Essential Thrombocythaemia (ET) (BSH 2010/2014)

50-60% JAK2 V617F

3-5% MPL

25% CALR

12-17% ‘Triple Negative’

 

WHO 2016 Diagnostic Criteria

 

Requires all major or 1-3 + the minor criteria

 

Major

  1. Platelet count >450

  2. BM Biopsy

  3. Not meeting criteria for other neoplasm

  4. JAK2, MPL or CALR mutation

 

Minor

  1. Presence of clonal marker or absence of reactive thrombocytosis

 

BCSH Diagnostic Criteria

 

Plt count >450 + JAK2/MPL/CALR mutation + No other myeloid malignancy

BM biopsy not required unless driver mutation not detected

 

BM Biopsy in ET Diagnosis

 

Required by WHO but not by BCSH

Good for excluding reactive / other causes and for disease re-assessment over time

 

Features

  • Prominent large megas with staghorn nuclei and emperipolesis

  • Wide spectrum of megakaryocyte morphology present

  • Reticulin not increased (WHO 0, Bain 1-2)

 

Significance of JAK2 ET vs CALR ET – No difference in Overall Survival but…

 

JAK2

Older age

Less high platelet count, but higher Hb and WBC

Increased VTE and transformation to PV

Lower rate of transformation to myelofibrosis

 

CALR

Younger age

Higher platelet count, but less high Hb and WBC

Reduced VTE and no transformations to PV

Higher rate of transformation to myelofibrosis

Other mutations in ET

High Molecular Risk (HMR) mutations include: SRSF2, SF3B1, U2AF1 and TP53

Associated with poor outcomes, but reduced rates of thrombosis

Suggested Investigative Pathway

ET.png

 

Prognosis

 

Life expectancy in first ten years from diagnosis not affected

Morbidity and mortality result from thrombosis, constitutional Sx, MF and AML

Thrombosis risk in ET = 12 per 1000 patient years (greater than MF/AML)

AML transformation – 98% mortality at 3 months without stem cell transplant

 

Older BCSH Thrombotic Risk Assessment

 

High risk                     Age >60 or ET-related thrombosis/haemorrhage or plt count >1500

Intermediate             Age 40-60 & no high-risk features

Low                             Age <40 & no high-risk features

 

WHO 2012 IPSET-Thrombosis Score

 

Found no association between thrombosis and platelet count

ET scoring.png

 

IPSET Updated in 2015: Taken out CVS risk factors and new categories: V Low, Low, Int, High

--> not used day to day at CUH. Not been linked to management decisions in clinical trials.

 

Management

 

All Patients

  • Aspirin 75mg OD (No prospective trial data. Take age and other factors into account)

    • (Haematologica 2016: Retrospective study, prone to bias. ?Aspirin not needed for CALR ET)

  • Manage CVS risk factors – HTN, Cholesterol, Diabetes, Smoking

 

BCSH Not High-Risk Patients

  • Only treat if symptomatic or in clinical trial

 

BCSH High-Risk Patients

  • Aim for platelet count in the normal range

  • First line

    • Hydroxycarbamide (NEJM 1995: thrombosis-free survival – 3% with HU, 28% no HU. NEJM 2005 PT-1 Trial)

  • Second line

    • Anagrelide – increased risk of MF (need BM biopsy every 3 years)

    • IFN-Alpha – younger or pregnant patients

      • Pegylated forms can —> molecular Remission (ASH 2017) but take longer to produce response than HU

    • (Buslafan, pipobroman, 32P are older alternatives – do increase AML risk)

 

MAJIC Trial 2016 ET Arm –-> Ruxolitinib FDA-approved 2nd line treatment. Can be accessed via compassionate use if intolerance of HU.

 

ET in Pregnancy

 

Preconception

  • Assess risks

  • Optimise therapy

 

All Patients

  • Aspirin 75mg OD

  • LMWH prophylaxis if indicated as per usual pregnancy risk assessment

  • Uterine Doppler at 20 weeks

    • Move to high-risk management if abnormal

  • Avoid dehydration

  • LMWH for 6 weeks post-partum

 

High Risk Patients

  • IFN-Alpha

  • Early LMWH prophylaxis

  • Regular fetal growth scans

 

ET in Children

 

Rare

Different symptoms, thrombosis and natural history compared to adults

Exclude other causes

Aim for conservative approach