week 32, patients who were randomized to
On the basis of these findings, a global phase 3 regis- BAT could cross over to ruxolitinib.
tration trial for ruxolitinib use in patients with PV was At 32 weeks, 77% of patients randomized to ruxoli-
initiated. This trial, known as RESPONSE (Randomized, tinib met at least 1 component of the primary end point,
BAT indicates best available therapy; CI, comfidence interval; Hct, hematocrit; OR. odds ratio; SV, spleen volume.
Source: Verstovsek S, et al. J Clin Oncol (ASCO Meeting Proceedings). 2014;32(suppl 5s): Abstract 7026.
and 21% met both components. Only 1% of the patients Vikas Gupta, MD, summarized the results of an Italian
receiving BAT achieved the primary end point (Figure study in which 44 patients with PV who were unrespon-
4).62 The majority (91%) of ruxolitinib-treated patients sive to maximum tolerated doses of hydroxyurea were
who achieved the primary end point had a confirmed re- randomized to givinostat (either 50 or 100 mg daily)
sponse at week 48, and the probability of maintaining a combined with hydroxyurea.63 ELN response criteria were
primary response for 1 year was 94%. The rate of throm- used to assess the primary end point after 12 weeks of
boembolic events was lower in the ruxolitinib group, with treatment. Complete or partial response was reported in
only 1 event (portal vein thrombosis) reported through 55% and 50% of patients receiving givinostat 50 mg or
week 32, compared with 6 events among patients receiv- givinostat 100 mg, respectively. Control of pruritus was
ing BAT. The RESPONSE trial investigators concluded reported in 64% and 67% of patients in the 50 and 100-
that in patients with PV who had an inadequate response mg groups, respectively. A total of 8 patients (18%) dis-
to, or were intolerant of, hydroxyurea, ruxolitinib was continued treatment, 4 in each arm. Grade 3 adverse
superior to BAT in controlling hematocrit without phle- events were reported in 1 patient in each treatment arm.
botomy, normalizing blood cell counts, reducing spleen The combination of givinostat and hydroxyurea was
volume, and improving PV-associated symptoms, includ- deemed safe and clinically effective in hydroxyurea-unre-
ing pruritus, fatigue, and night sweats.62 sponsive patients with PV.63
Ruxolitinib was generally well tolerated in the As they discussed the RESPONSE trial data for ruxoli-
RESPONSE trial, with 85% of ruxolitinib-treated pa- tinib use in patients with PV, panelists identified sub-
tients continuing to receive treatment after a median groups of persons with PV for whom the unmet need re-
follow-up of 81 weeks. Most adverse events were grade mains high. In these clinical circumstances, it may be
1/2, and few patients developed grade 3/4 cytopenias. The appropriate to consider ruxolitinib usage, presuming the
rate of herpes zoster infection was higher in the ruxoli- drug is approved for the treatment of PV. The following
tinib treatment group compared with the BAT arm. On groups of patients were included as possible candidates for
the basis of the RESPONSE study findings in patients ruxolitinib use:
with PV, global regulatory filings are under way. If ap- • Patients who are resistant to, or intolerant of, hydroxy-
proved, ruxolitinib will be the first JAK1/JAK2 inhibitor urea and have high-risk disease
available for patients with PV. • Patients who are taking low-dose hydroxyurea and
Although ruxolitinib is the farthest along in clinical cannot tolerate higher doses of the agent because of its
development for the treatment of PV, 3 other inhibitors effects on blood counts
of JAK1 and JAK2 are in clinical development for hema- • Patients who experience a thrombotic event while
tologic conditions, including MF, PV, and ET (Table 6). taking hydroxyurea
Histone deacetylase inhibitors, including vorinostat and • Patients with problematic PV-associated symptoms,
givinostat, are also being studied in patients with PV. such as pruritus