Approach

The treatment approach for patients with primary myelofibrosis (PMF) is based on a variety of considerations, including the presence of symptoms and risk factors.

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

The goals of treatment include relieving symptoms, improving blood counts, and preventing or delaying progression to advanced disease or leukaemia. Splenectomy or splenic irradiation are no longer widely used in the management of PMF.

Allogeneic haematopoietic stem cell transplant is the only treatment with curative potential.

Symptom assessment and risk stratification

Assessing symptoms and risk factors (for prognosis and risk stratification) are key to guiding treatment in patients with PMF.

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

The following validated prognostic scoring systems can be used for prognostication and risk stratification:

  • International Prognostic Scoring System (IPSS)[43]

  • Dynamic International Prognostic Scoring System (DIPSS)[11]

  • Dynamic International Prognostic Scoring System-plus (DIPSS-plus)[44] [ Dynamic International Prognostic Scoring System-Plus (DIPSS-Plus) Opens in new window ]

  • Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis (MIPSS70)[45]

  • Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis (MIPSS70-plus)[13] [ Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis in adults 70 and younger (MIPSS70+ version 2.0) Opens in new window ]

  • Genetically Inspired Prognostic Scoring System for Primary Myelofibrosis (GIPSS)[46] [ Genetically Inspired International Prognostic Scoring System (GIPSS) Opens in new window ]

IPSS is validated for assessing risk and prognosis at the time of diagnosis only, whereas DIPSS is validated for assessing risk and prognosis at any time during the disease course.

DIPSS uses the following risk factors to determine if a patient is low risk (DIPSS score 0), intermediate-1 risk (DIPSS score 1 or 2), intermediate-2 risk (DIPSS score 3 or 4), or high risk (DIPSS score 5 or 6):

  • Age >65 years

  • Haemoglobin <100 g/L (<10 g/dL)

  • Leukocyte count >25 × 10⁹/L

  • Circulating blasts ≥1%

  • Constitutional symptoms

DIPSS-plus is a modified version of DIPSS that incorporates the following additional risk factors:

  • Platelet count

  • Need for red blood cell transfusion

  • Unfavourable chromosome abnormalities

MIPSS70, MIPSS70-plus, and GIPSS all incorporate genetic mutations and should be used if molecular testing has been carried out.

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

Of note, an alternative risk assessment system - the Myelofibrosis Secondary to PV and ET-Prognostic Model (MYSEC-PM) - is used for patients with post-polycythaemia vera myelofibrosis and post-essential thrombocythaemia myelofibrosis.[34][49]​​​

Lower risk: asymptomatic patients

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]​​​​

A trial of oral folic acid may be reasonable for patients with anaemia. Allopurinol can be given to patients with hyperuricaemia.

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

Lower risk: symptomatic patients

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: for the treatment of symptomatic splenomegaly and constitutional symptoms (e.g., due to thrombocytosis or leukocytosis)

  • Pegylated interferon: to reduce marrow fibrosis and symptomatic splenomegaly, and 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; 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.

Hydroxycarbamide is not generally of use in treating PMF (although it is sometimes used for cytoreduction in an emergency). It should be considered with caution as it is teratogenic and leukaemogenic.

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; decisions should be individualised.

Higher-risk: patients suitable for stem cell transplant

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

Allogeneic HSCT is the only treatment with a curative potential for PMF.​[48][60]​​​​

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

Prospective studies are required to establish the most effective conditioning regimen, the optimal timing for transplantation, and which patients would benefit most from this procedure.

Identifying HSCT candidates

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]​​​​

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]

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

Pre-transplant Janus kinase (JAK) inhibitor

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]

Conditioning regimens for HSCT

Reduced-intensity conditioning and myeloablative conditioning are both options for patients with myelofibrosis. A reduced-intensity non-myeloablative conditioning regimen is recommended for older patients, and patients with significant comorbidities. For younger patients with good performance status, a myeloablative conditioning regimen should be considered.[48][65]

Higher-risk: patients not suitable for stem cell transplant

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.

Patients with thrombocytosis (non-pregnant)

  • Ruxolitinib: 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] 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.

  • 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]​ 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.

  • Momelotinib: recommended for symptomatic PMF patients (splenomegaly and constitutional symptoms) 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 other JAK inhibitors are ineffective or not tolerated.[26][53]

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

Patients without thrombocytosis (non-pregnant)

  • Pacritinib: 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. Pacritinib is effective in reducing splenomegaly and symptom burden in patients with myelofibrosis (including those with severe cytopenias).[54]

  • Momelotinib: 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.

Higher-risk PMF refractory to pharmacological agents

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

  • 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 radiotherapy) 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 patients

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 with PMF. 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]

  • JAK inhibitors, hydroxycarbamide, and thalidomide are contraindicated in pregnancy.

Higher-risk patients: adjunctive treatments

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

Patients with anaemia

  • 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]​​ Danazol and luspatercept are contraindicated in pregnancy. 

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

Patients with hyperuricaemia

  • Allopurinol is given to patients with hyperuricaemia.

  • In patients who are pregnant, 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.

Patients with extramedullary haematopoiesis

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

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