Myelofibrosis (BSH 2023(1) / 2023(2))

50-60% JAK2 V617F

15-35% CALR exon 9

6-9% MPL exon 10

10% ‘Triple Negative’ (HMR mutation +)

 

intro

UK incidence: 1-2 per 100,000 per year

Pathology:

  • Clonal haematopoietic stem cell proliferation and increased pro-inflammatory cytokines leading to reticulin deposition and collagen fibrosis.

  • 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, a multifunctional protein with roles that include regulating cell proliferation.

Classification (see below for diagnostic criteria):

  • Overt Primary Myelofibrosis (PMF)

  • Pre-Fibrotic Primary Myelofibrosis (Pre-PMF)

  • Post-PV/ET Myelofibrosis (Post-PV/ET MF)

  • Secondary bone marrow fibrosis

Clinical Features:

  • Progressive anaemia, leukopenia / leukocytosis, thrombocytopenia / thrombocytosis

  • Multi-organ extramedullary haematopoiesis, esp liver and spleen

  • Symptomatic splenomegaly (Pain, early satiety, weight loss, portal hypertension)

  • Constitutional symptoms

  • Thrombosis

  • Symptom burden can be recorded with the MPN-10 score

Natural history: 

  • Progressive marrow failure, pulmonary hypertension, non-cirrhotic portal hypertension, acute leukaemia and early death

Investigations:

  • Blood film

  • Bone marrow histology

    • Cellularity, megakaryocyte morphology, reticulin fibrosis (0-3 scale)

  • Cytogenetics

    • Poor outcomes with: inv(3), -5/5q, -7/7q, +8, 11q23, 12p-, i(17q), complex karyotype

  • Molecular

    • Driver mutations = JAK2 V617F, CALR exon 9, MPL exon 10

    • High Molecular Risk (HMR) = IDH1, IDH2, ASXL1, EZH2 or SRSF2

    • Additional poor risk mutations include: TP53, U2AF1, RUNX1, CBL, NRAS, KRAS

  • If portal hypertension, consider OGD to look for varices

  • Tests as needed to exclude secondary causes (see below)

diagnosis

differential diagnosis (causes of marrow fibrosis)

Infection - HIV, EBV, TB, Leishmaniasis

Autoimmune - SLE, Sjogren, Anti-Phospholipid Syn, JIA

Chronic Inflammation

Other Haem disorders - Hairy Cell Leukaemia, Mastocytosis, MDS, Hodgkin, CML, AMML, PNH, TAFRO

Metastatic malignancy

Toxic chronic myelopathy

Growth Factors - TPO agonists, IL-11

Bone/Metabolic disorders - Vit D deficiency, Hyperparathyroidism

Other causes of focal fibrosis - Osteonecrosis/myelitis, Irradiation, Trephine biopsy, Grey Platelet Syndrome

WHO 2022 Diagnostic Criteria for Overt MF (PMF)

 

Requires all three major criteria + at least one minor confirmed on two consecutive occasions

 

Major

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

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

3. Not meeting criteria for other neoplasms (ie CML, PV, ET, MDS, other myeloid neoplasms)

(Other clonal markers = ASXL1, EZH2, TET2, IDH1, SRSF2 & SF3B1)

 

Minor

a. Anaemia not otherwise attributable

b. WBC >11

c. Splenomegaly

d. Raised LDH

e. Leukoerythroblastosis

 

WHO 2022 Diagnostic Criteria for Post-PV/ET MF

Requires both major criteria + at least two minor confirmed on two consecutive occasions

 

Major

1. Documented previous diagnosis of PV or ET

2. BM biopsy with Grade 2-3 fibrosis

 

Minor

a. Anaemia of >20g/l decrease from baseline + sustained loss of need for phlebotomy/cytoreduction

b. Any 2 of: >10% weight loss in 6 months, night sweats, fever

c. Splenomegaly >5cm from baseline, or newly palpable

d. Raised LDH (Post-ET MF only)

e. Leukoerythroblastosis

WHO 2022 Diagnostic Criteria for Prefribrotic mf (Pre-PMF)

Requires all three major criteria + at least one minor confirmed on two consecutive occasions

N.B. Pre-PMF is separate from low-risk overt PMF.

