Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized by bone marrow fibrosis, abnormal megakaryocyte proliferation, extramedullary hematopoiesis, and progressive cytopenias. Driver mutations include JAK2 V617F (approximately 60%), CALR (25%), and MPL (5%), with 10% being triple-negative. Additional mutations in epigenetic regulators (ASXL1, TET2, EZH2) and splicing factors contribute to disease heterogeneity and prognosis. PMF causes marked splenomegaly, constitutional symptoms, and carries risk of transformation to acute myeloid leukemia. JAK inhibitors like ruxolitinib and fedratinib provide symptom control, while allogeneic stem cell transplantation remains the only curative option.
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name: Primary Myelofibrosis
creation_date: '2026-01-26T02:55:13Z'
updated_date: '2026-05-01T12:00:00Z'
description: >-
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm characterized
by bone marrow fibrosis, abnormal megakaryocyte proliferation, extramedullary
hematopoiesis, and progressive cytopenias. Driver mutations include JAK2 V617F
(approximately 60%), CALR (25%), and MPL (5%), with 10% being triple-negative.
Additional mutations in epigenetic regulators (ASXL1, TET2, EZH2) and splicing
factors contribute to disease heterogeneity and prognosis. PMF causes marked
splenomegaly, constitutional symptoms, and carries risk of transformation to
acute myeloid leukemia. JAK inhibitors like ruxolitinib and fedratinib provide
symptom control, while allogeneic stem cell transplantation remains the only
curative option.
categories:
- Hematologic Malignancy
- Myeloproliferative Neoplasm
parents:
- myeloproliferative neoplasm
stages:
- name: Prefibrotic PMF
description: >-
Early stage characterized by hypercellular marrow with megakaryocyte
proliferation and atypia, but minimal or absent reticulin fibrosis (grade 0-1).
Often presents with thrombocytosis and may be mistaken for essential
thrombocythemia.
- name: Overt PMF
description: >-
Advanced stage with significant reticulin or collagen fibrosis (grade 2-3),
progressive cytopenias, splenomegaly, and constitutional symptoms.
Leukoerythroblastic blood picture and tear-drop cells are characteristic.
pathophysiology:
- name: JAK-STAT Pathway Hyperactivation
description: >-
Driver mutations in JAK2, CALR, or MPL all converge on constitutive activation
of JAK-STAT signaling. JAK2 V617F directly activates the kinase; CALR and MPL
mutations lead to activation of MPL receptor signaling.
cell_types:
- preferred_term: megakaryocyte
term:
id: CL:0000556
label: megakaryocyte
- preferred_term: hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
biological_processes:
- preferred_term: JAK-STAT signaling pathway
modifier: INCREASED
term:
id: GO:0007259
label: cell surface receptor signaling pathway via JAK-STAT
locations:
- preferred_term: bone marrow
term:
id: UBERON:0002371
label: bone marrow
downstream:
- target: Abnormal Megakaryopoiesis
description: JAK-STAT activation drives megakaryocyte proliferation and atypia
- target: Cytokine-Mediated Marrow Fibrosis
description: Activated megakaryocytes release profibrotic cytokines
- name: Abnormal Megakaryopoiesis
description: >-
Driver mutations cause aberrant megakaryocyte proliferation and maturation.
Megakaryocytes show characteristic atypia with clustering, abnormal lobation,
and defective platelet production.
biological_processes:
- preferred_term: megakaryocyte differentiation
modifier: ABNORMAL
term:
id: GO:0030219
label: megakaryocyte differentiation
- name: Cytokine-Mediated Marrow Fibrosis
description: >-
Atypical megakaryocytes release profibrotic cytokines including TGF-beta,
PDGF, and bFGF, stimulating marrow stromal cells to deposit reticulin and
collagen fibers. Progressive fibrosis replaces normal hematopoietic tissue.
evidence:
- reference: PMID:41514563
reference_title: "A Review of the Pathological and Molecular Diagnosis of Primary Myelofibrosis."
supports: PARTIAL
snippet: "Primary myelofibrosis (PMF) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm (MPN) that features clonal proliferation of atypical megakaryocytes and myeloid cells, fibrosis of the bone marrow, extramedullary hematopoiesis, and increased risk of leukemic transformation to acute myeloid leukemia (AML)."
explanation: This abstract highlights bone marrow fibrosis and atypical megakaryocyte proliferation, supporting the fibrosis mechanism described.
biological_processes:
- preferred_term: extracellular matrix organization
modifier: INCREASED
term:
id: GO:0030198
label: extracellular matrix organization
downstream:
- target: Extramedullary Hematopoiesis
description: Progressive marrow fibrosis and failure drives hematopoiesis to shift to extramedullary sites
- name: Extramedullary Hematopoiesis
description: >-
As bone marrow function declines due to fibrosis, hematopoiesis shifts to
spleen, liver, and other sites. This causes massive splenomegaly and
hepatomegaly with associated symptoms.
locations:
- preferred_term: spleen
term:
id: UBERON:0002106
label: spleen
biological_processes:
- preferred_term: hematopoiesis
modifier: ABNORMAL
term:
id: GO:0030097
label: hemopoiesis
histopathology:
- name: Bone Marrow Fibrosis
finding_term:
preferred_term: Bone Marrow Fibrosis
term:
id: NCIT:C36212
label: Bone Marrow Fibrosis
frequency: VERY_FREQUENT
description: Primary myelofibrosis is characterized by bone marrow fibrosis.
evidence:
- reference: PMID:33477816
reference_title: "Focus on Osteosclerotic Progression in Primary Myelofibrosis."
supports: PARTIAL
snippet: "Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by"
explanation: Abstract describes PMF as a myeloproliferative neoplasm characterized by bone marrow fibrosis.
phenotypes:
- category: Abdominal
name: Splenomegaly
frequency: FREQUENT
diagnostic: true
description: >-
Massive splenomegaly from extramedullary hematopoiesis is a hallmark of PMF.
May extend to pelvis causing abdominal discomfort, early satiety, and
portal hypertension.
phenotype_term:
preferred_term: Splenomegaly
term:
id: HP:0001744
label: Splenomegaly
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001744 | Splenomegaly | Frequent (79-30%)"
explanation: Orphanet classifies splenomegaly as frequent (79-30%) in primary myelofibrosis.
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "for symptomatic splenomegaly, hydroxyurea and ruxolitinib"
explanation: Tefferi 2021 review identifies symptomatic splenomegaly as a major clinical feature requiring treatment.
- category: Hematologic
name: Anemia
frequency: FREQUENT
description: >-
Progressive anemia from bone marrow failure is common. May be multifactorial
including ineffective erythropoiesis, splenic sequestration, and iron deficiency.
phenotype_term:
preferred_term: Anemia
term:
id: HP:0001903
label: Anemia
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001903 | Anemia | Frequent (79-30%)"
explanation: Orphanet classifies anemia as frequent (79-30%) in primary myelofibrosis.
- reference: PMID:36332787
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical manifestations of MF include splenomegaly, constitutional symptoms, and anemia, whose pathogenesis is multifactorial and largely due to ineffective erythropoiesis and is clinically associated with poor quality of life and reduced overall survival."
explanation: Review confirms anemia as a key clinical manifestation with multifactorial pathogenesis.
