POLYCYTHEMIA VERA

Dr.Karthik.S
Moderator:Dr.Sumedh Shetty
 History
• Polycythemia vera [PV] , the sole clonal form of primary polycythemia,
was first described in 1892 by Vaquez.

• In 1903, Osler reviewed four of his own PV cases and an additional five
cases from the literature and wrote, the condition is characterized by
chronic cyanosis, polycythemia, and variable moderate enlargement of the
spleen.
• The chief symptoms have been weakness, prostration, constipation,
headache, and vertigo.

• The increased proliferation of granulocyte precursors and megakaryocytes

was first described by Türk in 1904.
 Definition
• The term polycythemia, denoting an increased amount of blood, has
traditionally been applied to those conditions in which the mass of
erythrocytes is increased.

• PV is a clonal hematopoietic stem cell disorder in which phenotypically

normal red cells, granulocytes, and platelets accumulate in the absence of
a recognizable physiologic stimulus
 Epidemiology
• The most common of the Myeloproliferative neoplasm.

• The incidence of PV is higher among men than among women in all races
and ethnicities, with rates of approximately 2.8 per 100,000 men and
approximately 1.3 per 100,000 women.

• Based on several small studies, the prevalence of PV is approximately 22

cases per 100,000 population.
• PV is typically diagnosed in persons 60 to 65 years of age, and the disorder
is relatively uncommon among individuals younger than 30 years.

• The condition is observed more often among Jews of Eastern European

descent than among other European populations and Asians

• Approximately 96% of patients with PV have a mutation of the Janus

kinase 2 (JAK2) gene. JAK2 is involved directly in intracellular signaling in
PV progenitor cells.
 World Health Organization Classification of Chronic
Myeloproliferative Neoplasms[MPN]
1. Chronic myeloid leukemia, bcr-abl–positive
2. Chronic neutrophilic leukemia
3. Chronic eosinophilic leukemia, not otherwise specified
4. Polycythemia vera
5. Primary myelofibrosis
6. Essential thrombocytosis
7. Mastocytosis
8. Myeloproliferative neoplasms, unclassifiable
 Common Features of Myeloproliferative
Neoplasms[MPN]
• Clonal involvement of a multipotent hematopoietic progenitor cell.

• Marrow hypercellularity with effective hematopoiesis (compared with

ineffective hematopoiesis, as in myelodysplastic syndrome)

• Extramedullary hematopoiesis; enlarged spleen and/or liver

• Thrombotic and hemorrhagic diathesis

• Potential evolution to Myelofibrosis, as well as to acute myeloid leukemia

(AML).
Classification of Polycythemia
 Clinical Features
• PV usually has an insidious onset, most commonly during the sixth decade
of life, although onset may occur from childhood to old age.

• Presenting signs and symptoms may include headache, plethora, pruritus,

thrombosis, and gastrointestinal bleeding.

• But many patients are diagnosed because elevated hemoglobin, and

sometimes other cell counts, are found on a periodic medical examination.
• Symptoms are reported by at least 30 percent of patients at
the time of diagnosis.
 Thrombosis
• Thrombotic episodes are the most common and most important
complication of PV.

• It occurrs in approximately one-third of PV patients.

• Ischemic strokes and transient ischemic attacks account for the majority of
arterial complication

• The most common serious complication is a cerebrovascular accident,

which accounts for approximately one-third of thrombotic events,
followed in frequency by myocardial infarction, deep vein thrombosis, and
pulmonary embolism.
 Cutaneous Findings
• Pruritus occurs in approximately 40 percent of PV patients. It is usually
aggravated by bathing or showering (aquagenic pruritus).

• It has been attributed to increased numbers of mast cells in the skin92 and
to elevated histamine levels,

• Several PV patients have developed the dermatologic disorder, acute

febrile neutrophilic dermatosis (i.e., Sweet syndrome)
 Erythromelalgia
• Erythromelalgia is a syndrome characterized by warmth of the
extremities, painful, reddened digits, a burning sensation and erythema of
the fingers, hands, and feet that is associated with thrombocytosis.

• It characteristically responds rapidly to low-dose aspirin therapy.

• In severe cases, it results in ischemic necrosis of the digits and may lead to
their amputation
 Abdominal Findings

• Portal hypertension, varices, and abdominal pain are not uncommon, and are
often caused by unrecognized splenic or hepatic vein thromboses [Budd-
Chiari Syndrome].

