{"entity":{"id":"primary-myelofibrosis","kind":"cancer","name":"Primary myelofibrosis","aka":["PMF","Myelofibrosis","Chronic idiopathic myelofibrosis","Agnogenic myeloid metaplasia","Post-PV and post-ET myelofibrosis (secondary myelofibrosis)"],"tldr":"Primary myelofibrosis is a blood cancer in which the marrow scars over, the spleen swells and patients become anaemic and exhausted. JAK inhibitors, ruxolitinib first (COMFORT) and then fedratinib, pacritinib and momelotinib (MOMENTUM), shrink the spleen and relieve symptoms; only a donor stem cell transplant can cure it.","summary":"Primary myelofibrosis arises from a haematopoietic stem cell carrying JAK2 V617F (about 60 percent), CALR (about 25 percent) or MPL (5 to 8 percent), or none of the three (triple negative, the worst group), with additional high-risk mutations in ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1. The clone drives cytokine release and megakaryocyte abnormalities that scar the marrow; blood production moves to the spleen and liver, which enlarge, and patients develop anaemia, constitutional symptoms, early satiety and bone pain. A prefibrotic phase resembles essential thrombocythaemia. Risk scores (IPSS, DIPSS-plus, MIPSS70 and MIPSS70-plus v2 with mutations and cytogenetics) predict survival and steer the transplant decision; about one in five progress to blast phase, which is close to untreatable.\n\nJAK inhibitors treat the disease's consequences. Ruxolitinib, the first, shrank the spleen by 35 percent or more in 41.9 percent of patients against 0.7 percent on placebo at 24 weeks in COMFORT-I (2012), and beat best available therapy in COMFORT-II, with symptom scores halving in nearly half; approval came in 2011 and a survival advantage emerged in pooled long-term data. Fedratinib (JAKARTA, 2019 approval) works after ruxolitinib failure but carries a warning for Wernicke encephalopathy; pacritinib (PERSIST-2, approved 2022) is the option when platelets fall below 50 x 10^9/L; and momelotinib, which also blocks ACVR1 and so raises haemoglobin, was approved in 2023 after MOMENTUM, in which 25 percent of anaemic, previously treated patients had their symptom score halve against 9 percent on danazol, with more becoming transfusion independent. None of them clears the clone.\n\nAllogeneic transplant is the only cure and is offered to fit patients with higher-risk disease (MIPSS70 high, typically under 70), with a JAK inhibitor to shrink the spleen beforehand; transplant-related mortality is substantial, and timing is the central clinical judgement. Anaemia is managed with momelotinib, erythropoietin, danazol, transfusion and, in trials, luspatercept (INDEPENDENCE). Combinations of ruxolitinib with navitoclax (TRANSFORM-1) or the BET inhibitor pelabresib (MANIFEST-2) roughly doubled spleen responses in phase 3 but have not yet reached approval, imetelstat is being tested against survival itself in IMpactMF, and interferon, selinexor and anti-fibrotic approaches are in trials; whether any drug changes the disease's course rather than its symptoms is the field's central question.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Primary_myelofibrosis","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Primary_myelofibrosis"},{"label":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}],"tags":["subtype-page"],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","allogeneic-hsct","transfusion-support"],"targets":["jak2"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["jak2-v617f","post-pv-myelofibrosis","anaemia","allogeneic-transplant"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","paper-momentum-momelotinib-lancet-2023"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"The rarest and most serious of the classic myeloproliferative neoplasms, about one new case per 100,000 people a year, mostly over 60; median survival is around six years but ranges from under two to more than fifteen depending on risk score.","subtypes":["Prefibrotic primary myelofibrosis","Overt primary myelofibrosis, lower risk (DIPSS low or intermediate-1, MIPSS70 low)","Overt primary