- category: Constitutional
name: Fatigue
frequency: FREQUENT
description: >-
Profound fatigue is one of the most debilitating symptoms, significantly
impacting quality of life.
phenotype_term:
preferred_term: Fatigue
term:
id: HP:0012378
label: Fatigue
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0012378 | Fatigue | Frequent (79-30%)"
explanation: Orphanet classifies fatigue as frequent (79-30%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical manifestations of MF include cytopenia, fatigue and constitutional symptoms such as low-grade fever, weight loss and night sweats."
explanation: Review identifies fatigue as a primary clinical manifestation of myelofibrosis.
- category: Constitutional
name: Cachexia
frequency: VERY_RARE
description: >-
Weight loss and cachexia from hypermetabolic state driven by inflammatory
cytokine production.
phenotype_term:
preferred_term: Cachexia
term:
id: HP:0004326
label: Cachexia
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0004326 | Cachexia | Very rare (<4-1%)"
explanation: Orphanet classifies cachexia as very rare in primary myelofibrosis.
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival."
explanation: Tefferi 2021 review lists cachexia as a recognized disease feature of PMF.
- category: Hematologic
name: Thrombocytopenia
frequency: FREQUENT
description: >-
Low platelet count develops as disease progresses, reflecting bone marrow
failure and splenic sequestration. Increases bleeding risk.
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001873 | Thrombocytopenia | Frequent (79-30%)"
explanation: Orphanet classifies thrombocytopenia as frequent (79-30%) in primary myelofibrosis.
- category: Abdominal
name: Hepatomegaly
frequency: FREQUENT
description: >-
Liver enlargement from extramedullary hematopoiesis and portal hypertension.
phenotype_term:
preferred_term: Hepatomegaly
term:
id: HP:0002240
label: Hepatomegaly
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0002240 | Hepatomegaly | Frequent (79-30%)"
explanation: Orphanet classifies hepatomegaly as frequent (79-30%) in primary myelofibrosis.
- category: Constitutional
name: Pallor
frequency: FREQUENT
description: >-
Pallor due to progressive anemia from ineffective erythropoiesis and
bone marrow failure.
phenotype_term:
preferred_term: Pallor
term:
id: HP:0000980
label: Pallor
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0000980 | Pallor | Frequent (79-30%)"
explanation: Orphanet classifies pallor as frequent (79-30%) in primary myelofibrosis.
- category: Abdominal
name: Hepatosplenomegaly
frequency: FREQUENT
description: >-
Combined hepatic and splenic enlargement from extramedullary hematopoiesis
is a characteristic finding, particularly in overt PMF.
phenotype_term:
preferred_term: Hepatosplenomegaly
term:
id: HP:0001433
label: Hepatosplenomegaly
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001433 | Hepatosplenomegaly | Frequent (79-30%)"
explanation: Orphanet classifies hepatosplenomegaly as frequent (79-30%) in primary myelofibrosis.
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival."
explanation: Tefferi 2021 review lists hepatosplenomegaly as a core disease feature.
- category: Hematologic
name: Abnormal Megakaryocyte Morphology
frequency: FREQUENT
diagnostic: true
description: >-
Megakaryocyte atypia with clustering, abnormal lobation (cloud-like and
hyperlobated nuclei), and aberrant maturation is a hallmark diagnostic
feature of PMF.
phenotype_term:
preferred_term: Abnormal megakaryocyte morphology
term:
id: HP:0012143
label: Abnormal megakaryocyte morphology
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0012143 | Abnormal megakaryocyte morphology | Frequent (79-30%)"
explanation: Orphanet classifies abnormal megakaryocyte morphology as frequent (79-30%) in primary myelofibrosis.
- reference: PMID:41514563
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Primary myelofibrosis (PMF) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm (MPN) that features clonal proliferation of atypical megakaryocytes and myeloid cells, fibrosis of the bone marrow, extramedullary hematopoiesis, and increased risk of leukemic transformation to acute myeloid leukemia (AML)."
explanation: Review highlights atypical megakaryocyte proliferation as a defining feature of PMF.
- category: Hematologic
name: Abnormal Bone Marrow Cell Morphology
frequency: VERY_FREQUENT
diagnostic: true
description: >-
Characteristic bone marrow morphological changes including reticulin and
collagen fibrosis, megakaryocyte atypia, and abnormal myeloid maturation
are the primary diagnostic criteria for PMF.
phenotype_term:
preferred_term: Abnormal bone marrow cell morphology
term:
id: HP:0005561
label: Abnormal bone marrow cell morphology
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0005561 | Abnormality of bone marrow cell morphology | Very frequent (99-80%)"
explanation: Orphanet classifies abnormality of bone marrow cell morphology as very frequent (99-80%) in primary myelofibrosis.
- category: Constitutional
name: Low-Grade Fever
frequency: OCCASIONAL
description: >-
Low-grade fever is a constitutional symptom driven by aberrant inflammatory
cytokine expression, particularly IL-6 and TNF-alpha.
phenotype_term:
preferred_term: Low-grade fever
term:
id: HP:0011134
label: Low-grade fever
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0011134 | Low-grade fever | Occasional (29-5%)"
explanation: Orphanet classifies low-grade fever as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical manifestations of MF include cytopenia, fatigue and constitutional symptoms such as low-grade fever, weight loss and night sweats."
explanation: Review identifies low-grade fever as one of the constitutional symptoms of myelofibrosis.
- category: Constitutional
name: Fever
frequency: OCCASIONAL
description: >-
Fever occurs as a constitutional symptom in PMF, driven by the inflammatory
cytokine milieu. Must be distinguished from infection-related fever.
phenotype_term:
preferred_term: Fever
term:
id: HP:0001945
label: Fever
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001945 | Fever | Occasional (29-5%)"
explanation: Orphanet classifies fever as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:32300883
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF), are rare clonal hematopoietic stem cell disorders accompanied by a strong inflammatory milieu, which is directly responsible for constitutional symptoms associated with the disease, such as fever, weight loss or night sweats."
explanation: Confirms fever as a constitutional symptom directly caused by the inflammatory milieu in MPN including myelofibrosis.
- category: Constitutional
name: Anorexia
frequency: OCCASIONAL
description: >-
Loss of appetite contributing to weight loss and cachexia, driven by
inflammatory cytokines and mechanical effects of splenomegaly.
phenotype_term:
preferred_term: Anorexia
term:
id: HP:0002039
label: Anorexia
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0002039 | Anorexia | Occasional (29-5%)"
explanation: Orphanet classifies anorexia as occasional (29-5%) in primary myelofibrosis.
- category: Hematologic
name: Pancytopenia
frequency: OCCASIONAL
description: >-
Reduction in all blood cell lineages due to progressive marrow failure
from fibrosis. More common in advanced (overt) PMF.
phenotype_term:
preferred_term: Pancytopenia
term:
id: HP:0001876
label: Pancytopenia
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001876 | Pancytopenia | Occasional (29-5%)"
explanation: Orphanet classifies pancytopenia as occasional (29-5%) in primary myelofibrosis.
- category: Hematologic
name: Thrombocytosis
frequency: OCCASIONAL
description: >-
Elevated platelet count, particularly in prefibrotic PMF where it may
mimic essential thrombocythemia. Platelet count declines as disease
progresses to overt fibrotic phase.
phenotype_term:
preferred_term: Thrombocytosis
term:
id: HP:0001894
label: Thrombocytosis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001894 | Thrombocytosis | Occasional (29-5%)"
explanation: Orphanet classifies thrombocytosis as occasional (29-5%) in primary myelofibrosis.
