Myelofibrosis (BCSH 2012/2014, WHO 2016)

50-60% JAK2 V617F

5-10% MPL

30% CALR

10% ‘Triple Negative’ (HMR mutation +)

 

WHO 2016 Diagnostic Criteria for Overt MF

 

Requires all major criteria + at least one minor

 

Major

1.     BM biopsy with Grade 2-3 fibrosis + megakaryocytic proliferation

2.     Not meeting criteria for other neoplasms

3.     JAK2, MPL, CALR or another clonal marker or absence of reactive fibrosis

 

Minor

a.     Anaemia not otherwise attributable

b.     WBC >11

c.      Palpable splenomegaly

d.     Raised LDH

e.     Leukoerythroblastosis

 

(Pre-MF – as for overt MF except fibrosis grade 1 or less and without (e).)

 

High Molecular Risk (HMR) Mutations

 

Separate from driver mutations (JAK2, MPL, CALR), the number of high molecular risk mutations detected predicts overall survival and disease transformation.

 

HMR defined by 5 genes

-       IDH1, IDH2, ASXL1, EZH2, SRSF2

 

‘Triple Negative’ Myelofibrosis patients more likely to have HMR mutations present

 

BCSH Diagnostic Criteria (Campbell and Green)

 

Primary MF = A1 + A2 + Any three B’s

-       A1       Marrow fibrosis Bain grade 3 or 4

-       A2       Pathogenic mutation or absence of BCR-ABL and other reactive causes

-       B1       Splenomegaly

-       B2       Unexplained anaemia

-       B3       Leukoerythroblastic film

-       B4       Tear drop red cells

-       B5       Constitutional symptoms

-       B6       Histological evidence of extramedullary haematopoiesis

 

Secondary MF (2o meaning post ET or PV) = A1 + A2 + any two B’s

-       A1       Marrow fibrosis Bain grade 3 or 4

-       A2       Prev Dx of PV or ET

-       B’s       New palpable splenomegaly or 5cm increase in size, unexplained anaemia with 20g/l decrease from baseline, B3-6 from above.

 

Pathophysiology

 

Clonal haematopoietic stem cell proliferation results in a leucoerythroblastic blood film and increased pro-inflammatory and pro-angiogenic cytokines

 

Clinical Features

 

Progressive anaemia, leukopenia / leukocytosis, thrombocytopenia / thrombocytosis

Multi-organ extramedullary haematopoiesis, esp liver and spleen

Symptomatic splenomegaly

Constitutional symptoms

 

Natural History

 

Progressive marrow failure, pulmonary hypertension, acute leukaemia and early death

 

Prognostic Scores

 

IPSS 2009

-       Use at diagnosis

-       Age >65, Hb <100, WBC >25, Blasts >1%, Constitutional Symptoms

dipps.png

 

MIPSS70 Score (for pts under age of 70)

-       Adds bone marrow fibrosis, absence of CALR type 1, HMR mutations

-       Good at identifying low risk patients

 

Personalised Risk Assessment

-       ASH Abstract 2017

-       Used PT-1 and COMFORT data

-       Modelled graph of risks of outcomes for individual patients based on mutation profile

-       Will become available as an online calculator shortly

 

Treatment

 

Ruxolitinib (JAK2 Inhibitor) – NICE approved in Int-2 or High only

 

-       COMFORT-II demonstrated increased survival over best available therapy

o   Median OS not reached by 5 yrs for Ruxolitinib, 4.1 years for best available therapy

o   Median duration of response 3.2 years

-       1st line for:

o   Symptomatic splenomegaly

o   MF-related constitutional symptoms affecting QoL

o   Hepatomegaly & portal hypertension when due to MF

-       Not recommended for asymptomatic patients

-       Contraindicated when platelet count <50

-       Median duration of response = 3 years

-       Side Effects:

o   Anaemia. Peaks at wks 12-16 of treatment and then improves

o   Early onset cytopenias (0-3 months): Adjust dose, pause treatment

o   Late onset cytopenias (6-12 months): More suspicious of disease progression

o   Severe atypical infections – TB react., Hep B react., PML, Cryptococcus

-       Monitoring

o   Assess symptom response (new MPN10 score) for objective assessment

o   Decision to stop treatment depends on benefit vs SE, aim to trial for at least 24 weeks before abandoning.

-       Discontinuing

o   Disease symptoms and splenomegaly with recur, sometimes rapidly

o   Consider weaning over 7-10 days with steroid cover

 

Splenomegaly & Extramedullary Haematopoiesis

 

-       Medical management preferred but none offer sustained response

-       Hydroxycarbamide

o   Popular choice, limited evidence, complete response is rare

-       Thalidomide + Pred

o   Response in 1/3 of patients, only 8% have reduction in spleen size

-       Cladribine

o   Maybe useful for post-splenectomy thrombocytosis / hepatomegaly

-       Splenectomy

o   For drug-refractory symptomatic splenomegaly

-       Radiotherapy

o   Possible use for those not fit for splenectomy, EMH in vital organs, severe bone pain

 

Anaemia

 

-       Blood transfusion – iron overload does not affect outcomes except in HSCT

-       Erythropoietin

o   For moderate anaemia where Epo level low

o   Takes 3 months to respond. Median duration of response 12 months

o   May worsen splenomegaly

-       Androgens

o   e.g. Danazol – for transfusion-dependent patients. ORR 30% (Cervantes 2015)

o   Treat for 6 months and then assess response

o   Monitor LFTs and yearly USS liver for malignancy. Check PSA in men.

-       If inadequate response to androgens, consider IMiDs (high toxicity)

Myelosuppressive Therapy

 

-       Not curative. May control hypercatabolism, hepatosplenomegaly, leuko/thrombocytosis

-       HU, Anagrelide, IFN-Alpha

 

Allogeneic HSCT

 

-       Potentially curative with reversal of marrow fibrosis

-       No head-to-head trials to guide best transplant practice

-       Eligibility: simply defined as ‘fit enough for transplant’ with suitable donor

o   <5% of all patients

-       Aim to transplant prior to 20 units of blood transfused

-       Outcomes correlate with DIPSS risk (Leukaemia 2015)

o   Patients with a median survival of 5 years or less may benefit from transplant

o   i.e. patients <70 y.o. with a Int-2 or High risk score

o   ?Consider <60 y.o. with Int-1 risk plus another good reason to transplant

 

Blast Phase MF (synonymous with AML)

 

-       Diagnosis as for AML. Or PB blasts >20% for >8 weeks if BM hard to assess

-       Prognosis: 6 months to 1 year

-       Palliative goal: Supportive care vs Azactidine 75mg/m2

-       Curative goal: Intensive chemo followed by early allograft

 

New Agents?

-       PERSIST-1 – Pacritinib – JAK inhib - phase 1/2 trials – available on compassionate use

-       IMBARK – Imetelstat – telomerase inhibitor

-       PROMOTE – Pentraxin (PTX-2) – bone marrow fibrosis inhibitor

-       SIMPLIFY – Momelotinib – JAK inhibitor – company not pursuing development

-       Sotatercept / Luspatercept – Activin receptor IIA ligand trap

-       JAKARTA – Fedratinib – JAK inhib

 

Pregnancy

 

-       Enroll in prospective data collection

-       Management as per ET guidelines

 

Childhood Primary MF

 

-       Very rare

-       May burn out after 2-3 years with spontaneous recovery. If not à Allograft

-       Differential

o   Acute megakaryocytic leukaemia (AMKL in Downs)

o   Ricketts

o   Familial infantile MF

o   Autoimmune disease, NK cell proliferation, Acute panmyelosis, hypoplastic MDS