83 Polycythemia Vera Flashcards
The term denoting an increased amount of blood cells that has traditionally been applied to conditions in which the mass of erythrocytes is increased
Polycythemia
TRUE OR FALSE
In polycythemia vera, there is more than one cell lineage increased at diagnosis and through the course of the untreated disease, from erythrocytosis, an invariably unilineage increase in red cells
TRUE
In polycythemia vera, there is more than one cell lineage increased at diagnosis and through the course of the untreated disease, from erythrocytosis, an invariably unilineage increase in red cells
A characteristic feature of PV on BMA
Endogenous erythroid colonies (EECs)
Erythropoietin-independent BFU-E precursors
A situation wherein a part of a chromosome comes in two copies from one parent and no copy from the other parent.
Uniparental disomy (UPD)
In PV, UPD is the acquired somatic event generated by mitotic crossover, wherein one part of the chromosome is duplicated and the other is deleted as it happens in at least part of the PV clone.
JAK2 V617F is located at what chromosome
Chromosome 9p
The V617F mutation is present in:
PV:
ET and PMF:
PV: All
ET and PMF: more than 50%
In PV (unlike in ET), it is often in its associated (homozygous or heterozygous) form as a result of UPD, at least in some of the progenitors
In PV (unlike in ET), it is often in its associated HOMOZYGOUS form as a result of UPD, at least in some of the progenitors
Patients bearing homozygous JAK2 V617F tend to have:
Longer duration of disease
Higher hemoglobin levels
Increased incidence of pruritus
More likely to transform to post-polycythemia vera MF (post-PV MF)
Increased spleen volume
Increased leukocytosis
Increased severity of MF
Kind of JAK2 mutation is present in PV patients who are JAK2 V617F -negative
JAK2 exon 12 mutations
Patients with JAK2 exon 12 mutations have:
Erythrocytosis only
Occurs at a younger age
Higher hemoglobin
Normal EPO level
Differences in marrow morphology- megakaryocytic clusters are largely absent and lack of panmyelosis
Disease course and clinical outcome, however, are similar.
Mutation in patients with polycythemia with eosinophilia which has no evidence of uniparental disomy and all erythropoietin-independent BFU-E were heterozygous for this novel JAK2 mutant.
JAK2 exon 13
The risk of acquiring a JAK2 V617F -positive MPN is three- to fourfold higher in patients with the_________________haplotype.
JAK2 GGCC (46/1) haplotype
Could be considered be the “fourth” driver mutation in Philadelphia chromosome negative MPNs, in addition to JAK2, CALR and cMPL
LNK protein mutations (encoded by SH2B3 gene)
A history of any autoimmune disorder has been associated with a _____ increased risk of developing an MPN
20%
PV usually has an insidious onset, most commonly during the _________ decade of life, although onset may occur from childhood to old age.
Sixth decade of life
TRUE OR FALSE
Other PV patients may be uncovered during investigation for arterial or venous thrombosis, or iron deficiency.
TRUE
Other PV patients may be uncovered during investigation for arterial or venous thrombosis, or iron deficiency.
The most common symptoms of PV
Headache
In decreasing order of frequency: headache, fatigue, weakness, pruritus, dizziness, and night sweats, but these symptoms are more likely in patients with PV transforming to MF
The most common and most important complication of PV
Thrombotic episodes
Thrombotic episodes occur in about _________ of PV patients
One-third
The most common serious complication of PV
Cerebrovascular accident
Bleeding and bruising is a common complication of PV, occurring in approximately __________of patients in some series.
One-quarter
TRUE OR FALSE
Bleeding is more common in persons with marked thrombocytopenia
FALSE
Bleeding is more common in persons with marked thrombocytosis (>1000 × 10 9 /L).
Syndrome caused by a thrombosis in the hepatic venous outflow, leading to ischemia from reduced perfusion through hepatic arterioles and necrosis of hepatocytes
Budd-Chiari syndrome
Budd-Chiari syndrome may be the first clinical manifestation of PV
TRUE OR FALSE
PV is the most frequent underlying disease associated with Budd-Chiari syndrome.
TRUE
PV is the most frequent underlying disease associated with Budd-Chiari syndrome.
Treatment for Budd-Chiari syndrome
Transjugular intrahepatic portosystemic shunt placement Liver transplantation
Cause of aquagenic pruritus in PV patients
Increased numbers of mast cells in the skin and elevated histamine levels
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.
Erythromelalgia
- A causative role for transient microvascular occlusion by platelet aggregates has been proposed
- It is not specific to PV or other MPNs
Treatment for erythromelalgia
Low-dose aspirin
TRUE OR FALSE
It is advised to normalize blood counts and blood volume before surgical interventions, and use specific preventive measures preoperatively.
TRUE
It is advised to normalize blood counts and blood volume before surgical interventions, and use specific preventive measures preoperatively.
