Myelofibrosis

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

lower risk: asymptomatic

1st line – observation

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1st line –

observation

Symptoms and their severity/burden should be assessed at diagnosis and at each clinical review using a validated tool (e.g., Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [MPN-SAF TSS]).[39][42]

A validated prognostic scoring system can be used for prognostication and risk stratification (e.g., International Prognostic Scoring System [IPSS]; Dynamic International Prognostic Scoring System [DIPSS]; Dynamic International Prognostic Scoring System-plus [DIPSS-plus]; Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70]; Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis [MIPSS70-plus]; Genetically Inspired Prognostic Scoring System for Primary Myelofibrosis [GIPSS]).[11][13][43][44][45][46]

Up to 30% of patients may be asymptomatic at diagnosis.[35]

Asymptomatic lower-risk patients (e.g., DIPSS score ≤2; MIPSS70 score ≤3) without hyperuricaemia or a remedial cause of anaemia require no therapy. Observation is recommended.[26][50]

Asymptomatic leukocytosis with a normal serum uric acid level or thrombocytosis requires no therapy.

Enrolment in a clinical trial should be considered for all patients with PMF.

Consider – folic acid

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Consider –

folic acid

Additional treatment recommended for SOME patients in selected patient group

A trial of oral folic acid may be reasonable for patients with anaemia.

Primary options

folic acid: 1 mg orally once daily

Consider – allopurinol

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Consider –

allopurinol

Additional treatment recommended for SOME patients in selected patient group

Allopurinol can be given for 2-3 days to patients with hyperuricaemia.

Primary options

allopurinol: 600-800 mg/day orally given in 2-3 divided doses

lower risk: symptomatic

1st line – Janus kinase (JAK) inhibitor or peginterferon alfa

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1st line –

Janus kinase (JAK) inhibitor or peginterferon alfa

Symptomatic lower-risk patients (e.g., DIPSS score ≤2; MIPSS70 score ≤3) may require treatment with a Janus kinase (JAK) inhibitor or peginterferon alfa-2a.[26][50][51]

Ruxolitinib (a JAK 1/2 inhibitor) can be used to treat symptomatic splenomegaly and constitutional symptoms (e.g., due to thrombocytosis or leukocytosis).

Ruxolitinib is given continuously. It should be started at a low dose and slowly escalated. When discontinuing ruxolitinib (e.g., due to lack of response) the dose should be tapered to minimise the risk of withdrawal symptoms, rebound leukocytosis and thrombocytosis, and cytokine storm. Abrupt discontinuation should be avoided.

Pegylated interferon can be used to reduce marrow fibrosis and symptomatic splenomegaly, and to improve blood counts.[52]

Alternative JAK inhibitors are useful in specific circumstances, or when a patient is resistant to, or intolerant of, ruxolitinib.[24][26][50]

Pacritinib, a JAK2 and FMS-like tyrosine kinase-3 (FLT3) inhibitor, can be used for patients with a platelet count <50 × 10⁹/L.[53][54]

Momelotinib, a JAK1/2 and activin A receptor type 1 (ACVR1) inhibitor, may be considered for patients with anaemia.[55][56][57]

Fedratinib, a JAK2/FLT3 inhibitor, is an option for patients with a platelet count ≥50 × 10⁹/L and splenomegaly.[58][59] Serious and fatal cases of encephalopathy have been reported with fedratinib. Wernicke's encephalopathy has been reported in patients receiving fedratinib.[73] If Wernicke's encephalopathy is suspected, fedratinib should be discontinued immediately and parenteral thiamine initiated. Fedratinib should not be used in patients with thiamine deficiency.

Enrolment in a clinical trial should be considered for all patients with PMF.

Primary options

ruxolitinib: 5-25 mg orally twice daily

peginterferon alfa 2a: consult specialist for guidance on dose

Secondary options

pacritinib: 200 mg orally twice daily

momelotinib: 200 mg orally once daily

fedratinib: 400 mg orally once daily

2nd line – consider stem cell transplant

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2nd line –

consider stem cell transplant

Evaluation for allogeneic HSCT may be considered for selected lower-risk PMF patients with a DIPSS intermediate-1 score or MIPSS70 intermediate score and additional risk factors. Transplantation-related morbidity and mortality are high, so decisions should be individualised.

