7/27/2019 MPD - Polycythemia Vera 2006
1/21
Polycythemia Vera
Jeff Singerman
December 19, 2006
7/27/2019 MPD - Polycythemia Vera 2006
2/21
Classification
One of the chronic myeloproliferativedisorders
Includes PV, ET, MMM, and CML PV- clonal erthyrocytosis
MMM- marrow fibrosis
ET- clonal thrombocytosis withouterythrocytosis or marrow fibrosis
7/27/2019 MPD - Polycythemia Vera 2006
3/21
Epidemiology
Incidence- 2/100,000 cases per year,increased in Jewish populations
Median age of onset- 60 (although canoccur at any age)
Slightly higher incidence in males vs.female (1.2:1)
7/27/2019 MPD - Polycythemia Vera 2006
4/21
Presentation
Non-specific symptoms most common
HA, weakness, dizziness, excess sweating
Pruritis
aquagenic pruritis Mechanism poorly understood
GI complaints- epigastric pain, ulceration orerosions
Erythromelalgia- acral dysesthesia anderythema
7/27/2019 MPD - Polycythemia Vera 2006
5/21
Erythromelalgia
7/27/2019 MPD - Polycythemia Vera 2006
6/21
Bleeding
Spontaneous bleeding at superficialsites and mucous membranes
Risk is increased by extremeelevations thrombocytosis
Risk also increased by use of
antiplatelet agents
Mechanism not fully elucidated
7/27/2019 MPD - Polycythemia Vera 2006
7/21
Thrombosis
May involve venous, arterial, ormicrovascular circulation
Venous: PE, DVT, Budd-Chiari, PVT, MVT, SVT
Arterial: CVA, ACS
Microcirculation: Erythromelalgia, transientneuro dysfunction, transient visual disturbances
Mechanism is multifactorial Increased blood viscocity
Displacement of platelets along the vessel wall
7/27/2019 MPD - Polycythemia Vera 2006
8/21
Physical Exam
Splenomegaly
Facial plethora
Hepatomegaly
Conjunctival injection
Excoriation of skin (suggests pruritis)
7/27/2019 MPD - Polycythemia Vera 2006
9/21
Laboratory Findings
Elevated Hcrt (>52 in males, >48 in females)
Does not need to be present for dx
Increased Red Cell Mass (RCM) Do not need to check if Hcrt >60 in males, >56 in females
Platelets > 400,000 (60% of patients)
WBC > 12,000 (40% of patients) Neutrophil predominance
Elevated LAP score
Elevated B12 or unbound serum B12 bindingcapacity
Low or normal EPO levels
7/27/2019 MPD - Polycythemia Vera 2006
10/21
Bone Marrow Biopsy
Hypercellular with increased megakaryocytes, giantmegakaryocytes, and decreased marrow iron stores
7/27/2019 MPD - Polycythemia Vera 2006
11/21
Genetics
JAK2 V617F mutation is associated with allCMPDs (except CML) Present in up to 97% of PV patients
Janus kinase/signal trasducers and activators oftrascription (JAK/STAT) pathway plays a centralrole in initiating signal transduction fromhematopoietic growth factor receptors
V617F mutation releases the autoinhibitoryaction of the JAK2 domain and results inincreased expression
Even in the absence of growth factor, JAK2V617F continues to signal transcription ofhematopoietic precursors.
7/27/2019 MPD - Polycythemia Vera 2006
12/21
JAK/STAT Pathway
7/27/2019 MPD - Polycythemia Vera 2006
13/21
Diagnosis
Polycythemia Vera Study Group (1975) Major Criteria
Increased Red Cell Mass (>36 males, >32 females)
Arterial oxygen saturation > 92%
Splenomegaly
Minor Criteria Platelets > 400,000
WBC > 12,000 LAP score > 100
Serum B12 > 900 or serum unbound B12 bindingcapacity >2200
7/27/2019 MPD - Polycythemia Vera 2006
14/21
Diagnosis
WHO Criteria: Increased RCM and absence of disorders causing
secondary erythrocytosis AND
Splenomegaly OR clonal genetic abnormalityother than BCR-ABL OR sponaneous EEC OR twoor more of the following: Platelets > 400,000
WBC > 12,000 Low serum EPO levels
Bone marrow showing panmyelosis wih prominenterythroid and megakaryocytic proliferation
7/27/2019 MPD - Polycythemia Vera 2006
15/21
Diagnosis
7/27/2019 MPD - Polycythemia Vera 2006
16/21
Prognosis
Untreated: 6 - 18 months
Treated: 9 years
Worsened Prognosis:
Thrombosis
Heme Complications
Transformation into myelofibrosis withmyeloid metaplasia (MMM)
Evolution into AML/MDS
7/27/2019 MPD - Polycythemia Vera 2006
17/21
Treatment
Phlebotomy
Low-Dose ASA
Reduces risk of thrombosis
Cytoreductive Agents
7/27/2019 MPD - Polycythemia Vera 2006
18/21
Cytoreductive Agents
Hydroxyurea- inhibits DNA synthesis
Leukemogenic?
IFN-- Inhibits stem cell proliferation
Anagrelide- platelet function inhibitorand thrombocytopenic agent
Busulphan- leukemogenic
Radiotherapy- leukemogenic
7/27/2019 MPD - Polycythemia Vera 2006
19/21
Treatment
Recommendations From the British Committee for Standards in
Haematology
Phlebotomy to maintain Hcrt < 45 Low Dose ASA unless contraindicated
Cytoreduction considered if: Poor tolerance to phlebotomy
Symptomatic or progressive splenomegaly
Other evidence of disease progression (weightloss, night sweats)
Thrombocytosis
7/27/2019 MPD - Polycythemia Vera 2006
20/21
Treatment
Recommendations Choice of Cytoreductive Agent:
Less than 40 years old:
1st line: IFN 2nd line: Hydroxyurea or Anagrelide
Age 40 - 75:
1st line: Hydroxyurea
2nd line: IFN or Anagrelide
Greater than 75 years old:
1st line: Hydroxyurea
2nd Line: Radiotherapy or Busulphan
7/27/2019 MPD - Polycythemia Vera 2006
21/21
References
McMullin, MF et al. Guidelines for the diagnosis, investivation,and management of polycythaemia/erythrocytosis. BritishJournal of Haematology. 2005; 130: 174-195.
Schafer, AI. Molecular basis of the diagnosis and treatment of
polycythemia vera and essential thrombocythemia. Blood.2006; 107: 4214-4222.
Tefferi, A. Polycythemia vera: a comprehensive review andclinical recommendations. Mayo Clinic Procedings. 2003; 78:174-194.
Tefferi, A. Prognosis and treatment of polycythemia vera, UpTo Date.
Tefferi, A. Diagnostic approach to the patient with suspectedpolycythemia vera, Up To Date.