Phase of PV characterized by a combination of anemia (non–iron deficiency), progressive increase of splenic size, and in most, but not all instances, represents post-PV MF
Spent phase of PV
- First noticed when phlebotomy requirements decrease
- The appearance of significant anisocytosis and poikilocytosis and teardrop cells (dacryocytes) heralds the onset of the spent phase and postPV MF
- Associated with an increased risk of leukemic transformation
In the updated 2016 WHO diagnostic criteria for PV, the hemoglobin level must be:
Male:
Female:
Male:16.5 g/dL
Female: 16.0 g/dL
TRUE OR FALSE
In patients treated with HU, MCV decreases to very low values
FALSE
In patients treated with HU, MCV increases to very high values
TRUE OR FALSE
Red cell mass determination is not useful in distinguishing PV from secondary erythrocytosis because the red cell mass is increased in both disorders.
TRUE
Red cell mass determination is not useful in distinguishing PV from secondary erythrocytosis because the red cell mass is increased in both disorders.
The principal value of red cell mass determination is to
Distinguish PV from apparent or spurious erythrocytosis
Distinguishing cases of masked PV from ET
Absolute neutrophilia occurs in about __________ of patients with PV.
Two-thirds
Neutrophils may be an important factor in PV-associated thrombosis.
Basophilia occurs in approximately _____________of patients with uncontrolled disease.
Two-thirds
The platelet count is increased in approximately_______ of patients with PV at the time of diagnosis, and in approximately ______of patients it is greater than 1000 × 10 9 /L
50% has increased platelet count
10% of patients it is greater than 1000 × 10 9 /L
TRUE OR FALSE
There are no consistent abnormalities of thrombopoietin levels in patients with PV.
TRUE
There are no consistent abnormalities of thrombopoietin levels in patients with PV.
TRUE OR FALSE
Patients with MPNs often display a nearly pathognomonic defect in the primary wave of platelet aggregation induced by epinephrine
TRUE
Patients with MPNs often display a nearly pathognomonic defect in the primary wave of platelet aggregation induced by epinephrine
Platelet counts over 1000 × 10 9 /L are associated with
Acquired, type 2 von Willebrand disease
Increased risk of bleeding, but not of thrombosis
Plasma levels of Vitamin B12 and Uric Acid are (increased or decreased)
INCREASED
TRUE OR FALSE
Plasma has been used for detection of the JAK2 V617F DNA and mRNA mutation and zygosity state, plasma analysis is reliable.
FALSE
Plasma has been used for detection of the JAK2 V617F DNA and mRNA mutation and zygosity state, but plasma analysis is not reliable.
TRUE OR FALSE
JAK2 exon 12 mutations are found in ET.
FALSE
JAK2 exon 12 mutations are not found in ET.
Serum erythropoietin levels in patients with PV is (below or above) the normal reference range.
Below the normal reference range
TRUE OR FALSE
An elevated erythropoietin level generally excludes the diagnosis of PV, but a normal or even increased erythropoietin levels can be seen in Budd-Chiari syndrome; normal erythropoietin is more likely to be encountered in PV subjects with JAK2 exon 12 mutations.
TRUE
An elevated erythropoietin level generally excludes the diagnosis of PV, but a normal or even increased erythropoietin levels can be seen in Budd-Chiari syndrome; normal erythropoietin is more likely to be encountered in PV subjects with JAK2 exon 12 mutations.
The most specific and sesitive test for PV
Detection of EECs in cultures of blood or marrow
In terms of EECs, difference between PV vs PFCP and congenital disorders of hypoxia sensing
EECs in PFCP and congenital disorders of hypoxia sensing, are abrogated by pretreatment with erythropoietin and erythropoietin receptor-blocking antibodies
TRUE OR FALSE
Absent or decreased iron stores are seen in the marrow of many patients with PV.
TRUE
Absent or decreased iron stores are seen in the marrow of many patients with PV.
World Health Organization Criteria for
The Diagnosis of Polycythemia Vera, 2016
Major Criteria
1. Hemoglobin >16.5 g/dL (men), >16.0 g/dL (women) OR Hematocrit >49% (men), >48% (women) OR Increased red cell mass >25% above mean predicted value
2. Bone marrow biopsy showing hypercellular for age, trilineage myeloproliferation (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes (differences in size)
3. Presence of JAK2V617F or JAK2 exon 12 mutation
Minor Criterion
1. Subnormal serum erythropoietin level
A diagnosis of PV requires the presence of all three major criteria or
the first two major criteria and the one minor criterion.
Criterion number 2 (bone marrow biopsy) may not be required in:
Sustained absolute erythrocytosis: hemoglobin
levels >18.5 g/dL in men (hematocrit 55.5%) or >16.5 g/dL in women (hematocrit 49.5%)
If major criterion 3 and the minor criterion are
present.