• The incidence of peptic ulcer is four to five times greater than in the general
population.

Cardiovascular Findings

• Angina, myocardial infarction, and congestive heart failure, related to a

predisposition to thrombosis in the coronary circulation .
 Pulmonary Hypertension

• Pulmonary hypertension occurs in a higher than expected frequency in patients

with PV.

Neurologic Findings
• Neurologic symptoms such as dizziness and headache are very common in PV.
• Spinal cord compression secondary to extramedullary hematopoiesis has been
documented.

Other Findings
• Increase in blood uric acid levels [ can cause exacerbation of gout in some patients]
 SPENT PHASE OF POLYCYTHEMIA VERA
• The spent phase of PV, also referred to as post-PV MF, is a frequent and
often terminal complication of the disease.

• Combination of anemia (non–iron deficiency), progressive increase of

splenic size and marrow fibrosis .

• The spent phase may first be noticed when phlebotomy requirements

decrease.

• Thrombocytosis and granulocytosis (often with immature myeloid cells)

are common. In a minority of cases, thrombocytopenia and
granulocytopenia may occur.
• Affected individuals are frequently symptomatic with anemia, bleeding, splenic
enlargement with early satiety, and or upper abdominal pain secondary to splenic
infarcts.

• Most patients become dependent on transfusions or erythropoietin therapy.

• Development of the spent phase is associated with an increased risk of leukemic

transformation.
World Health Organization Diagnostic Criteria for Polycythemia Vera

• PV diagnosis requires meeting either both major criteria and 1

minor criterion or the first major criterion and 2 minor criteria.

Major Criteria
• 1.Hb >18.5 g/dL (men)/>16.5 g/dL (women) or Hb or Hct >99th percentile
of reference 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 (women) if
associated with a sustained increase of ≥2 g/dL from baseline that cannot
be attributed to correction of iron deficiency

• 2.Presence of JAK2 V617F or JAK2 exon 12 mutation

• Minor Criteria

• 1. BM trilineage myeloproliferation

• 2.Subnormal serum Epo level

• 3. EEC growth

BM indicates bone marrow; EEC, endogenous erythroid colony;

Epo, erythropoietin; Hct, hematocrit; Hb, hemoglobin; PV, polycythemia vera; RBC,
red blood cell.
 Investigations:Blood findings

1. Erythrocytes

• Hemoglobin concentration, erythrocyte count, and hematocrit are

usually increased.
• Mean cell volume is usually low-normal or low in untreated patients, and
low in patients who have undergone phlebotomies or had
gastrointestinal bleeding episodes.
• Red cells are hypochromic and microcytic, with morphology
characteristic of iron deficiency.
• The appearance of significant aniso- and poikilocytosis and tear drop
cells heralds the onset of the spent phase and post-PV MF.
2. Leukocytes

• Absolute neutrophilia occurs in approximately two-thirds of PV patients.

• Occasional myelocytes and metamyelocytes are present in the blood, and

considerable degrees of cell immaturity are present in patients with longstanding,
advanced disease.

• Basophilia occurs in approximately two-thirds of patients with uncontrolled

disease.

• The proportion of activated neutrophils is increased.

• The leukocyte alkaline phosphatase level is elevated in approximately 70 percent

of patients with PV.
3. Platelets

• The platelet count is increased in approximately 50 percent of PV patients at the

time of diagnosis, and in approximately 10 percent of patients it is greater than
1000 × 109 /L.

Other nonspecific platelet abnormalities

• Increased platelet thromboxane A2 generation and increased excretion of
thromboxane metabolites.
• Platelet factor-4 levels are elevated.
• Platelet survival may be shortened.
• Fibrinogen binding after stimulation with a platelet-activating factor is
diminished.
• Reduced expression of the thrombopoietin receptor.

• Platelet counts greater than 1000 to 1500 × 109 /L are associated with
progressive decrease of von Willebrand factor (an acquired, type 2 von
Willebrand disease) .
4. Plasma
• Serum lysozyme levels are slightly increased in some patients.

• Because of increased leukocyte turnover and increased levels of B12 binding

protein, serum B12 determination is usually increased.

• Hyperuricemia, a consequence of hyperproliferative myelopoiesis, is frequently

encountered.

5. JAK2V617F AND EXON 12 MUTATIONS

Impact of JAK2 V617F Allele Burden
JAK2 and Other Mutations in Patients with Myeloproliferative
Neoplasms
6. ERYTHROPOIETIN LEVELS

• PV is distinguished by the fact that erythroid cells proliferate even in the absence of
normal levels of erythropoietin.

