Polycythaemia

(BCSH 2018 & 2018(2), WHO 2016)

95-97% JAK2 V617F, 2% 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

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: Prognosis in 1500 contemporary PV patients)

  • 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 Efficacy and safety of low-dose aspirin in PV)

 

Venesection is 1st line treatment

  • Reduce Hct to <0.45 (NEJM 2013 Marchiolo et al CYTO-PV trial)

  • 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

  • Other options:  Busulfan, 32P, pipobroman (all leukaemogenic).

 

Ruxolitinib?

RESPONSE Trial NEJM 2015

  • 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

RELIEF Trial Blood 2014

  • Ruxolitinib for symptom relief in PV. No better than HU.

MAJIC Trial 2016 PV arm results awaited

 

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)