Polycythemia Vera
Kimberly Truong | Wendy Yang
Definitions
• PVera: Increase in RBC mass with/without
increase in granulocytes and platelets in the
absence of physiologic stimulus
• Hb is >16.5 (w) or >18.5 (m)
• HCT >48 (w) or >52 (m)
• Polycythemia/Erythrocytosis: Relative vs.
absolute
Etiology-Relative polycythemia
• Dehydration
• Stress erythrocytosis (Gaisbock's disease)chronically reduced plasma volume
Etiology-Absolute polycythemia
Secondary
• +Reactive: increased EPO
• EPO producing tumors
– RCC, HCC, PCC, cerebellar,
cushing’s
• Hypoxemia:
cardiopulmonary, OSA,
altitude, RBC defects
(smoking)
• Anabolic steroids
Primary
• +Mutation
• Pvera (JAK 2)
• Chuvash polycythemia
(VHL)
• Other gene mutations
Signs/Symptoms1
• Hyperviscocity: headache, dizziness, tinnitus,
blurry vision
• Thrombosis: transient vision disturbances,
erythromalgia, budd chiari, DVT, MI, stroke
• Bleeding: easy bruising, epistaxis
• Pruritis, gout
• Signs: HTN, plethora, splenomegaly
Diagnosis-Revised WHO Criteria2
•
Major criteria
– Hemoglobin >18.5 g/dL in men, 16.5 g/dL in women
– Presence of JAK2 617V>F or other functionally similar mutation such as JAK2 exon 12 mutation
•
Minor criteria
– Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis)
with prominent erythroid, granulocytic, and megakaryocytic proliferation
– Serum erythropoietin level below the reference range for normal
– Endogenous erythroid colony formation in vitro
•
2 major + 1 minor OR 1st major + 2 minor
•
Workup:
–
–
–
–
–
–
H/H
EPO
SaO2
JAK2 screen (95-100% pts with PV have JAK2 mutation3)
Bone marrow
EEC: endogenous erythroid colony formation
Work Up
+Pvera features
*increased red cell mass with SaO2≥92 percent,
splenomegaly, thrombocytosis, and leukocytosis.
-Pvera features
Prognosis
• Prognosis:
– Untreated median survival: 6-18 months
– Treated median survival: 13 years4
– Most common cause of death:
•
•
•
•
•
thrombosis (29 percent)
hematologic malignancies (23 percent)
non-hematologic malignancies (16 percent)
hemorrhage (7 percent)
myelofibrosis (3 percent)
Treatment
1. Phlebotomy : goal Hct<42%/45%5
2. Low dose aspirin in all
3. Hydroxyurea if high risk of thrombosis
(Age>60, prior thrombosis)
4. Symptomatic (allopurinol, antihistamines)
• Responsiveness of treatment at 4.4 years:6
1. Complete response - 24%
2. Partial response - 66%
3. No response - 10%
• No medication has been shown to improve
survival or decrease risk of leukemic
transformation in PV.
References
1.
Tefferi A, Rumi E, Finazzi G, Gisslinger H, Vannucchi AM, Rodeghiero F, Randi ML, Vaidya R, Cazzola M,
Rambaldi A, Gisslinger B, Pieri L, Ruggeri M, Bertozzi I, Sulai NH, Casetti I, Carobbio A, Jeryczynski G, Larson
DR, Müllauer L, Pardanani A, Thiele J, Passamonti F, Barbui T. Survival and prognosis among 1545 patients with
contemporary polycythemia vera: an international study. Leukemia. 2013;27(9):1874.
2.
Tefferi A, Thiele J, Orazi A, Kvasnicka HM, Barbui T, Hanson CA, Barosi G, Verstovsek S, Birgegard G, Mesa R,
Reilly JT, Gisslinger H, Vannucchi AM, Cervantes F, Finazzi G, Hoffman R, Gilliland DG, Bloomfield CD, Vardiman
JW. Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera,
essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert
panel. Blood. 2007;110(4):1092.
3.
Scott LM. The JAK2 exon 12 mutations: a comprehensive review. Am J Hematol. 2011;86(8):668.
4.
Tefferi A, Guglielmelli P, Larson DR, Finke C, Wassie EA, Pieri L, Gangat N, Fjerza R, Belachew AA, Lasho TL,
Ketterling RP, Hanson CA, Rambaldi A, Finazzi G, Thiele J, Barbui T, Pardanani A, Vannucchi AM. Long-term survival
and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and
myelofibrosis. Blood. 2014 Oct;124(16):2507-13. Epub 2014 Jul 18.
5.
Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R,
Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D,
Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G,
Vannucchi AM, Barbui T, CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in
polycythemia vera. N Engl J Med. 2013;368(1):22.
6.
Barosi G, Mesa R, Finazzi G, Harrison C, Kiladjian JJ, Lengfelder E, McMullin MF, Passamonti F, Vannucchi AM,
Besses C, Gisslinger H, Samuelsson J, Verstovsek S, Hoffman R, Pardanani A, Cervantes F, Tefferi A, Barbui T.