• Several studies have documented serum erythropoietin levels below the normal
reference range in patients with PV.

• An elevated erythropoietin level generally excludes the diagnosis of PV, but a low
erythropoietin level is not pathognomonic of PV.
7. ERYTHROID COLONY CULTURES

• In vitro assays of erythroid progenitor cells permit the study of their responsiveness
to erythropoietin.

• In PV patient samples, erythroid progenitors grow in culture without added

erythropoietin, forming colonies that are termed EECs.

• Detection of EECs in cultures of blood or marrow had previously been the most
specific test for PV
8. MARROW FINDINGS

• In PV, the marrow is characteristically hypercellular, with an increase in erythroid

and granulocytic precursor cells and megakaryocytes.

• Absent or decreased iron stores are seen in the marrow of most PV patients.
 Treatment
• The major causes of morbidity and mortality in PV are an increased
incidence of vascular complications (i.e., thrombosis and/or hemorrhage),
and progression to MF or acute leukemia/myelodysplasia.

• Presently, the age of the patient (>60 years) and previous thrombotic
events are universally acknowledged major risk factors for major vascular
complications in PV.
• Other risk factors may also play a role in the pathogenesis of thrombosis, such as
hypertension, diabetes, or smoking, as well as leukocytosis and JAK2V617F
mutational allele burden.

• An elevated platelet count does not increase the risk of thrombosis, but it may
increase the risk of hemorrhage.

• It is useful to consider treatment for the plethoric and spent phases separately.
Treatment Algorithm for Polycythemia Vera Patients
 Plethoric phase
• Treatment of PV patients in the plethoric phase of the disease is aimed at
reducing marrow proliferation and blood counts, thereby ameliorating symptoms
and decreasing the risk of thrombosis and bleeding.

 Phlebotomy and Antiplatelet Agents

• Phlebotomy offers prompt and effective reduction of the red cell mass and
blood volume to normal values.

• The goal of phlebotomy is to induce a state of iron deficiency with a normal Hb

concentration that will itself suppress erythrocytosis
• The goal of phlebotomy should be to maintain the hematocrit in the normal range
(42%-44% for men and 39%-42% for women).

• Achieved by the removal of 450 mL of blood at one time every 2 to 4 days; smaller
amounts should be removed from patients who weigh less than 50 kg.

• Aspirin is generally given in daily doses of 80 to 100 mg.

• Contraindications for aspirin:

1. Bleeding diathesis,
2. Individuals with platelet counts >1000 × 109/L
 Myelosuppression

• Myelosuppression decreases blood counts, decreases the risk of vascular events,

and ameliorates symptoms, thus increasing an overall sense of well-being.

1. Hydroxyurea[HU] (Dose : 20-30 mg/kg PO)

• Most common myelosuppressive agent used in the treatment of PV.

• HU is an effective therapy for controlling erythrocyte, leukocyte, and platelet

counts, and it decreases the risk of thrombosis during the first few years of
therapy when compared to an historical cohort treated with phlebotomy alone.

ADVANTAGES DISADVANTAGES
•Short acting •Leukemogenic risk
•Blood counts increases after few days of •Resistance
Stopping drug in case of excessive •Intolerance
suppression
• According to the European LeukemiaNet (ELN), hydroxyurea
resistance is characterized by any of the following:
– Need for phlebotomy to keep hematocrit <45% after 3 months of hydroxyurea
at a dose of 2 g/day
– Platelets >400 × 109/L and WBCs >10 × 109/L after 3 months of hydroxyurea at a
dose of 2 g/day
– Failure to reduce splenomegaly by 50%, or failure to relieve symptoms of
splenomegaly after 3 months of hydroxyurea at a dose of 2 g/day.

• ELN defines hydroxyurea intolerance as cytopenias, including neutropenia

(absolute neutrophil count <1 × 109/L), thrombocytopenia (platelet count <100 ×
109/L), or anemia (Hb <10 g/dL), or the presence of mucocutaneous
manifestations, such as leg ulcers, gastrointestinal symptoms, pneumonitis, or
fever.
2. Interferon

• Recombinant human interferon-α is an agent with clear efficacy in PV.

• In general, interferon appears to control leukocytosis and thrombocytosis and

to reduce or eliminate the need for phlebotomy in a significant proportion of
patients as well as improving pruritis.

