Polycythaemia
(BSH 2018/2018(2)/2021, WHO 2016)
96-97% JAK2 V617F
3% JAK2 Exon 12
Rarely ‘Triple Negative’
Del (13q), Del (20q), Del (1q), Trisomy 8/9
Definitions
Polycythaemia – increase in red cell numbers
Erythrocytosis – more specifically a documented increase in red cell mass
Absolute Erythrocytosis
Men: Hct >0.60 alone or >0.52 + RCM >25% of mean
Women: >0.56 alone or >0.48 + RCM >25% of mean
Apparent Erythrocytosis (Does not require further investigation)
Men: Hct >0.52 + normal RCM
Women: Hct >0.48 + normal RCM
Relative erythrocytosis (Does not require further investigation)
Normal RCM + Reduced plasma volume (pathological dehydration)
WHO 2016 PV Diagnostic Criteria
Requires all major or 1-2 plus the minor criteria
Major
1. (Male) Hb >165 or Hct >0.49. (Female) Hb >160, Hct >0.48. Or RCM >25% above baseline
2. BM Biopsy
3. JAK2 V617F or Exon 12
Minor
1. Subnormal Erythropoeitin level
BSH 2018 Diagnostic Criteria
JAK2 Positive PV = A1 + A2
A1: (Male) Hct >0.52. (Female) Hct >0.48. Or RCM >25% above baseline
A2: JAK2 mutation detected
BM biopsy not required at diagnosis
JAK2 Negative PV (Very Rare) = A1-4 + either one more A or two B’s
A1: (Male) Hct >0.60. (Female) Hct >0.56. Or RCM >25% above baseline
A2: No JAK2 mutation
A3: No secondary cause of erythrocytosis
A4: Bone marrow histology consistent with PV
A5: Palpable splenomegaly
A5: Acquired genetic abnormality in BM cells
B’s: Plt >450 - Neut >10 (>12.5 in smokers) - USS splenomegaly - Low Epo level
investigations
Stage 1 Investigations
History & Examination
Oxygen saturations
FBC + Film – 66% neutrophilia, 50% thrombocytosis
Ferritin, U&E, LFTs, Calcium
Erythropoietin
Typically low in PV
Typically high in chronic hypoxia, endogenous overproduction and exogenous administration
JAK2 V617F mutation (peripheral blood)
Quantitative allele burden can be reported but no single threshold confirms or refutes a PV diagnosis.
Low level allele burden (<1-3%) has been seen in normal individuals and the frequency of this increases with age. A low level mutation is still diagnostic of PV if the result is reproducible and found in a patient with otherwise unexplained, persistent erythrocytosis.
Role of bone marrow biopsy in JAK2 positive patients
Not mandatory for diagnosis by BSH criteria but may aid future patient management
E.g. Patients presenting with atypical features such as splanchnic vein thrombosis or marked splenomegaly may have an occult MPN.