 

Major

1. BM biopsy megakaryocytic proliferation and atypia, increased marrow cellularity, granulocytic proliferation and decreased erythropoiesis. Without reticulin fibrosis >1

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

3. Not meeting criteria for other neoplasms (ie CML, PV, ET, MDS, other myeloid neoplasms)

(Other clonal markers = ASXL1, EZH2, TET2, IDH1, SRSF2 & SF3B1)

 

Minor

a. Anaemia not otherwise attributable

b. WBC >11

c. Splenomegaly

d. Raised LDH

e. Leukoerythroblastosis

 

Prognostic scoring

Intro

  • Wide prognosis in MF

  • Triple neg pts have the worst prognosis (median OS 3.2 years, vs 17 yrs for best risk CALR mut.)

  • JAK2/MPL may have worse outcomes than CALR Type 1 / Type 1-like mutations

  • High Molecular Risk (HMR) mutations ass. with worse OS and increased risk of leukaemic transformation

  • >1 HMR is worse than 1 HMR

  • Other cytogenetic and molecular findings also affect prognosis (see top of page)

  • Pros and cons to the different available scoring systems

Dynamic IPSS Plus (DIPPS Plus)

  • Age >65, Hb <100, WBC >25, PB Blasts >1%, Plt <100, Transfusion dependent, Unfavourable karyotype

  • Use at any time in disease course

  • Median survival by risk group:

    • Low: 15 years

    • Int-1: 6.5 years

    • Int-2: 2.9 years

    • High: 1.3 years

MIPSS 70+ Score (for pts under age of 70)

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

  • Correlates with post-transplant outcomes

  

Personalised Risk Assessment (Grinfeld NEJM 2018)

  • Used PT-1 and COMFORT data

  • Modelled 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

Other Scoring systems

 

management

Principles

Individualised treatment, consider:

  • Clinical Phenotype / Symptoms burden (MPN-10 score)

  • Prognostic group

  • Fitness - Age, performance status, co-morbidities

  • Vascular risk factors - Smoking, BP, Diabetes, Lipids, Weight etc

  • Cases should be reviewed at MDT, and consideration given to clinical trials

Management Overview

  • Low risk / Int-1 asymptomatic: Observation / Clinical Trial

  • Low risk / Int-1 symptomatic: JAK inh, Peg-IFN, Hydroxycarbamide, Clinical Trial

  • Int-2 / High risk transplant eligible: JAK inh to maximum symptom response then Allograft

  • Int-2 / High risk not transplant eligible: JAK inh followed by 2nd line medications / supportive care

jak inhibitors

Ruxolitinib (NICE 2016)

MOA: JAK1/JAK2 inhibitor

Indication:

  • Disease-related splenomegaly or symptoms in adult patients with DIPPS Int-2 or High

  • Not recommended for asymptomatic patients

Response:

  • Majority patients response, often rapidly within 8 weeks

  • Median time on treatment = 3 years

Dosing: Based on platelet count. See guideline or SPC.

Contraindications: Thrombocytopenia (plt <50)

Side Effects:

  • Anaemia/Thrombocytopenia. 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

  • Sudden withdrawal can cause SIRS

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

  • Increased risk of skin cancer

Monitoring / Supportive Care

  • Assess symptom response, consider documenting with MPN-10 score

  • FBC + LFT every 2-4 weeks at start of treatment

  • Inactivated shingles vaccination (Shingrix)

  • Consider aciclovir prophylaxis

  • Epo / Danazol / Transfusion support of anaemia.

Discontinuing

  • Disease symptoms and splenomegaly will recur, sometimes rapidly

  • Consider weaning over 7-10 days with steroid cover

Trials: COMFORT-II demonstrated probable increased survival over best available therapy

  • Reduced spleen size, improved QoL

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

  • Median duration of response 3.2 years

Fedratinib (NICE 2021)

MOA: JAK2 inhibitor

Indication: 2nd line for patients who have already received ruxolitinib

Dose: Starting dose is 400mg OD

Side Effects:

  • Black box warning for Wernicke’s encephalopathy

  • GI disturbance, Anaemia & thrombocytopenia are common

Monitoring

  • Very close monitoring of patients at initiation (GI side effects)

  • Thiamine levels should be checked prior to, and during, treatment

  • When switching from ruxolitinib to fedratinib monitor for withdrawal reaction

Trials:

  • JAKARTA-2 Trial 2017

    • Phase 2, single arm, 97 patients already resistant/intolerant of ruxolitinib

    • 55% of 83 assessable patients had a reduction in spleen size

  • JAKARTA Trial

    • Phase 3, placebo controlled, approx. 200 pts 1st line for Int-2 and High risk

    • Reduced spleen size and constitutional symptoms compared to placebo

Note other trials terminated early due to suspected cases of Wernicke’s encephalopathy

Momelotinib (NICE 2024)

MOA: JAK1, JAK2 and ACVR1 inhibitor. Downregulates hepcidin (among other actions).