The major causes of morbidity and mortality in PV
- Increased incidence of vascular complications (ie, thrombosis and/or hemorrhage)
- Progression to post-PV MF or acute leukemia/ myelodysplasia
Major risk factors for serious vascular complications in PV
Age of the patient (>60 years)
Previous thrombotic events
Classifications of PV
Low risk
Intermediate risk: age older than 60 years
High risk: previous thrombotic events (including transient ischemic attacks)
The most adverse additional somatic PV mutations in terms of overall, leukemia‐free, and fibrosis‐free survival in PV:
ASXL1, SRSF2, and IDH2 mutations
Durable response must last at least _____ weeks
12 weeks
Large improvement in symptoms means:
A ≥10-point decrease in MPN
Symptom Assessment Form total assessment score
Treatment for plethoric phase
Nonspecific myelosuppression
Phlebotomies
+ Aspirin
Most commonly used myelosuppressive agents
HU and pegylated IFN-α preparations
Indicated for those who are resistant or intolerant to HU
Targeted JAK2 inhibitors
Among treatment for spent phase this have been proven to be beneficial in prospective trials
JAK2 inhibitors
Treatment for spent phase PV
HU
Transfusion
Erythropoiesis-stimulating drugs
JAK2 inhibitors
Hypomethylating agents
Splenectomy
Allogeneic stem cell transplantation
Most common myelosuppressive agent used in the treatment of PV
Hydroxyurea
initial therapy (1000–1500 mg qd) and long-term treatment (500–2000 mg qd)
An effective therapy for controlling erythrocyte, leukocyte, and platelet counts, and it decreases the risk of thrombosis
Hydroxyurea
About _____ of PV patients develop HU resistance or intolerance (ie, skin ulcers or gastrointestinal intolerance)
10%
Resistance to HU has been correlated with decreased survival and a higher rate of transformation to AML or MF.
A side effect in a small number of patients with PV, especially in areas with increased UV exposure
Nonmelanoma skin cancers
Causes long-lasting marrow suppression; can be given intermittently at a dose of 2–8 mg daily for a period not exceeding several weeks
Busulfan
Has increased incidence of transformation to leukemia
Busulfan
Dose of Radioactive Phosphorus used in PV
2–4 mCi
It could be a treatment option for older patients and patients who may be difficult to follow living in remote areas.
Radioactive Phosphorus
Its use results in a decrease in JAK2V617F allelic burden and conversion from clonal to polyclonal hematopoiesis
IFN-α
Drug of choice in pregnant PV patients
PEG-IFN-α
Better tolerated than standard IFN-α and requires less frequent administration
The initial treatment for patients with uncomplicated PV
Phlebotomy
Recommended therapy for low-risk PV cases:
Phlebotomy + low-dose aspirin
When phlebotomy is instituted, the hemoglobin may be reduced to normal or near-normal values by the removal of ______ mL of blood at one time every ______days
450 mL of blood at one time every 2–4 days
Smaller amounts should be removed from patients who weigh less than 50 kg
TRUE OR FALSE
Patients with impaired cardiovascular function are better treated with smaller phlebotomies at less frequent intervals.
FALSE
Patients with impaired cardiovascular function are better treated with smaller phlebotomies at more frequent intervals.
This treatment does not reduce the leukocyte or platelet count, nor does it affect pruritus or gout.
Phlebotomy
The usual consequences of repeated phlebotomies:
Iron deficiency and resulting microcytosis
TRUE OR FALSE
In patients with Chuvash erythrocytosis, the risk of stroke is independent of hematocrit and increased by phlebotomies
TRUE
In patients with Chuvash erythrocytosis, the risk of stroke is independent of hematocrit and increased by phlebotomies
Can be used in PV to decrease thrombocytosis, as an adjunct to other treatments
Anagrelide
Starting dose of Anagrelide
0.5 or 1.0 mg given four times daily
Average dose required to control the platelet count was 2.4 mg per day
TRUE OR FALSE
Control of pruritus is achieved using myelosuppression.
TRUE
Control of pruritus is achieved using myelosuppression.
Aside from myelosuppression, agents helpful for pruritus
Photochemotherapy with psoralens and ultraviolet light
The study that showed that daily low-dose aspirin decreased arterial and venous thromboses, albeit incompletely.
ECLAP study
TRUE OR FALSE
Aspirin should be used when the platelet count exceeds 1000–1500 × 109/L
FALSE
Aspirin should not be used when the platelet count exceeds 1000–1500 × 109/L
An oral JAK1/JAK2 inhibitor is now FDA-approved for patients with PV that is resistant or intolerant to HU.
Ruxolitinib
TRUE OR FALSE
JAK2 inhibition does not change or modify the natural course of PV, but mainly ameliorates the symptoms.
TRUE
JAK2 inhibition does not change or modify the natural course of PV, but mainly ameliorates the symptoms.
No conclusive evidence of its benefits for prevention of thromboses and transformation to post-PV MF and AML.
An HDAC inhibitor that specifically inhibits the proliferation of JAK2V617F-positive cells compared with normal cells by inhibiting hematopoietic transcription factors NFE2 and c-MYB.
Givinostat
Post-PV MF usually occurs after_______ years or more
15 years
The treatment of choice in patients with early signs of MDS/AML transformation, it is the only treatment offering the possibility of a cure
Hematopoietic Stem Cell Transplantation
TRUE OR FALSE
Chlorambucil should no longer be used for PV therapy.
TRUE