The degree of baseline fibrosis, abnormal karyotype and molecular abnormalities may provide prognostic information (15% of PV patients have mutations of ASXL1, SRSF2 and IDH2 which have been associated with poorer overall survival, but testing not yet routine practice)
Investigation of JAK2 V617F-negative Erythrocytosis
Red Cell Mass (RCM) Study
Confirms absolute erythrocytosis if RCM >25% above mean
(N.B. Patients with Hct >0.60 / >0.56 M/F can be assumed to have absolute erythrocytosis)
USS Abdo
Liver / kidneys / spleen
Then if Normal or Low EPO Level:
JAK2 Exon 12 mutation
Typically younger patients with higher Hct but lower WBC and Platelet Count
Bone Marrow Biopsy
Hypercellular with erythroid hyperplasia + increased megas / myeloids
Wide variation in size of megas
Absent iron stores
Mild to moderate increase in reticulin
Moelcular / Cytogenetics
SH2B3 (LNK) mutations
Del (13q), Del (20q), Del (1q), Trisomy 8/9
(TET2 and DNMT3A mutations reported in PV but also seen in healthy individuals and so not currently considered diagnostic)
Or if High EPO Level:
Requires thorough investigation for secondary causes and this may include:
Imaging for rare tumours ass. with erythrocytosis – e.g. cerebellar haemangioblastoma, phaeochromocytoma, meningioma, parathyroid tumours
Oxygen dissociation curve
Sleep Study
Lung function tests
CAUSES OF SECONDARY ERYTHROCYTOSIS
Congenital – high oxygen affinity haemoglobin, Chuvash erythrocytosis (VHL), 2,3 Biphosphoglycerate mutase deficiency (BPGM mutation), Epo-receptor-mediated disorders, EGLN1 mutation, EPAS1 mutation
Exogenous Epo – Androgens, post-renal transplant, idiopathic
Central Hypoxia-driven – chronic lung disease, R to L shunts, carbon monoxide poisoning, smoking, sleep apnoea, high altitude habitat
Renal Hypoxia – renal artery stenosis, ESRF, hydronephrosis, polycystic kidney disease
Pathological Epo production – hepatocellular cancer, RCC, cerebellar haemangioblastoma, parathyroid cancer, uterine leiomyomas, phaeochromocytomas, meningioma
Drug-associated – Erythrpoietin, Androgens, Diuretics, SGLT2 Inhibitors
Alcohol Excess
Postrenal Transplant Erythrocytosis
PV BASICS
1-28 per million per year
Median age: 60
Male = Female
PC: Incidental finding, arterial/venous thrombosis, skin/GI haemorrhage
HPC: Splenic pain, gout, itch, constitutional symptoms
Natural history
Median survival 18 months if untreated
Myelofibrotic transformation
5-15% transform to myelofibrosis over 10 years.
Risk factors: WBC >15 at diagnosis, LDH, JAK2V617F allele burden, fibrosis grade >1, abnormal karyotype and high risk mutations
Leukaemic Transformation (Leukaemia 2013)
2.3% at 10 years
5.5% at 15 years
7.9% at 20 years
pv risk stratification
High Risk:
Age >65 and/or prior history of PV-associated thrombosis
Low Risk:
Age <65 and no prior history of PV-associated thrombosis
Note:
Some ‘low risk’ patients should be consider high risk in the presence of cardiovascular risk factors, high WBC, extreme thrombocytosis or poor Hct control with venesection
PV MANAGEMENT
Goals
1. Reduce thrombosis and haemorrhage
2. Minimise risk of myelofibrosis / AML transformation
3. Manage complications & symptoms
4. Achieve good haematocrit control to <0.45
5. Manage special situations (e.g. pregnancy)
Aspirin for all patients (NEJM 2004)
Venesection is 1st line treatment
Reduce Hct to <0.45 (NEJM 2013)
Volume removed adjusted to patient size and comorbidities
May result in iron deficiency. If symptomatic, alternative approach may be considered
Cytoreduction if:
High-risk patients (see above)
Or low-risk with poor tolerance of venesection, progressive splenomegaly, persistent WBC >15, platelet count >1500, constitutional symptoms or history of IHD/Diabetes/Hypertension.
Drug Choice:
First Line: Hydroxycarbamide (HU) or Interferon (IFN)
Second line: HU or IFN, whichever not used first line
Ruxolintib: 2nd or 3rd line in HU resistant/intolerant patients (NICE appraisal in progress, as of 2023))
Other options: Busulfan, 32P, pipobroman (all leukaemogenic).
Ruxolitinib?
222 patients venesection dependent, splenomegaly and HU intolerant or resistant
Complex study, hard to enroll, confounding factors
Lead to Ruxolitinib license for PV resistant/intolerant to HU
Ruxolitinib for symptom relief in PV. No better than HU.
180 pts. Phase 2. Ruxolitinib vs Best Available Therapy for HU-intolerant/resistant PV
1o outcome = CR within 1yr. 43% in ruxolitinib arm vs 26% BAT.