The Myelofibrosis Transplant Scoring System (MTSS) may be helpful in assessing risk when considering stem cell transplant.[47][48]

higher risk: younger stem cell transplant candidate without comorbidities

1st line – myeloablative stem cell transplant

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1st line –

myeloablative stem cell transplant

Allogeneic haematopoietic stem cell transplant is the only treatment option with curative potential.[48][60]

Symptoms and their severity/burden should be assessed using a validated tool (e.g., Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [MPN-SAF TSS]).[39][42]

The Myelofibrosis Transplant Scoring System (MTSS) may be helpful in assessing risk when considering stem cell transplant.[47][48]

Higher-risk patients (e.g., DIPSS score >2; MIPSS70 >3) should be considered for allogeneic haematopoietic stem cell transplant, if eligible.[26][50]

Patients must be fit enough to undergo the procedure (e.g., based on age and performance status), have manageable comorbidities, and have an acceptable human leukocyte antigen (HLA)-matched donor (HLA-matched sibling donors are preferred).[48][50]

Reduced-intensity conditioning and myeloablative conditioning are both options for patients with myelofibrosis. For younger patients with good performance status, a myeloablative conditioning regimen should be considered.[48][65]

High survival rates have been reported for stem cell transplant performed in younger patients (i.e., <50 years of age) with a matched related donor.[60][61][62]

Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion.[48]

Enrolment in a clinical trial should be considered for all patients with PMF.

Consider – pre-transplant Janus kinase (JAK) inhibitor

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Consider –

pre-transplant Janus kinase (JAK) inhibitor

Additional treatment recommended for SOME patients in selected patient group

Larger spleen size is associated with higher rates of relapse following transplant. Patients who are candidates for allogeneic haematopoietic stem cell transplant (HSCT) with symptomatic splenomegaly or splenomegaly >5 cm below the left costal margin should receive a JAK inhibitor to reduce spleen size and manage symptoms prior to transplant.[48]

Bridging therapy with ruxolitinib appears to improve post-transplant outcomes among patients who experience clinical improvement with this JAK inhibitor.[84][85] Fedratinib, pacritinib, momelotinib have shown efficacy in reducing splenomegaly and may be considered for some patients, although there is a lack of evidence on their use before transplantation.[48]

Patients already taking a JAK inhibitor should continue treatment. JAK inhibitor therapy should be gradually stopped before, or shortly after, starting conditioning.[26][48]

Ruxolitinib should be started at a low dose and slowly escalated. When discontinuing ruxolitinib the dose should be tapered to minimise the risk of withdrawal symptoms, rebound leukocytosis and thrombocytosis, and cytokine storm. Abrupt discontinuation should be avoided.

Serious and fatal cases of encephalopathy have been reported with fedratinib. Wernicke's encephalopathy has been reported in patients receiving fedratinib.[73] If Wernicke's encephalopathy is suspected, fedratinib should be discontinued immediately and parenteral thiamine initiated. Fedratinib should not be used in patients with thiamine deficiency.

Primary options

ruxolitinib: 5-25 mg orally twice daily

Secondary options

fedratinib: 400 mg orally once daily

momelotinib: 200 mg orally once daily

pacritinib: 200 mg orally twice daily

higher risk: stem cell transplant candidate >70 years or younger stem cell transplant candidate with comorbidities

1st line – non-myeloablative stem cell transplant

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1st line –

non-myeloablative stem cell transplant

Allogeneic haematopoietic stem cell transplant is the only treatment option with curative potential.[48][60]

Symptoms and their severity/burden should be assessed using a validated tool (e.g., Myeloproliferative Neoplasm Symptom Assessment Form total symptom score [MPN-SAF TSS]).[39][42]

