Myelofibrosis (BSH 2012/2014)

50-60% JAK2 V617F

5-10% MPL

30% CALR

10% ‘Triple Negative’ (HMR mutation +)

 

note

JAK2 - Janus-Associated Kinase. JAK2 usually requires phosphorylation before activating the transmembrane protein it is attached to, e.g. the Epo receptor). When mutated, JAK2 is constantly activated and the downstream effects drive proliferation (JAK-STAT pathway. STAT, PI3K etc).

 

MPL - MyeloProliferative Leukaemia. It is the thrombopoietin receptor.

 

CALR - Calreticulin

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

 

BSH Diagnostic Criteria

 

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

 

Driver mutation & prognosis (Rumi E. Blood 2014)

  • Triple negative patients have the worst prognosis (median survival 3.2 years, versus 17 years for best risk CALR mutation)

 

Personalised Risk Assessment (Grinfeld NEJM 2018)

  • Used PT-1 and COMFORT data

  • Modeled graph of risks of outcomes for individual patients based on mutation profile

  • Conclusion: Genomics contributes to risk of transformation, but not to death in chronic phase

  • Available as an online calculator

 

Treatment

 

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

COMFORT-II demonstrated increased survival over best available therapy

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

  • Median duration of response 3.2 years

1st line for:

  • Symptomatic splenomegaly

  • MF-related constitutional symptoms affecting QoL

  • 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:

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

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

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

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

Monitoring

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

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

Discontinuing

  • Disease symptoms and splenomegaly with recur, sometimes rapidly

  • Consider weaning over 7-10 days with steroid cover

 

Splenomegaly & Extramedullary Haematopoiesis

Medical management preferred but none offer sustained response

Hydroxycarbamide

  • Popular choice, limited evidence, complete response is rare

Thalidomide + Pred

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

Cladribine

  • Maybe useful for post-splenectomy thrombocytosis / hepatomegaly

Splenectomy

  • For drug-refractory symptomatic splenomegaly

Radiotherapy

  • 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

  • For moderate anaemia where Epo level low

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

  • May worsen splenomegaly

Androgens

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

  • Treat for 6 months and then assess response

  • 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

Options - 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

  • <5% of all patients

Aim to transplant prior to 20 units of blood transfused

Outcomes correlate with DIPSS risk (Leukaemia 2015)

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

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

  • ?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 & Their Trials

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

  • Acute megakaryocytic leukaemia (AMKL in Downs)

  • Ricketts

  • Familial infantile MF

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