Ruxolitinib can also produce a molecular response, which correlated with better outcomes.
Thrombotic Risk
Screen for hypertension, diabetes, cholesterol, smoking
No need to screen for thrombophilias
Other Risk factors for thrombosis:
Increasing age, prev thrombosis, WBC >15, JAK2V617F allele burden >75%
Thrombosis
Arterial and peripheral vascular thrombosis more common than venous.
Acute management is as per normal guidelines
In unprovoked VTE, anticoagulation should continue long-term
Unusual site VTE is more common in MPN, esp. younger patients and associated with protein S deficiency. Risk of recurrence is high.
Haemorrhage
Less frequent & less severe than thrombosis
Associated with increased platelet count
Think of Acquired Von Willebrands (up to 12% of PV patients)
Pruritis
Cytoreduction, venesection, antihistamines, iron replacement, pUVA therapy, SSRI’s
Insufficient evidence to recommend:
Targeting a lower WBC, lower allele burden or monitoring of bone marrow response (see guideline for more)
PREGNANCY MANAGEMENT
ET literature suggests 36% miscarriage, 8% stillbirth and increased rate of growth restriction
Pre-conception
Stop teratogenic medication (ie HU) 3 months before conception (Men as well as women)
Address CVS risk factors
Start aspirin
Pregnancy
Start LMWH prophylaxis at positive pregnancy test
Increase LMWH to BD at 16-20 weeks if not already done
High risk patients should start interferon
Monthly FBC, BP and urinalysis to 24 weeks, then fortnightly
Aim for Hct below normal range for gestation – will change through pregnancy
Standard USS + uterine dopplers at 20 weeks
If abnormal Doppler: Increase LMWH, start Vit C and E, deliver before 38 weeks
Delivery:
Stop LMWH at start of labour, re-start post-part ASAP
Avoid dehydration
Active management of third stage of labour
Post-Partum:
6 weeks LMWH
Breast feeding contraindicated if on cytoreductive therapy
OTHER VENESECTION TARGETS
Apparent Erythrocytosis
Confirm over 3-month period, reduce or eliminate causes (smoking, alcohol)
Vensect if Hct >0.54 and/or recent thrombosis
Target Hct: <0.45
Idiopathic Erythrocytosis
Venesect if Hct >0.54 and increased risk of thrombosis
Target Hct: Tailor to patient’s risk factors. <0.55 or <0.45
Do not use cytoreductive therapy
High Oxygen Affinity Haemoglobins
Consider venesect if thrombosis, dizziness, SOB, angina, or asymptomatic with a relative who has had thrombosis. Give regard to fact that the raised Hct is a physiological consequence of the congenital erythrocytosis.
Target Hct <0.52
Consider exchange transfusion prior to major surgery
Hypoxic Pulmonary Disease
Venesect if Hct >0.56 or symptomatic hyperviscosity
Target Hct 0.5-0.52
Long-term oxygen therapy +/- ACE Inhibitor
Cyanotic Congenital Heart Disease
Isovolumetric venesection if symptomatic hyperviscosity
Manage at tertiary cardiac unit to ensure new interventions are considered
Post-Renal Transplant
Occurs 8-12 months after a successful transplant. May be self-limiting
Target Hct <0.50
Avoid dehydration. ACE inhibitors reduce Hct in majority of patients.
Chuvash Polycythaemia (Homoxygous VHL gene mutation)
Consider ruxolitinib (the VHL protein is a regulator of JAK2)
Screen for pulmonary hypertension and neuroendocrine tumours
Target Hct <0.52
Scenarios when GP should refer to MPN clinic
(Taken from local practice)
JAK2+ at any Hct level
Isolated Hct >0.52/0.48 (Male/Female) on one occasion if MPN symptoms
Isolated Hct >0.52/0.48 (Male/Female) persistent for >2 months with no 2o causes.
Isolated Hct >0.55 on one occasion (0.55 is a totally arbitrary cut off)