The Myelofibrosis Transplant Scoring System (MTSS) may be helpful in assessing risk when considering stem cell transplant.[47][48]

Higher-risk patients (e.g., DIPSS score >2; MIPSS70 >3) should be considered for allogeneic haematopoietic stem cell transplant, if eligible.[26][51]

In patients aged over 70 years, allogeneic HSCT should be considered on an individual basis, balancing patient preferences and disease-associated and patient-associated features.[48] A reduced-intensity non-myeloablative conditioning regimen is recommended for older patients, and patients with significant comorbidities.[48][65]

Studies report promising outcomes for older patients with good performance status after allogeneic HSCT with a suitable donor.[63][64]

Regular post-transplantation driver mutation monitoring is recommended to detect and treat early relapse with donor lymphocyte infusion.[48]

Enrolment in a clinical trial should be considered for all patients with PMF.

Consider – pre-transplant Janus kinase (JAK) inhibitor

Back

Consider –

pre-transplant Janus kinase (JAK) inhibitor

Additional treatment recommended for SOME patients in selected patient group

Larger spleen size is associated with higher rates of relapse following transplant. Patients who are candidates for allogeneic HSCT with symptomatic splenomegaly or splenomegaly >5 cm below the left costal margin should receive a JAK inhibitor to reduce spleen size and manage symptoms prior to transplant.[48]

Patients already taking a JAK inhibitor should continue treatment. JAK inhibitor therapy should be gradually stopped before, or shortly after, starting conditioning.[26][48]

Primary options

ruxolitinib: 5-25 mg orally twice daily

Secondary options

fedratinib: 400 mg orally once daily

momelotinib: 200 mg orally once daily

pacritinib: 200 mg orally twice daily

higher risk: not stem cell transplant candidate

with thrombocytosis: non-pregnant

1st line – Janus kinase (JAK) inhibitor

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1st line –

Janus kinase (JAK) inhibitor

Higher-risk patients (e.g., with DIPSS score >2; MIPSS70 >3) who are not suitable for stem cell transplant should undergo treatment to manage symptomatic splenomegaly and/or constitutional symptoms (e.g., due to thrombocytosis or leukocytosis).

Splenomegaly is very common and often the most distressing complication of PMF, leading to mechanical discomfort, inanition (severe weakness and wasting), splenic infarction, portal and pulmonary hypertension, and blood cell sequestration.

Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, is recommended for controlling organomegaly and blood counts in PMF.[26][50] It is approved for use in intermediate-risk or high-risk patients. Ruxolitinib is effective in reducing splenomegaly and constitutional symptoms in these patients.[66][67][68][69][70] Early initiation may improve outcomes, including durable spleen reduction and overall survival.[71]

Fedratinib, a JAK2 and FMS-like tyrosine kinase-3 (FLT3) inhibitor, can be used to control organomegaly and blood counts in PMF.[26][50] It is approved for use in adult patients with intermediate-2 or high-risk primary or secondary (post-polycythaemia vera or post-essential thrombocythaemia) myelofibrosis. Fedratinib is effective in reducing splenomegaly and symptom burden in patients with myelofibrosis who are JAK-inhibitor-naive, or resistant or intolerant to ruxolitinib.[59][72]

Momelotinib, a JAK1/2 and activin A receptor type 1 (ACVR1) inhibitor, is recommended for symptomatic PMF patients with anaemia.[26][50][55][56][57] It is approved for use in patients with intermediate-risk or high-risk PMF and disease-related anaemia. Momelotinib may be considered if ruxolitinib or other JAK inhibitors are ineffective or not tolerated.[26][50]

Pacritinib may be considered if ruxolitinib and fedratinib are ineffective.[26][53]

If initial treatment is unsuccessful, an alternative, untried JAK inhibitor or enrolment into a clinical trial should be considered.

Primary options

ruxolitinib: 5-25 mg orally twice daily

fedratinib: 400 mg orally once daily

momelotinib: 200 mg orally once daily

Secondary options

pacritinib: 200 mg orally twice daily

Consider – erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

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Consider –

erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

Additional treatment recommended for SOME patients in selected patient group

Transfusion may be needed for short-term symptomatic relief while optimising treatment.