- category: Hematologic
name: Leukocytosis
frequency: OCCASIONAL
description: >-
Elevated white blood cell count, a minor diagnostic criterion for PMF.
Leukocytosis is an independent risk factor for thrombosis in prefibrotic PMF.
phenotype_term:
preferred_term: Leukocytosis
term:
id: HP:0001974
label: Increased total leukocyte count
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001974 | Leukocytosis | Occasional (29-5%)"
explanation: Orphanet classifies leukocytosis as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Minor criteria, include a) anemia not attributed to a comorbid condition, b) leukocytosis ≥ 11 × 109, c) palpable splenomegaly, d) lactate dehydrogenase (LDH) level above normal limit of institutional reference range and e) leukoerythroblastosis"
explanation: WHO diagnostic criteria list leukocytosis as a minor criterion for PMF diagnosis.
- category: Hematologic
name: Extramedullary Hematopoiesis
frequency: OCCASIONAL
description: >-
Hematopoiesis shifts to spleen, liver, and other sites as bone marrow
function declines. Drives organomegaly and can cause complications at
unusual sites including pleura, peritoneum, and CNS.
phenotype_term:
preferred_term: Extramedullary hematopoiesis
term:
id: HP:0001978
label: Extramedullary hematopoiesis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001978 | Extramedullary hematopoiesis | Occasional (29-5%)"
explanation: Orphanet classifies extramedullary hematopoiesis as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Additional disease features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival."
explanation: Tefferi 2021 review lists extramedullary hematopoiesis as a core disease feature of PMF.
- category: Hematologic
name: Poikilocytosis
frequency: OCCASIONAL
description: >-
Abnormal red blood cell shapes including dacrocytes (tear-drop cells)
are characteristic of the leukoerythroblastic blood picture in PMF.
phenotype_term:
preferred_term: Poikilocytosis
term:
id: HP:0004447
label: Poikilocytosis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0004447 | Poikilocytosis | Occasional (29-5%)"
explanation: Orphanet classifies poikilocytosis as occasional (29-5%) in primary myelofibrosis.
- category: Hematologic
name: Abnormal Bleeding
frequency: OCCASIONAL
description: >-
Bleeding complications from thrombocytopenia, platelet functional defects,
and portal hypertension-related varices. Bleeding events are more common
in MF than in other MPNs.
phenotype_term:
preferred_term: Abnormal bleeding
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001892 | Abnormal bleeding | Occasional (29-5%)"
explanation: Orphanet classifies abnormal bleeding as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Bleeding and thrombosis are long recognized complications of myelofibrosis (MF) and contribute significantly to its morbidity and mortality."
explanation: Review confirms bleeding as a recognized complication contributing to MF morbidity and mortality.
- category: Vascular
name: Arterial Thrombosis
frequency: OCCASIONAL
description: >-
Arterial thrombotic events include stroke, peripheral vascular disease,
and acute coronary syndrome. Risk is comparable to essential thrombocythemia.
phenotype_term:
preferred_term: Arterial thrombosis
term:
id: HP:0004420
label: Arterial thrombosis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0004420 | Arterial thrombosis | Occasional (29-5%)"
explanation: Orphanet classifies arterial thrombosis as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both arterial and venous thrombotic events are not uncommon in patients with PMF"
explanation: Review confirms arterial thrombosis as a recognized complication of PMF.
- category: Vascular
name: Venous Thrombosis
frequency: OCCASIONAL
description: >-
Venous thrombotic events including deep vein thrombosis, pulmonary embolism,
and splanchnic vein thrombosis (portal vein, Budd-Chiari syndrome).
phenotype_term:
preferred_term: Venous thrombosis
term:
id: HP:0004936
label: Venous thrombosis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0004936 | Venous thrombosis | Occasional (29-5%)"
explanation: Orphanet classifies venous thrombosis as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Both arterial and venous thrombotic events are not uncommon in patients with PMF"
explanation: Review confirms venous thrombosis as a recognized complication of PMF.
- category: Abdominal
name: Portal Hypertension
frequency: OCCASIONAL
description: >-
Portal hypertension from splanchnic vein thrombosis, extramedullary
hematopoiesis in the liver, and increased hepatic blood flow. Can lead
to variceal bleeding and ascites.
phenotype_term:
preferred_term: Portal hypertension
term:
id: HP:0001409
label: Portal hypertension
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0001409 | Portal hypertension | Occasional (29-5%)"
explanation: Orphanet classifies portal hypertension as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:25755427
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Portal hypertension is found in up to 7% of patients."
explanation: Reports portal hypertension frequency of up to 7% in myeloproliferative disease patients.
- category: Dermatologic
name: Petechiae
frequency: OCCASIONAL
description: >-
Small hemorrhagic spots from thrombocytopenia and platelet dysfunction.
phenotype_term:
preferred_term: Petechiae
term:
id: HP:0000967
label: Petechiae
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0000967 | Petechiae | Occasional (29-5%)"
explanation: Orphanet classifies petechiae as occasional (29-5%) in primary myelofibrosis.
- category: Dermatologic
name: Purpura
frequency: OCCASIONAL
description: >-
Purpuric skin lesions from thrombocytopenia and platelet dysfunction.
phenotype_term:
preferred_term: Purpura
term:
id: HP:0000979
label: Purpura
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0000979 | Purpura | Occasional (29-5%)"
explanation: Orphanet classifies purpura as occasional (29-5%) in primary myelofibrosis.
- category: Dermatologic
name: Ecchymosis
frequency: OCCASIONAL
description: >-
Easy bruising from thrombocytopenia and coagulopathy.
phenotype_term:
preferred_term: Ecchymosis
term:
id: HP:0031364
label: Ecchymosis
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0031364 | Ecchymosis | Occasional (29-5%)"
explanation: Orphanet classifies ecchymosis as occasional (29-5%) in primary myelofibrosis.
- category: Abdominal
name: Flank Pain
frequency: OCCASIONAL
description: >-
Flank pain from massive splenomegaly or splenic infarction.
phenotype_term:
preferred_term: Flank pain
term:
id: HP:0030157
label: Flank pain
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0030157 | Flank pain | Occasional (29-5%)"
explanation: Orphanet classifies flank pain as occasional (29-5%) in primary myelofibrosis.
- category: Other
name: Lymphadenopathy
frequency: OCCASIONAL
description: >-
Lymph node enlargement may occur due to extramedullary hematopoiesis
at lymph node sites.
phenotype_term:
preferred_term: Lymphadenopathy
term:
id: HP:0002716
label: Lymphadenopathy
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0002716 | Lymphadenopathy | Occasional (29-5%)"
explanation: Orphanet classifies lymphadenopathy as occasional (29-5%) in primary myelofibrosis.