Dose: Starting dose 200mg

Side Effects: Gastrointestinal

NICE approved for MF-related splenomegaly or symptoms, only if Int-2 or High risk MF. Before or after Ruxol.

Trials: SIMPLIFY-1 2017, SIMPLIFY-2 2018 and MOMENTUM 2023

Pacritinib (not NICE approved as of 2023)

MOA: JAK2 + FLT3 inhibition

May be available on compassionate access

Trials: PERSIST-1, PERSIST-2 and PACIFICA

other agents

Hydroxycarbamide

  • Anti-metabolite inhibiting ribonucleotide reductase

  • Use to control proliferative counts

  • Symptomatic responses are infrequent

Pegylated Interferon

  • Consider for low/int-1 patients with proliferative counts, or for pre-PMF

  • Potential symptomatic benefit in some patients

Anti-platelets

  • Unclear role for aspirin in PMF

  • For post-PV/ET MF, continue aspirin in absence of any contraindication

  • For pre-PMF, aspiring is recommended

Specific scenarios

Anaemia

Multifactorial - ineffective erythropoiesis, hypersplenism, bleeding, cytoreduction, haematinic def,

Consider autoimmune haemolysis (rare)

Erythropoietin

  • For moderate anaemia where Epo level <500 mU/ml (better response rate if epo <150)

  • 50% respond, may take 3 months to do so. Median duration of response 12 months

  • May worsen splenomegaly

Androgens

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

  • Treat for 3 months and then assess response

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

  • If inadequate response, consider IMiDs (high toxicity and limited access)

Blood transfusion

  • Iron overload does not affect outcomes except in HSCT, consider chelation for transplant candidates

Thrombocytopenia

Presence of thrombocytopenia associated with other high-risk features and higher symptom burden

Affects dosing of JAK inhibitors (see chart in guideline)

TPO-agonists do not produce sustained responses

Splenomegaly refractory to drug therapies

Splenectomy

  • Consider if drug refractory, symptomatic portal hypertension or high transfusion burden

  • High morbidity and mortality rate from surgery

  • High thrombosis risk post-op

  • Don’t forget usual splenectomy care (vaccines, abx etc)

Radiotherapy

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

  • May exacerbate cytopenias, which may be severe —> close monitoring required

Accelerated/Blast Phase MF (synonymous with AML)

Blasts 10-19% (accelerated) or >20% (blast) persistently

Prognosis: 6 months to 1 year

Palliative goal: Supportive care vs Azactidine 75mg/m2 vs Clinical Trial

Curative goal: Intensive chemo followed by early allograft

Teenage and Young Adult (TYA)

Rare. 5% of all (already rare) MPNs in TYA patients

High rates of thrombosis and disease transformation

No consensus guidelines for treatment (as of 2023)

Children

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

Differential Diagnosis

  • Acute megakaryocytic leukaemia (AMKL in Downs)

  • Ricketts

  • Familial infantile MF

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

Pregnancy

Increased risk of IUGR, placental insufficiency and foetal loss

Manage in joint obs-haem clinic

Pre-conception counselling, including planning of teratogenic drugs (HU, warfarin etc)

See ET guidelines for general considerations

Allograft

Potentially curative with reversal of marrow fibrosis

Eligibility (ELN guidelines)

  • Consider for all patients <70 yo with Int-2/High risk disease

  • Or Int-1 patients with particular high risk features (e.g. transfusion-dependent, PB Blasts >2% etc)

  • Do not transplant low risk disease

Pre-transplant considerations

  • Bulky splenomegaly impacts on transplant outcomes, aim to allograft at time of max. response to JAKinh

  • Iron overload - aim to transplant prior to 20 units of blood transfused, or use chelation

  • OGD to look for varices

  • Liver imaging

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