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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:
Phase 2, single arm, 97 patients already resistant/intolerant of ruxolitinib
55% of 83 assessable patients had a reduction in spleen size
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