- category: Hematologic
name: Increased Circulating Lactate Dehydrogenase Concentration
frequency: VERY_RARE
diagnostic: true
notes: >-
Orphanet classifies LDH elevation as very rare, but it is a WHO minor
diagnostic criterion for PMF. The Orphanet frequency likely reflects
population-level reporting rather than clinical prevalence among
diagnosed patients, where LDH elevation is common.
description: >-
Elevated LDH reflecting increased cell turnover and extramedullary
hematopoiesis. A WHO minor diagnostic criterion for PMF that correlates
with disease activity.
phenotype_term:
preferred_term: Increased circulating lactate dehydrogenase concentration
term:
id: HP:0025435
label: Increased circulating lactate dehydrogenase concentration
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0025435 | Increased circulating lactate dehydrogenase concentration | Very rare (<4-1%)"
explanation: Orphanet classifies increased LDH as very rare in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Minor criteria, include a) anemia not attributed to a comorbid condition, b) leukocytosis ≥ 11 × 109, c) palpable splenomegaly, d) lactate dehydrogenase (LDH) level above normal limit of institutional reference range and e) leukoerythroblastosis"
explanation: LDH above normal is a WHO minor diagnostic criterion for PMF.
- category: Hematologic
name: Bone Marrow Hypercellularity
frequency: OCCASIONAL
description: >-
Increased age-adjusted bone marrow cellularity, particularly in the
prefibrotic phase, with granulocytic proliferation and megakaryocyte
atypia.
phenotype_term:
preferred_term: Bone marrow hypercellularity
term:
id: HP:0031020
label: Bone marrow hypercellularity
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "HP:0031020 | Bone marrow hypercellularity | Occasional (29-5%)"
explanation: Orphanet classifies bone marrow hypercellularity as occasional (29-5%) in primary myelofibrosis.
- reference: PMID:28808761
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "megakaryocytic proliferation and atypia, without reticulin fibrosis > grade 1, accompanied by increased age-adjusted bone marrow (BM) cellularity, granulocytic proliferation, and often decreased erythropoiesis"
explanation: WHO diagnostic criteria for prefibrotic PMF include increased age-adjusted bone marrow cellularity.
biochemical:
- name: Lactate Dehydrogenase (LDH)
notes: >-
LDH is elevated reflecting increased cell turnover and extramedullary
hematopoiesis. Levels correlate with disease activity.
- name: Peripheral Blood Smear
notes: >-
Leukoerythroblastic picture with tear-drop cells (dacrocytes), nucleated
red blood cells, and immature granulocytes is characteristic of PMF.
genetic:
- name: JAK2
association: Somatic Activating Mutations
notes: >-
JAK2 V617F occurs in approximately 60% of PMF patients. Provides rationale
for JAK inhibitor therapy.
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "JAK2 | Janus kinase 2 | hgnc:6192 | Disease-causing somatic mutation(s) in"
explanation: Orphanet confirms JAK2 as harboring disease-causing somatic mutations in PMF.
- name: CALR
association: Somatic Frameshift Mutations
notes: >-
CALR exon 9 frameshift mutations occur in approximately 25% of PMF, mostly
type 1 (52bp deletion) or type 2 (5bp insertion). Generally associated
with better prognosis than JAK2 mutations.
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "CALR | calreticulin | hgnc:1455 | Disease-causing somatic mutation(s) in"
explanation: Orphanet confirms CALR as harboring disease-causing somatic mutations in PMF.
- name: MPL
association: Somatic Activating Mutations
notes: >-
MPL W515L/K mutations occur in approximately 5% of PMF. Activates JAK-STAT
signaling through the thrombopoietin receptor.
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "MPL | MPL proto-oncogene, thrombopoietin receptor | hgnc:7217 | Disease-causing somatic mutation(s) in"
explanation: Orphanet confirms MPL as harboring disease-causing somatic mutations in PMF.
- name: TET2
association: Somatic Loss-of-Function Mutations
notes: >-
TET2 mutations are found in a subset of PMF patients and contribute to
epigenetic dysregulation. TET2 encodes a methylcytosine dioxygenase
involved in DNA demethylation.
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "TET2 | tet methylcytosine dioxygenase 2 | hgnc:25941 | Disease-causing somatic mutation(s) in"
explanation: Orphanet lists TET2 as harboring disease-causing somatic mutations in primary myelofibrosis.
- name: ASXL1
association: Somatic Loss-of-Function Mutations
notes: >-
ASXL1 mutations are adverse prognostic markers independent of driver
mutation status. Part of high molecular risk (HMR) category.
evidence:
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors."
explanation: Tefferi 2021 review confirms ASXL1 as an adverse prognostic mutation in PMF.
- name: EZH2
association: Somatic Loss-of-Function Mutations
notes: >-
EZH2 mutations contribute to epigenetic dysregulation in PMF.
EZH2 encodes a histone methyltransferase in the polycomb repressive
complex 2 (PRC2).
- name: SRSF2
association: Somatic Mutations
notes: >-
SRSF2 mutations predict inferior survival in PMF, independent of
driver mutation status and other risk factors. Part of high molecular
risk (HMR) category. SRSF2 encodes a serine/arginine-rich splicing factor.
evidence:
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors."
explanation: Tefferi 2021 review identifies SRSF2 as an adverse prognostic mutation in PMF.
- name: U2AF1
association: Somatic Mutations
notes: >-
U2AF1 Q157 mutations predict inferior survival in PMF, independent of
driver mutation status. U2AF1 encodes a small subunit of the U2
auxiliary splicing factor.
evidence:
- reference: PMID:33197049
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF, independent of each other and other risk factors."
explanation: Tefferi 2021 review identifies U2AF1-Q157 as an adverse prognostic mutation in PMF.
treatments:
- name: Ruxolitinib
description: >-
JAK1/JAK2 inhibitor approved for intermediate-2 and high-risk PMF. Provides
marked reduction in spleen size and constitutional symptoms but does not
significantly alter disease course or prevent leukemic transformation.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
- name: Fedratinib
description: >-
JAK2 inhibitor approved for intermediate-2 and high-risk PMF, including
patients previously treated with ruxolitinib. Selective JAK2 inhibition
with similar efficacy profile.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: fedratinib
term:
id: NCIT:C88293
label: Fedratinib
- name: Allogeneic Stem Cell Transplantation
description: >-
Only potentially curative treatment for PMF. Considered for younger patients
with high-risk disease. Significant transplant-related morbidity and mortality
must be weighed against disease risk.
treatment_term:
preferred_term: hematopoietic stem cell transplantation
term:
id: MAXO:0000747
label: hematopoietic stem cell transplantation
- name: Hydroxyurea
description: >-
Cytoreductive therapy for symptomatic splenomegaly or thrombocytosis.
Provides modest benefit but does not address constitutional symptoms
as effectively as JAK inhibitors.
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000646
label: cancer chemotherapy
therapeutic_agent:
- preferred_term: hydroxyurea
term:
id: CHEBI:44423
label: hydroxyurea
- name: Anagrelide
description: >-
Platelet-lowering agent used for thrombocytosis when present. Selective
megakaryocyte inhibitor.
treatment_term:
preferred_term: targeted therapy
term:
id: NCIT:C93352
label: Targeted Therapy
therapeutic_agent:
- preferred_term: anagrelide
term:
id: CHEBI:142290
label: anagrelide
- name: Momelotinib
description: >-
JAK1/JAK2 and ACVR1/ALK2 inhibitor FDA-approved in 2023 for intermediate-
or high-risk PMF with anemia. Uniquely addresses anemia by suppressing
hepcidin through ACVR1 inhibition. Demonstrated durable symptom, spleen,
and anemia benefits in the MOMENTUM trial.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: momelotinib
term:
id: CHEBI:91407
label: momelotinib
evidence:
- reference: PMID:37517413
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48."
explanation: MOMENTUM phase 3 trial demonstrates durable efficacy of momelotinib for symptom, spleen, and anemia endpoints in previously JAK inhibitor-treated MF patients.