myelofibrosis, higher risk (DIPSS intermediate-2 or high, MIPSS70 high; transplant candidates)","Myelofibrosis with anaemia (momelotinib, luspatercept trials)","Myelofibrosis with severe thrombocytopenia (pacritinib)","Post-polycythaemia vera and post-essential thrombocythaemia myelofibrosis","Accelerated or blast phase myelofibrosis (MPN blast phase)"],"biomarkers":["JAK2 V617F, CALR and MPL driver mutations (or triple negative)","High-molecular-risk mutations: ASXL1, SRSF2, EZH2, IDH1/2, U2AF1","DIPSS-plus and MIPSS70-plus v2 scores","Marrow fibrosis grade","Spleen volume by imaging","Haemoglobin, platelet count and transfusion dependence","Blast percentage","Symptom score (MPN-SAF TSS)"],"standardOfCare":[{"setting":"Lower-risk, asymptomatic","approach":"Observation; aspirin for thrombosis risk where platelets are high; hydroxyurea or interferon for proliferative features.","refs":["aspirin","hydroxyurea","ropeginterferon-alfa-2b","peginterferon-alfa-2b"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Symptomatic splenomegaly or constitutional symptoms","approach":"Ruxolitinib (COMFORT-I and II) first; fedratinib after ruxolitinib failure or intolerance; pacritinib if platelets are below 50 x 10^9/L; momelotinib if anaemic.","refs":["ruxolitinib","fedratinib","pacritinib","momelotinib"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Anaemia of myelofibrosis","approach":"Momelotinib (MOMENTUM), erythropoiesis-stimulating agents where erythropoietin is low, danazol, transfusion with iron chelation; luspatercept in trials (INDEPENDENCE).","refs":["momelotinib","epoetin-alfa","transfusion-support","luspatercept","nct04717414","nct05320198"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Higher-risk, fit for transplant","approach":"Allogeneic stem cell transplant, usually under 70 and at MIPSS70 high or DIPSS intermediate-2 or higher, after JAK inhibitor to reduce spleen size.","refs":["allogeneic-hsct","ruxolitinib","conditioning-regimen"],"guideline":{"version":"NCCN Guidelines: Myeloproliferative Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1477"}},{"setting":"Ruxolitinib failure and trials","approach":"Switch JAK inhibitor; combination trials of ruxolitinib with navitoclax, pelabresib, selinexor or imetelstat; imetelstat versus best available therapy in IMpactMF.","refs":["navitoclax","pelabresib","selinexor","imetelstat","nct04468984","nct04562389","nct04576156","nct03441113"]}],"stateOfArt":["Four approved JAK inhibitors cover the main clinical problems: spleen and symptoms (ruxolitinib, fedratinib), low platelets (pacritinib) and anaemia (momelotinib).","Allogeneic transplant remains the only cure and the hardest decision, with mutation-based scores now guiding who and when.","Combination phase 3 trials doubled spleen responses but have not yet shown disease modification or survival gain."],"history":[{"year":1879,"title":"Heuck describes myelofibrosis","refs":[]},{"year":2005,"title":"JAK2 V617F discovered in most polycythaemia vera and half of myelofibrosis","refs":["jak2","jak2-v617f"]},{"year":2011,"title":"Ruxolitinib approved: the first JAK inhibitor, after COMFORT-I and II","refs":["ruxolitinib"]},{"year":2013,"title":"CALR mutations found in most JAK2-negative myelofibrosis","refs":[]},{"year":2018,"title":"MIPSS70 adds mutations to risk scoring for transplant decisions","refs":[]},{"year":2019,"title":"Fedratinib approved after JAKARTA","refs":["fedratinib"]},{"year":2022,"title":"Pacritinib approved for severe thrombocytopenia after PERSIST-2","refs":["pacritinib"]},{"year":2023,"title":"Momelotinib approved for anaemic myelofibrosis after MOMENTUM","refs":["momelotinib"]}],"pipeline":["momelotinib","pacritinib","navitoclax","pelabresib","imetelstat","luspatercept","nct04468984","nct04717414","nct04576156","nct04562389","allogeneic-hsct"],"openProblems":["No drug has been shown to change the course of the disease rather than its symptoms.","Transplant timing: too early risks a fatal procedure in someone with years to live, too late loses the window.","Blast phase myelofibrosis has no effective