Revised response criteria for polycythemia vera and essential thrombocythemia: an ELN and IWG-MRT consensus
project. lood. 2013;121(23):4778.
MKSAP-like Questions
1.
A 66 year old male is evaluated for a 1-month h/o headache and
blurred vision, early satiety, and itching that occurs after
showering. He has a 90-pack-year smoking history. He has no
history of cardiopulmonary or sleep disorders, no other medical
problems, and he takes no medications.
On exam, temp is nl, BP 160/90, HR 90, RR 18, BMI 35, SaO2 94%
on ambient air. His face is erythematous and round.
Cardiopulmonary and neurologic exam are normal. Abdominal
exam +splenomegaly.
Labs:
Hb: 19g/dL
WbC 13,500/uL w/ nl differentiation
Plt 595,000
1. Which of the following is the most
appropriate next step in diagnosis?
A.
B.
C.
D.
BCR-ABL gene analysis
Bone marrow biopsy
Epo level
Polysomnography
PV Work Up
+Pvera features
*increased red cell mass with SaO2≥92 percent,
splenomegaly, thrombocytosis, and leukocytosis.
-Pvera features
2. The patient’s epo level was below normal
range. You order a JAK2 mutation analysis
which comes back (+) for an exon 14 JAK2
mutation. A diagnosis of PV is made. In
addition to aspirin, which of the following is
the most appropriate treatment for this
patient?
A. Phlebotomy only with goal Hct <42%
B. Phlebotomy with goal Hct<42%, plus
hydroxyurea
C. Phlebotomy only with goal Hct <45%
D. Phlebotomy with goal Hct <45%, plus
hydroxyurea
Treatment
1. Phlebotomy : goal Hct<42% (F) /45% (M)5
2. Low dose aspirin in all
3. Hydroxyurea if high risk of thrombosis
(Age>60, prior thrombosis)
4. Symptomatic (allopurinol, antihistamines)
3. In addition to aspirin and hyroxyurea, the patient begins
phlebotomy at 250cc of blood every other day until his
hematocrit falls below 45%. During a follow-up appt, he
states he is doing well with some mild pruritus. Followup labs show:
– Ferritin: 10 (L) (nl: 15-200 μg/L)
– Iron: 5 (L) (nl: 11-29 μmol/L)
– Transferrin sat: 20% (L)
Which is the most appropriate management of this
patient’s new iron-deficiency state?
A.
B.
C.
D.
Start oral iron therapy
Start parenteral iron therapy
Give 1u pRBC
No intervention
Since phlebotomy is effective in controlling
polycythemia by producing a state of relative
or absolute iron deficiency, iron
supplementation should not be given.
(In other words, you want the patient to be irondeficient. Iron deficiency indicates effective
phlebotomy therapy.)
4. Five years later, the patient urgently presents to your
clinic with severe RUQ pain and jaundice. On exam,
you note scleral icterus, new mild hepatomegaly with
RUQ tenderness to palpation and an abdominal fluid
wave sign.
AST: 250, ALT: 300, ALK PHOS: 300, TBili: 2.5
You send the patient to the ER and order stat imaging.
What are you most concerned about?
A. Autoimmune hepatitis
B. Drug-induced hepatitis
C. Budd chiari syndrome
D. Acute cholecystitis
• As many as 50 percent of all cases of the BuddChiari syndrome may be due to an underlying
chronic myeloproliferative disorder (including PV)
and an accompanying hypercoagulable state.
– In a study with 163 budd chiari cases, the most
common risk factor was myeloproliferative disorders
• Darwish, et al. Etiology, management, and outcome of the
Budd-Chiari syndrome. Ann Intern Med. 2009;151(3):167.
• According to UpToDate: “We suggest that
patients diagnosed with Budd-Chiari syndrome in
whom no underlying disorder can be identified
be tested for a JAK2 mutation."
5. The patient was treated
appropriately for his Budd Chiari
syndrome and was discharged
home. The patient was doing well
until five years later, he complained
of slow-progressing fatigue. His Hb:
12.5, WBC: 14,400, Plt: 148.
His peripheral blood smear is shown above.
Bone marrow cannot be aspirated.
Which of the following does this patient now have?
A. Secondary myelofibrosis
B. Essential thrombocytopenia
C. Acute myelogenous leukemia
D. Chronic myelogenous leukemia
Life-time transformation rate in patients with PV
• Polycythemia Vera  Myelofibrosis: 20%4
• Polycythemia Vera  AML/MDS: 7%
• Polycythemia Vera  CML: rare
4 Tefferi
A, et al. Long-term survival and blast
transformation in molecularly annotated essential
thrombocythemia, polycythemia vera, and myelofibrosis.
Blood. 2014 Oct;124(16):2507-13. Epub 2014 Jul 18.