- name: Pacritinib
description: >-
Selective JAK2/IRAK1/ACVR1 inhibitor, JAK1-sparing, FDA-approved in 2022
for PMF with severe thrombocytopenia (platelets less than 50 x 10^9/L).
Can be administered at full dose regardless of baseline platelet count.
treatment_term:
preferred_term: pharmacotherapy
term:
id: MAXO:0000058
label: pharmacotherapy
therapeutic_agent:
- preferred_term: pacritinib
term:
id: CHEBI:231350
label: pacritinib
evidence:
- reference: PMID:35622972
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the dose finding PAC203 study endorsed the safety and efficacy of 200 mg twice daily, leading to the approval of PAC for the treatment of patients with MF with platelets ≤ 50 × 109/L."
explanation: Review of pacritinib development describes its approval for thrombocytopenic MF.
epidemiology:
- name: European Annual Incidence
description: >-
Annual incidence of primary myelofibrosis in Europe estimated at
1-9 per 100,000.
unit: cases per 100,000
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "1-9 / 100 000 | Europe | Annual incidence | EXPERT"
explanation: Orphanet reports European annual incidence of 1-9 per 100,000 based on expert opinion.
- name: European Point Prevalence
description: >-
Point prevalence of primary myelofibrosis in Europe estimated at
1-9 per 100,000.
unit: cases per 100,000
evidence:
- reference: ORPHA:824
supports: SUPPORT
snippet: "1-9 / 100 000 | Europe | Point prevalence | INST"
explanation: Orphanet reports European point prevalence of 1-9 per 100,000 based on institutional data.
disease_term:
preferred_term: primary myelofibrosis
term:
id: MONDO:0009692
label: primary myelofibrosis
classifications:
icdo_morphology:
classification_value: Leukemia
harrisons_chapter:
- classification_value: cancer
- classification_value: hematologic malignancy
references:
- reference: DOI:10.1007/s00277-025-06191-7
title: How I diagnose and treat patients in the pre-fibrotic phase of primary myelofibrosis (pre-PMF) - practical approaches of a German expert panel discussion in 2024
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: How I diagnose and treat patients in the pre-fibrotic phase of primary myelofibrosis (pre-PMF) - practical approaches of a German expert panel discussion in 2024
supporting_text: The prefibrotic phase of primary myelofibrosis (pre-PMF) represents a distinct subentity within the spectrum of myeloproliferative neoplasms (MPNs), recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC).
evidence:
- reference: DOI:10.1007/s00277-025-06191-7
reference_title: How I diagnose and treat patients in the pre-fibrotic phase of primary myelofibrosis (pre-PMF) - practical approaches of a German expert panel discussion in 2024
supports: SUPPORT
evidence_source: OTHER
snippet: The prefibrotic phase of primary myelofibrosis (pre-PMF) represents a distinct subentity within the spectrum of myeloproliferative neoplasms (MPNs), recognized by the World Health Organization (WHO) and the International Consensus Classification (ICC).
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1007/s00428-022-03480-8
title: 'International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms'
supporting_text: The recently published International Consensus Classification (ICC) of myeloid neoplasms summarized the results of an in-depth effort by pathologists, oncologists, and geneticists aimed to update the 2017 World Health Organization classification system for hematopoietic tumors.
evidence:
- reference: DOI:10.1007/s00428-022-03480-8
reference_title: 'International Consensus Classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms'
supports: SUPPORT
evidence_source: OTHER
snippet: The recently published International Consensus Classification (ICC) of myeloid neoplasms summarized the results of an in-depth effort by pathologists, oncologists, and geneticists aimed to update the 2017 World Health Organization classification system for hematopoietic tumors.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1007/s10238-025-01830-9
title: 'From symptom scales to regulatory endpoints: the evolution and clinical impact of patient-reported outcome measures in myeloproliferative neoplasms'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myeloproliferative neoplasms (MPNs) are symptom-driven hematologic malignancies characterized by persistent and heterogeneous symptom burden that significantly impairs health-related quality of life (HRQoL).
supporting_text: Myeloproliferative neoplasms (MPNs) are symptom-driven hematologic malignancies characterized by persistent and heterogeneous symptom burden that significantly impairs health-related quality of life (HRQoL).
evidence:
- reference: DOI:10.1007/s10238-025-01830-9
reference_title: 'From symptom scales to regulatory endpoints: the evolution and clinical impact of patient-reported outcome measures in myeloproliferative neoplasms'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myeloproliferative neoplasms (MPNs) are symptom-driven hematologic malignancies characterized by persistent and heterogeneous symptom burden that significantly impairs health-related quality of life (HRQoL).
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1007/s11899-024-00739-6
title: Prognostic and Predictive Models in Myelofibrosis
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: of Review Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF).
supporting_text: of Review Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF).
evidence:
- reference: DOI:10.1007/s11899-024-00739-6
reference_title: Prognostic and Predictive Models in Myelofibrosis
supports: SUPPORT
evidence_source: OTHER
snippet: of Review Myelofibrosis (MF) includes prefibrotic primary MF (pre-PMF), overt-PMF and secondary MF (SMF).
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1007/s12325-024-02928-4
title: 'Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis.
supporting_text: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis.
evidence:
- reference: DOI:10.1007/s12325-024-02928-4
reference_title: 'Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1038/s41408-023-00878-8
title: 'Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm'
supporting_text: Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as “blast-phase MPN”, is the most feared disease complication, with incidence estimates of 1–4% for essential thrombocythemia, 3–7% for polycythemia vera, and 9–13% for primary myelofibrosis.
evidence:
- reference: DOI:10.1038/s41408-023-00878-8
reference_title: 'Blast phase myeloproliferative neoplasm: contemporary review and 2024 treatment algorithm'
supports: SUPPORT
evidence_source: OTHER
snippet: Leukemic transformation in myeloproliferative neoplasms (MPN), also referred to as “blast-phase MPN”, is the most feared disease complication, with incidence estimates of 1–4% for essential thrombocythemia, 3–7% for polycythemia vera, and 9–13% for primary myelofibrosis.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1038/s41408-024-01029-3
title: 'Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval'
supporting_text: 'Momelotinib for myelofibrosis: our 14 years of experience with 100 clinical trial patients and recent FDA approval'
- reference: DOI:10.1093/oncolo/oyab058
title: Treatment Patterns, Health Care Resource Utilization, and Cost in Patients with Myelofibrosis in the United States
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: This study analyses treatment patterns, health care resource utilization (HCRU), and costs in patients with myelofibrosis (MF) and a subgroup treated with ruxolitinib (RUX).
supporting_text: This study analyses treatment patterns, health care resource utilization (HCRU), and costs in patients with myelofibrosis (MF) and a subgroup treated with ruxolitinib (RUX).
evidence:
- reference: DOI:10.1093/oncolo/oyab058
reference_title: Treatment Patterns, Health Care Resource Utilization, and Cost in Patients with Myelofibrosis in the United States
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This study analyses treatment patterns, health care resource utilization (HCRU), and costs in patients with myelofibrosis (MF) and a subgroup treated with ruxolitinib (RUX).