PMF-associated anaemia may be managed with recombinant erythropoietin therapy if serum erythropoietin (EPO) levels <500 mU/mL.[26][78] Erythropoietin therapy is effective and well tolerated when used in combination with ruxolitinib.[79] However, it can cause a reversible increase in splenomegaly or hepatomegaly. Patients most likely to respond are those with a low transfusion requirement.[80]

Danazol or luspatercept can be considered if serum EPO levels ≥500 mU/mL.[26][81][82][83]

Further options may include immunomodulatory agents (thalidomide or lenalidomide) with or without prednisolone.[26]

Primary options

epoetin alfa: consult specialist for guidance on dose

danazol: consult specialist for guidance on dose

luspatercept: consult specialist for guidance on dose

Secondary options

thalidomide: consult specialist for guidance on dose

lenalidomide: consult specialist for guidance on dose

thalidomide: consult specialist for guidance on dose

lenalidomide: consult specialist for guidance on dose

-- AND --

prednisolone: consult specialist for guidance on dose

Consider – allopurinol

Back

Consider –

allopurinol

Additional treatment recommended for SOME patients in selected patient group

Allopurinol is given for 2-3 days to patients with hyperuricaemia.

Primary options

allopurinol: 600-800 mg/day orally given in 2-3 divided doses

Consider – local irradiation

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Consider –

local irradiation

Additional treatment recommended for SOME patients in selected patient group

Local irradiation is appropriate for the management of non-pregnant patients with symptomatic extramedullary haematopoiesis in tissues and organs other than the spleen.[24]

without thrombocytosis: non-pregnant

1st line – Janus kinase (JAK) inhibitor

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1st line –

Janus kinase (JAK) inhibitor

Pacritinib, a JAK2/FLT3 inhibitor, is the preferred option for higher-risk patients without thrombocytosis.[26] It is approved for the treatment of intermediate- or high-risk PMF in patients with a platelet count <50 × 10⁹/L (<50,000/microlitre). Pacritinib is effective in reducing splenomegaly and symptom burden in patients with myelofibrosis (including those with severe cytopenias).[54]

Momelotinib, a JAK1/2 and activin A receptor type 1 (ACVR1) inhibitor, may be considered as an alternative option for higher-risk patients without thrombocytosis.[26]

If initial treatment is unsuccessful, an alternative, untried JAK inhibitor or enrolment into a clinical trial should be considered.

Primary options

pacritinib: 200 mg orally twice daily

Secondary options

momelotinib: 200 mg orally once daily

Consider – erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

Back

Consider –

erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

Additional treatment recommended for SOME patients in selected patient group

Transfusion may be needed for short-term symptomatic relief while optimising treatment.

Danazol or luspatercept can be considered if serum EPO levels ≥500 mU/mL.[26][81][82][83]

Further options may include immunomodulatory agents (thalidomide or lenalidomide) with or without prednisolone.[26]

Primary options

epoetin alfa: consult specialist for guidance on dose

danazol: consult specialist for guidance on dose

luspatercept: consult specialist for guidance on dose

Secondary options

thalidomide: consult specialist for guidance on dose

lenalidomide: consult specialist for guidance on dose

thalidomide: consult specialist for guidance on dose

lenalidomide: consult specialist for guidance on dose

-- AND --

prednisolone: consult specialist for guidance on dose

Consider – allopurinol

Back

Consider –

allopurinol

Additional treatment recommended for SOME patients in selected patient group

Allopurinol is given for 2-3 days to patients with hyperuricaemia.

Primary options

allopurinol: 600-800 mg/day orally given in 2-3 divided doses

Consider – local irradiation

Back

Consider –

local irradiation

Additional treatment recommended for SOME patients in selected patient group

Local irradiation is appropriate for the management of non-pregnant patients with symptomatic extramedullary haematopoiesis in tissues and organs other than the spleen.[24]

2nd line – splenectomy or splenic irradiation

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2nd line –

splenectomy or splenic irradiation

Non-pharmacological measures, such as splenectomy or splenic irradiation, are no longer widely used for PMF.