treatment."],"parent":"myeloproliferative-neoplasms"},"route":"/cancers/primary-myelofibrosis/","neighbours":{"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"transfusion-support","kind":"technology","name":"Transfusion support and anaemia management","route":"/technologies/transfusion-support/"}],"target":[{"id":"jak2","kind":"target","name":"JAK2","route":"/targets/jak2/"}],"term":[{"id":"allogeneic-transplant","kind":"term","name":"Allogeneic stem cell transplant (allo-SCT)","route":"/terms/allogeneic-transplant/"},{"id":"anaemia","kind":"term","name":"Anaemia","route":"/terms/anaemia/"},{"id":"conditioning-regimen","kind":"term","name":"Conditioning regimen (myeloablative, reduced-intensity)","route":"/terms/conditioning-regimen/"},{"id":"jak2-v617f","kind":"term","name":"JAK2 V617F","route":"/terms/jak2-v617f/"},{"id":"post-pv-myelofibrosis","kind":"term","name":"Post-PV myelofibrosis (spent phase)","route":"/terms/post-pv-myelofibrosis/"}],"paper":[{"id":"paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012","kind":"paper","name":"COMFORT-I: ruxolitinib, the first JAK inhibitor, versus placebo for myelofibrosis","route":"/key-papers/paper-comfort-1-ruxolitinib-myelofibrosis-nejm-2012/"},{"id":"paper-momentum-momelotinib-lancet-2023","kind":"paper","name":"MOMENTUM: momelotinib versus danazol for myelofibrosis patients with anaemia after a prior JAK inhibitor","route":"/key-papers/paper-momentum-momelotinib-lancet-2023/"}],"drug":[{"id":"aspirin","kind":"drug","name":"Aspirin","route":"/drugs/aspirin/"},{"id":"epoetin-alfa","kind":"drug","name":"Epoetin alfa","route":"/drugs/epoetin-alfa/"},{"id":"fedratinib","kind":"drug","name":"Fedratinib","route":"/drugs/fedratinib/"},{"id":"hydroxyurea","kind":"drug","name":"Hydroxyurea (hydroxycarbamide)","route":"/drugs/hydroxyurea/"},{"id":"imetelstat","kind":"drug","name":"Imetelstat","route":"/drugs/imetelstat/"},{"id":"luspatercept","kind":"drug","name":"Luspatercept","route":"/drugs/luspatercept/"},{"id":"momelotinib","kind":"drug","name":"Momelotinib","route":"/drugs/momelotinib/"},{"id":"navitoclax","kind":"drug","name":"Navitoclax","route":"/drugs/navitoclax/"},{"id":"pacritinib","kind":"drug","name":"Pacritinib","route":"/drugs/pacritinib/"},{"id":"peginterferon-alfa-2b","kind":"drug","name":"Peginterferon alfa-2b","route":"/drugs/peginterferon-alfa-2b/"},{"id":"pelabresib","kind":"drug","name":"Pelabresib","route":"/drugs/pelabresib/"},{"id":"ropeginterferon-alfa-2b","kind":"drug","name":"Ropeginterferon alfa-2b","route":"/drugs/ropeginterferon-alfa-2b/"},{"id":"ruxolitinib","kind":"drug","name":"Ruxolitinib","route":"/drugs/ruxolitinib/"},{"id":"selinexor","kind":"drug","name":"Selinexor","route":"/drugs/selinexor/"}],"trial":[{"id":"nct04576156","kind":"trial","name":"A Study Comparing Imetelstat Versus Best Available Therapy for the Treatment of Intermediate-2 or High-risk Myelofibrosis (MF) Who Have Not Responded to Janus Kinase (JAK)-Inhibitor Treatment","route":"/trials/nct04576156/"},{"id":"nct04717414","kind":"trial","name":"An Efficacy and Safety Study of Luspatercept (ACE-536) Versus Placebo in Subjects With Myeloproliferative Neoplasm-Associated Myelofibrosis on Concomi","route":"/trials/nct04717414/"},{"id":"nct03441113","kind":"trial","name":"Extended Access of Momelotinib in Adults With Myelofibrosis","route":"/trials/nct03441113/"},{"id":"nct05320198","kind":"trial","name":"Study of DISC-0974 (RALLY-MF) in Participants With Myelofibrosis or Myelodysplastic Syndrome and Anemia","route":"/trials/nct05320198/"},{"id":"nct04468984","kind":"trial","name":"Study of Oral Navitoclax Tablet in Combination With Oral Ruxolitinib Tablet Versus Best Available Therapy to Assess Change in Spleen Volume in Adult Participants With Relapsed/Refractory Myelofibrosis","route":"/trials/nct04468984/"},{"id":"nct04562389","kind":"trial","name":"Study of Selinexor in Combination With Ruxolitinib in Myelofibrosis","route":"/trials/nct04562389/"}],"cancer":[{"id":"myeloproliferative-neoplasms","kind":"cancer","name":"Myeloproliferative neoplasms (PV, ET, myelofibrosis)","route":"/cancers/myeloproliferative-neoplasms/"}]}}