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1111/bjh.19164
title: 'Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline'
supporting_text: 'Diagnosis and evaluation of prognosis of myelofibrosis: A British Society for Haematology Guideline'
- reference: DOI:10.1182/blood-2024-210274
title: Real-Word Effectiveness of Pacritinib in Patients with Myelofibrosis Who Have Thrombocytopenia and Anemia
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: The co-occurrence of thrombocytopenia and anemia (bicytopenia) in patients with myelofibrosis (MF) is a therapeutic challenge because of treatment-related myelosuppression from JAK1/2 inhibitors.
supporting_text: The co-occurrence of thrombocytopenia and anemia (bicytopenia) in patients with myelofibrosis (MF) is a therapeutic challenge because of treatment-related myelosuppression from JAK1/2 inhibitors.
evidence:
- reference: DOI:10.1182/blood-2024-210274
reference_title: Real-Word Effectiveness of Pacritinib in Patients with Myelofibrosis Who Have Thrombocytopenia and Anemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The co-occurrence of thrombocytopenia and anemia (bicytopenia) in patients with myelofibrosis (MF) is a therapeutic challenge because of treatment-related myelosuppression from JAK1/2 inhibitors.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1182/hematology.2022000340
title: New approaches to tackle cytopenic myelofibrosis
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation.
supporting_text: Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation.
evidence:
- reference: DOI:10.1182/hematology.2022000340
reference_title: New approaches to tackle cytopenic myelofibrosis
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myelofibrosis (MF) is a clonal hematopoietic stem cell neoplasm characterized by constitutional symptoms, splenomegaly, and risks of marrow failure or leukemic transformation and is universally driven by Jak/STAT pathway activation.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.1186/s13045-024-01571-4
title: 'A practical approach on the classifications of myeloid neoplasms and acute leukemia: WHO and ICC'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'In 2022, two new classifications of myeloid neoplasms and acute leukemias were published: the 5th edition WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC).'
supporting_text: 'In 2022, two new classifications of myeloid neoplasms and acute leukemias were published: the 5th edition WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC).'
evidence:
- reference: DOI:10.1186/s13045-024-01571-4
reference_title: 'A practical approach on the classifications of myeloid neoplasms and acute leukemia: WHO and ICC'
supports: SUPPORT
evidence_source: OTHER
snippet: 'In 2022, two new classifications of myeloid neoplasms and acute leukemias were published: the 5th edition WHO Classification (WHO-HAEM5) and the International Consensus Classification (ICC).'
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3389/fonc.2024.1411972
title: Momelotinib – a promising advancement in the management of myelofibrosis in adults with anemia
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes.
supporting_text: Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes.
evidence:
- reference: DOI:10.3389/fonc.2024.1411972
reference_title: Momelotinib – a promising advancement in the management of myelofibrosis in adults with anemia
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myelofibrosis (MF) is a rare BCR-ABL negative myeloproliferative neoplasm characterized by clonal proliferation of stem cells, with mutations in JAK2, CALR, or MPL genes.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/cancers15133331
title: Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles.
supporting_text: Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles.
evidence:
- reference: DOI:10.3390/cancers15133331
reference_title: Association of Myelofibrosis Phenotypes with Clinical Manifestations, Molecular Profiles, and Treatments
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myelofibrosis (MF) presents an array of clinical manifestations and molecular profiles.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/cancers15205027
title: A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure.
supporting_text: Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure.
evidence:
- reference: DOI:10.3390/cancers15205027
reference_title: A Prognostic Model to Predict Ruxolitinib Discontinuation and Death in Patients with Myelofibrosis
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Most patients with myelofibrosis (MF) discontinue ruxolitinib (JAK1/JAK2 inhibitor) in the first 5 years of therapy due to therapy failure.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/cancers16071416
title: Real-World Electronic Medical Records Data Identify Risk Factors for Myelofibrosis and Can Be Used to Validate Established Prognostic Scores
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia.
supporting_text: Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia.
evidence:
- reference: DOI:10.3390/cancers16071416
reference_title: Real-World Electronic Medical Records Data Identify Risk Factors for Myelofibrosis and Can Be Used to Validate Established Prognostic Scores
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myelofibrosis (MF) is a myeloproliferative neoplasia arising de novo as primary myelofibrosis (PMF) or secondary to polycythemia vera or essential thrombocythemia.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/cancers16234114
title: Biological Markers of Myeloproliferative Neoplasms in Children, Adolescents and Young Adults
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages.
supporting_text: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages.
evidence:
- reference: DOI:10.3390/cancers16234114
reference_title: Biological Markers of Myeloproliferative Neoplasms in Children, Adolescents and Young Adults
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Myeloproliferative neoplasms (MPNs) are clonal hematopoietic cancers characterized by hyperproliferation of the myeloid lineages.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/cancers17111834
title: Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow.
supporting_text: Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow.
evidence:
- reference: DOI:10.3390/cancers17111834
reference_title: Current Advances in the Diagnosis and Treatment of Major Myeloproliferative Neoplasms
supports: SUPPORT
evidence_source: OTHER
snippet: Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers characterized by the excessive production of blood cells in the bone marrow.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/curroncol32060339
title: 'Myelofibrosis: Treatment Options After Ruxolitinib Failure'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: 'Myelofibrosis: Treatment Options After Ruxolitinib Failure'
supporting_text: While allogeneic hematopoietic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, its applicability is limited both by the high morbidity and mortality associated with the procedure and by the fact that only a minority of patients are eligible due to age or comorbidities.
evidence:
- reference: DOI:10.3390/curroncol32060339
reference_title: 'Myelofibrosis: Treatment Options After Ruxolitinib Failure'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: While allogeneic hematopoietic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, its applicability is limited both by the high morbidity and mortality associated with the procedure and by the fact that only a minority of patients are eligible due to age or comorbidities.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
- reference: DOI:10.3390/hematolrep16040067
title: 'Treatment Strategies Used in Treating Myelofibrosis: State of the Art'
found_in:
- Primary_Myelofibrosis-deep-research-falcon.md
findings:
- statement: Current drug therapy for myelofibrosis does not alter the natural course of the disease or prolong survival, and allogeneic stem cell transplantation is the only curative treatment modality.
supporting_text: Current drug therapy for myelofibrosis does not alter the natural course of the disease or prolong survival, and allogeneic stem cell transplantation is the only curative treatment modality.
evidence:
- reference: DOI:10.3390/hematolrep16040067
reference_title: 'Treatment Strategies Used in Treating Myelofibrosis: State of the Art'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Current drug therapy for myelofibrosis does not alter the natural course of the disease or prolong survival, and allogeneic stem cell transplantation is the only curative treatment modality.
explanation: Deep research cited this publication as relevant literature for Primary Myelofibrosis.