• Pegylated interferon-α may decrease the expression of JAK2 V617F.

• DISADVANTAGES:
o The hematologic toxicities include anemia, thrombocytopenia, and
neutropenia.

o Other effects of interferon-α: depression, mood changes, disabling fatigue, skin

toxicity, hair loss, nausea, diarrhea, weight loss, liver function abnormalities,
and cardiac and neurologic toxicity.
3. JAK2 Inhibitors

• The JAK2 inhibitor ruxolitinib has been demonstrated to improve symptoms and
quality of life in PV patients, particularly those who have developed myelofibrosis.

• Several studies have recently reported high efficacy of ruxolitinib in PV patients

refractory to hydroxyurea compared to several other alternative agents.

• This effect was observed in patients who had splenomegaly and who did not,
suggesting that it was not dependent on a clinical setting of myelofibrosis.

• DOSE: 10 mg two times daily

4. Alkylating Agents

• BUSULFAN :

• The marrow suppression produced by this drug is long-lasting and, as a

consequence, it can be given intermittently at a dose of 2 to 8 mg daily for a period
not exceeding several weeks.

• Advantage and Disadvantage: Prolonged depression of marrow activity

Other disadvantage: Incidence of transformation to leukemia may be increased.

5. Other Agents/Modalities

 Radioactive Phosphorus:
• 32 P therapy was one of the first effective modes of treatment used in PV.
• Satisfactory control of the disease usually can be achieved with initial doses of 2 to
4 mCi.

 Anagrelide
• Anagrelide is a platelet-aggregating agent used in the control of thrombocytosis
refractory to hydroxyurea or interferon in myeloproliferative disorders.
• The starting dose was 0.5 or 1.0 mg given four times daily, and a response was
noted in most patients within 1 week.
• The average dose required to control the platelet count was 2.4 mg per day.
• Adverse events included headache, palpitations, diarrhea, and fluid retention, and
were occasionally sufficiently severe to require discontinuation of the treatment.
 THE SPENT PHASE
• Treatment of this phase of the disease is difficult .
• Requires the judicious use of a combination of therapeutic approaches,
including HU, erythropoiesis-stimulating drugs, transfusions, JAK2
inhibitors, and/or allogeneic stem cell transplantation.

 Splenectomy

• Splenectomy may be warranted , particularly in patients with severe

fatigue and cytopenias, and in those where a greatly enlarged spleen
produces physical discomfort and postprandial fullness.
 Hematopoietic Stem Cell Transplantation

• Nonmyeloablative allogeneic stem cell transplantation should be

considered for otherwise healthy PV patients in the spent phase, even in
the seventh decade of life.

• Transplantation is the treatment of choice in patients with early signs of

MDS/AML transformation, and the only treatment offering the possibility
of a cure.

MDS: Myelodysplastic syndrome

AML: Acute Myeloid Leukemia
Response Criteria for Polycythemia Vera
Treatment of Polycythemia Vera
• Pruritus

• Most effective management of pruritus is establishing good hematologic

control of PV.

• In patients who would not otherwise be treated with cytoreduction,

symptoms can be controlled in many cases by strong antihistamines, by
cimetidine, or by serotonin release inhibitors.

• For patients whose symptoms are not relieved, hydroxyurea, interferon, or

ruxolitinib can decrease pruritis.

• Phototherapy: Used in refractory cases [either ultraviolet A or ultraviolet B

therapy]

• Mammalian target of rapamycin (mTOR) inhibitors have also decreased

pruritis associated with myeloproliferative disorders in clinical trials.
• Surgery

• Patients with poorly controlled PV are at increased risk for complications of

elective surgery.

• Complications primarily involve thrombotic events, but bleeding may also

be noted.

• In newly diagnosed patients who have not yet achieved a normal

hematocrit, elective surgery should be deferred until hematologic control is
obtained, with the traditional recommendation suggesting a 4-month
interval of well-maintained count.

• In more urgent surgery, normal blood counts should be obtained as quickly

as possible using phlebotomy with volume replacement, hydroxyurea, and
cytapheresis to control the platelet count if necessary, and should be
maintained as long as possible pre- and postoperatively.
 References
• Harrison’s Principles Of Internal Medicine :20th Edition

• Williams Hematology : 9th Edition

• Wintrobe’s Clinical Hematology : 14th edition

• THANK YOU