Splenectomy may be an option if pharmacological agents are ineffective in patients with severe symptomatic splenomegaly (e.g., with splenic abdominal pain, symptomatic portal hypertension, frequent red blood cell transfusions).[24][50][74] Splenectomy may also be used in some patients with extreme splenomegaly prior to transplant.[50][74]

Splenectomy is a high-risk procedure with potential complications such as bleeding (the greatest risk), postoperative thrombosis, infection, abdominal hernia, and difficult-to-control myeloproliferation with hepatomegaly; therefore, the decision to perform splenectomy requires careful consideration. Splenectomy for patients with PMF is associated with high mortality and morbidity rates (approximately 9% and 30%, respectively) with limited survival benefit.[24][75]

Splenic irradiation (e.g., with external-beam radiation therapy) can be effective at alleviating splenic pain and temporarily reducing spleen size.[76][77] However, its use should be restricted to patients unsuitable for splenectomy because there is an unpredictable risk of severe cytopenias.

pregnant

1st line – individualised care

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1st line –

individualised care

PMF in pregnancy is rare. Patients who become pregnant should be under the joint care of a haematologist and an obstetrician experienced in high-risk care. Treatment should be individualised.

Peginterferon alfa-2a may be considered for pregnant patients. Use can be limited by its induction of leukopenia or thrombocytopenia, but it can decrease splenomegaly. There is a lack of data for the use of peginterferon alfa-2a in pregnancy; it should be used only if the benefits outweigh the potential risk to the fetus.[26]

Janus kinase (JAK) inhibitors, hydroxycarbamide, and thalidomide are contraindicated in pregnancy.

Primary options

peginterferon alfa 2a: consult specialist for guidance on dose

Consider – erythropoietin

Back

Consider –

erythropoietin

Additional treatment recommended for SOME patients in selected patient group

PMF-associated anaemia may be managed with recombinant erythropoietin therapy if serum erythropoietin (EPO) levels <500 mU/mL.[26][78] However, it can cause a reversible increase in splenomegaly or hepatomegaly. Patients most likely to respond are those with a low transfusion requirement.[80]

Specialist consultation is advised in pregnant women.

Primary options

epoetin alfa: consult specialist for guidance on dose

Consider – allopurinol

Back

Consider –

allopurinol

Additional treatment recommended for SOME patients in selected patient group

Allopurinol should be considered if the benefit of treating the hyperuricaemia outweighs the risk of hyperuricaemia to the mother and child and no other safe alternatives are available.

Given for 2-3 days.

Primary options

allopurinol: 600-800 mg/day orally given in 2-3 divided doses

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Myelofibrosis

Treatment algorithm

lower risk: asymptomatic

observation

folic acid

Primary options

allopurinol

Primary options

lower risk: symptomatic

Janus kinase (JAK) inhibitor or peginterferon alfa

Primary options

Secondary options

consider stem cell transplant

higher risk: younger stem cell transplant candidate without comorbidities

myeloablative stem cell transplant

pre-transplant Janus kinase (JAK) inhibitor

Primary options

Secondary options

higher risk: stem cell transplant candidate >70 years or younger stem cell transplant candidate with comorbidities

non-myeloablative stem cell transplant

pre-transplant Janus kinase (JAK) inhibitor

Primary options

Secondary options

higher risk: not stem cell transplant candidate

Janus kinase (JAK) inhibitor

Primary options

Secondary options

erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

Primary options

Secondary options

allopurinol

Primary options

local irradiation

Janus kinase (JAK) inhibitor

Primary options

Secondary options

erythropoietin or danazol or luspatercept or thalidomide or lenalidomide

Primary options

Secondary options

allopurinol

Primary options

local irradiation

splenectomy or splenic irradiation

individualised care

Primary options

erythropoietin

Primary options

allopurinol

Primary options