Primary myelofibrosis is a clonal hematopoietic stem/progenitor cell neoplasm characterized by atypical megakaryocytic (and granulocytic) proliferation, progressive bone marrow (BM) fibrosis, and extramedullary hematopoiesis (EMH), which collectively drive cytopenias, splenomegaly, constitutional symptoms, and risk of leukemic transformation (martino2024treatmentstrategiesused pages 1-2, wang2025currentadvancesin pages 5-7). A recent pathologic review describes PMF as a Ph-negative MPN featuring “clonal proliferation of atypical megakaryocytes and myeloid cells, fibrosis of the bone marrow, extramedullary hematopoiesis, and increased risk of leukemic transformation to acute myeloid leukemia (AML)” (abstract) (https://doi.org/10.3390/cancers18010050; 2025-12) (shao2025areviewof pages 4-6).
PMF includes a prefibrotic/early PMF stage (hypercellular marrow with minimal fibrosis) and overt/fibrotic-stage PMF with advanced fibrosis and leukoerythroblastosis (wang2025currentadvancesin pages 4-5, wang2025currentadvancesin pages 5-7).
Because the current tool runs retrieved mostly primary literature and guideline-style reviews, ontology/administrative identifiers (ICD-10/ICD-11, MeSH, OMIM, Orphanet, MONDO) are not fully populated from the evidence captured here.
What can be stated from evidence: - Classification systems used clinically: WHO and ICC frameworks (WHO 5th edition/WHO-HAEM5; ICC 2022) are explicitly referenced in multiple sources for PMF/pre-PMF diagnosis and classification (https://doi.org/10.1007/s00277-025-06191-7; 2025-01) (wang2025currentadvancesin pages 5-7), and are discussed as contemporaneous classification systems (https://doi.org/10.1186/s13045-024-01571-4; 2024-07) (stuckey2025myelofibrosistreatmentoptions pages 8-10).
PMF is driven by constitutive activation of the JAK–STAT signaling axis, typically via somatic driver mutations in JAK2, CALR, or MPL (chifotides2023associationofmyelofibrosis pages 2-4, wang2025currentadvancesin pages 5-7). A 2022 ASH Education review states MF is “universally driven by Jak/STAT pathway activation” (https://doi.org/10.1182/hematology.2022000340; 2022-12) (reynolds2022newapproachesto pages 1-3).
Specific exogenous environmental causes (toxins, infections, etc.) were not identified in the retrieved evidence snippets. Host factors associated with outcomes/complications in real-world datasets include age and blood count abnormalities (martino2024treatmentstrategiesused pages 1-2, reynolds2022newapproachesto pages 1-3).
No specific genetic or environmental protective factors were captured in the current evidence set.
No PMF-specific gene–environment interaction evidence was captured in the current evidence set.
PMF exhibits heterogeneous presentation; ~25–33% can be asymptomatic initially (shao2025areviewof pages 4-6). Common manifestations include: - Splenomegaly (often marked), due to EMH (shao2025areviewof pages 4-6, wang2025currentadvancesin pages 5-7) - Anemia and progressive cytopenias (shao2025areviewof pages 4-6, wang2025currentadvancesin pages 5-7) - Leukoerythroblastosis and teardrop RBCs (peripheral smear) (shao2025areviewof pages 4-6) - Constitutional symptoms (fever, weight loss, night sweats) and cachexia (wang2025currentadvancesin pages 5-7) - Thrombosis/bleeding: a pathology review reports “Thromboembolic events occur in ~10–20% of patients” (https://doi.org/10.3390/cancers18010050; 2025-12) (shao2025areviewof pages 4-6).
Two clinically meaningful ends of a spectrum are highlighted: - Myeloproliferative phenotype: larger spleens, leukocytosis, normal/higher counts or mild anemia; fewer non-driver mutations and higher JAK2 allele burden; generally better response to ruxolitinib (chifotides2023associationofmyelofibrosis pages 2-4). - Myelodepletive/cytopenic phenotype: ≥2 cytopenias, transfusion dependence, modest splenomegaly; more HMR mutations and genomic complexity; inferior outcomes; emphasizes less myelosuppressive JAK inhibitors (momelotinib/pacritinib) (chifotides2023associationofmyelofibrosis pages 2-4, reynolds2022newapproachesto pages 1-3).
Quality of life is impacted by anemia, constitutional symptoms, and splenomegaly; treatment goals emphasize symptom and spleen improvement (martino2024treatmentstrategiesused pages 1-2, wang2025currentadvancesin pages 5-7).
The current evidence set supports that epigenetic regulators (e.g., ASXL1, DNMT3A, EZH2, TET2) are common co-mutations and carry prognostic relevance, but does not provide direct disease-specific methylation/histone profiling datasets (mora2024prognosticandpredictive pages 1-2).
A pathology review notes karyotypic abnormalities in up to ~45% of cases; common abnormalities include del(20q), del(13q), +8, +9 (shao2025areviewof pages 4-6). Another review gives a similar range (~30–50%) and lists del(13q), del(20q), +8, +9, del(12p), trisomy 1q (ozygała2024biologicalmarkersof pages 10-12).
1) Somatic driver mutation (JAK2/CALR/MPL) in hematopoietic stem/progenitor cells → constitutive JAK–STAT signaling (chifotides2023associationofmyelofibrosis pages 2-4, reynolds2022newapproachesto pages 1-3).
2) Expansion/dysregulation of myeloid lineages with atypical megakaryocytes → secretion of pro-inflammatory/pro-fibrotic mediators (IL-1β, TGF-β; PDGF, VEGF, b-FGF) (wang2025currentadvancesin pages 5-7).
3) Bone marrow microenvironment remodeling and activation of stromal programs → progressive reticulin/collagen fibrosis and ineffective hematopoiesis (martino2024treatmentstrategiesused pages 1-2, wang2025currentadvancesin pages 5-7).
4) BM failure drives EMH in spleen/liver and systemic symptoms (shao2025areviewof pages 4-6, wang2025currentadvancesin pages 5-7).
A pathology review states fibrosis is driven by profibrotic cytokines including “TGF-β, PDGF, VEGF” and implicates Gli1+ and Lepr+ mesenchymal stem cell populations in fibrotic remodeling, alongside pathways such as BMP/Wnt (shao2025areviewof pages 4-6).
Anemia is a hallmark and negative prognostic factor (mora2024prognosticandpredictive pages 1-2, reynolds2022newapproachesto pages 1-3). ACVR1 (ALK2) inhibition is used therapeutically to suppress hepcidin signaling and improve iron-restricted anemia; momelotinib is a JAK1/2 and ACVR1 inhibitor whose “dual inhibition mechanism addresses anemia by suppressing hepcidin production” (review abstract) (https://doi.org/10.3389/fonc.2024.1411972; 2024-06) (chifotides2023associationofmyelofibrosis pages 2-4).
GO Biological Process (examples): - “JAK-STAT cascade” (GO term; verify exact ID in implementation) - “Cytokine-mediated signaling pathway” - “Extracellular matrix organization” - “Collagen fibril organization” - “Hepcidin metabolic process” - “Inflammatory response”
Cell Ontology (CL) (examples): - Megakaryocyte (CL:0000554) - Hematopoietic stem cell (CL:0000037) - Mesenchymal stromal cell / mesenchymal stem cell (term exists; verify exact CL ID)
PMF is principally a somatic clonal neoplasm in the retrieved evidence set; germline Mendelian inheritance patterns are not emphasized in these sources.
Multiple sources converge on a major + minor criteria framework: - A 2023 British Society for Haematology guideline states: “Diagnosis requires all three major criteria and at least one minor criterion confirmed in two consecutive determinations.” (https://doi.org/10.1111/bjh.19164; 2023-11) (mclornan2023diagnosisandevaluation pages 6-6). - A 2024 review similarly summarizes diagnostic structure and provides a detailed minor-criteria list (anemia not due to comorbidity, leukocytosis ≥11×10^9/L, palpable splenomegaly, elevated LDH, leukoerythroblastosis) (martino2024treatmentstrategiesused pages 2-4).
Core diagnostic elements supported by evidence: - Bone marrow morphology: megakaryocytic proliferation/atypia and grading of fibrosis (pre-PMF ≤MF-1; overt PMF MF-2/3) (shao2025areviewof pages 4-6, wang2025currentadvancesin pages 5-7). - Clonality evidence: JAK2/CALR/MPL driver mutation or other clonal marker (martino2024treatmentstrategiesused pages 2-4, mclornan2023diagnosisandevaluation pages 6-6). - Exclusion of other myeloid neoplasms (including BCR::ABL1-positive CML) (martino2024treatmentstrategiesused pages 2-4, wang2025currentadvancesin pages 5-7).
Prognosis is heterogeneous and is commonly modeled using clinical, cytogenetic, and molecular risk systems. - A 2024 prognostic review provides median OS estimates by MF subtype: “Median overall survival (OS) of pre-PMF, overt-PMF and SMF patients is around 14 years, seven and nine years, respectively.” (abstract) (https://doi.org/10.1007/s11899-024-00739-6; 2024-08) (mora2024prognosticandpredictive pages 1-2). - Risk scores (IPSS/DIPSS/DIPSS-plus) span median OS approximately from ~11.3 years (low risk) to ~2.3 years (high risk) in one review summary (mora2024prognosticandpredictive pages 1-2). Another review provides representative medians by IPSS and DIPSS-plus categories (martino2024treatmentstrategiesused pages 2-4).
Common adverse features include older age, leukocytosis, anemia, thrombocytopenia, circulating blasts, constitutional symptoms, unfavorable karyotype, and HMR mutations (martino2024treatmentstrategiesused pages 2-4, mora2024prognosticandpredictive pages 1-2).
Goals emphasize symptom control and spleen volume reduction; transplantation is reserved for selected higher-risk patients (martino2024treatmentstrategiesused pages 1-2, martino2024treatmentstrategiesused pages 2-4). A 2024 review states: “Current drug therapy for myelofibrosis does not alter the natural course of the disease or prolong survival, and allogeneic stem cell transplantation is the only curative treatment modality.” (abstract) (https://doi.org/10.3390/hematolrep16040067; 2024-10) (martino2024treatmentstrategiesused pages 1-2).
Allo-HSCT is repeatedly stated as the only curative option, generally for transplant-eligible higher-risk patients (martino2024treatmentstrategiesused pages 1-2, stuckey2025myelofibrosistreatmentoptions pages 8-10). (A detailed 2024 EBMT/ELN transplant guideline was not obtainable in this run, so granular transplant outcome statistics cannot be quoted here.)
No established primary prevention strategies are identified in the retrieved evidence, consistent with PMF being largely a sporadic somatic neoplasm in most clinical contexts. Secondary/tertiary prevention focuses on monitoring, symptom control, transfusion support, thrombosis/bleeding management, and preventing/mitigating progression via risk-adapted therapy (martino2024treatmentstrategiesused pages 2-4, mclornan2023diagnosisandevaluation pages 6-6).
No naturally occurring PMF in non-human species was captured in the retrieved evidence snippets.
The retrieved evidence references stromal-cell involvement and fibrosis pathways (e.g., Gli1+ and Lepr+ mesenchymal stem cells) as part of mechanistic understanding, but does not provide specific PMF model organism systems in the captured snippets (shao2025areviewof pages 4-6).
1) Expanded therapeutic landscape for cytopenic/anemic MF: momelotinib approval (2023-09-15) and anemia-focused evidence (SIMPLIFY-2 subgroup TI improvements) (chifotides2023associationofmyelofibrosis pages 2-4, wang2025currentadvancesin pages 5-7).
2) Real-world data scaling using EHR networks: TriNetX-based MF studies spanning >64,000 MF patients to validate risk factors and simplified IPSS approaches (https://doi.org/10.3390/cancers16071416; 2024-04) (martino2024treatmentstrategiesused pages 1-2).
3) Modern prognostication: emphasis on mutation-informed models (MIPSS70+ v2.0) and integrated risk modeling (mora2024prognosticandpredictive pages 1-2, mclornan2023diagnosisandevaluation pages 6-6).
4) Recognition of phenotypic heterogeneity (proliferative vs cytopenic): linking clinical phenotype with allele burden and co-mutation architecture to tailor therapy (chifotides2023associationofmyelofibrosis pages 2-4, reynolds2022newapproachesto pages 1-3).
| Feature category | PMF finding | Approximate frequency / definition | Clinical or biologic association |
|---|---|---|---|
| Driver mutation | JAK2 V617F | ~60% of PMF; alternatively described as about two-thirds of PMF (chifotides2023associationofmyelofibrosis pages 2-4, mora2024prognosticandpredictive pages 1-2) | Higher allele burden is associated with the myeloproliferative phenotype; lower burden with myelodepletive/cytopenic phenotype (chifotides2023associationofmyelofibrosis pages 2-4) |
| Driver mutation | CALR exon 9 | ~25–30% of PMF; another source gives ~25% (chifotides2023associationofmyelofibrosis pages 2-4, mora2024prognosticandpredictive pages 1-2) | CALR is a major clonal driver used in diagnosis; type 1/like CALR is incorporated in molecular prognostic models such as MIPSS70 (martino2024treatmentstrategiesused pages 2-4, mora2024prognosticandpredictive pages 1-2) |
| Driver mutation | MPL (classically W515L/K) | ~5–10% of PMF; another source gives ~10% (chifotides2023associationofmyelofibrosis pages 2-4, mora2024prognosticandpredictive pages 1-2) | Canonical MPN driver used in WHO/ICC-style diagnostic workup (martino2024treatmentstrategiesused pages 2-4, mclornan2023diagnosisandevaluation pages 6-6) |
| Driver-negative subset | Triple-negative PMF | ~10% in one review; ~10–15% in another broader MPN review (mora2024prognosticandpredictive pages 1-2, ozygała2024biologicalmarkersof pages 10-12) | Generally considered biologically adverse in PMF literature; requires other clonal evidence/exclusion of reactive fibrosis in diagnostic frameworks (mclornan2023diagnosisandevaluation pages 6-6, ozygała2024biologicalmarkersof pages 10-12) |
| High molecular risk (HMR) definition | ASXL1, EZH2, IDH1, IDH2, SRSF2, U2AF1 Q157 | HMR genes are the adverse mutation set used in contemporary prognostic models; BSH notes MIPSS70+ v2.0 incorporates HMR genes plus U2AF1 Q157 (chifotides2023associationofmyelofibrosis pages 2-4, mclornan2023diagnosisandevaluation pages 6-6) | Associated with worse overall survival, higher blast-phase risk, and more aggressive biology (chifotides2023associationofmyelofibrosis pages 2-4, mora2024prognosticandpredictive pages 1-2) |
| Common co-mutations | ASXL1, DNMT3A, TET2 | Co-mutations occur in ~50% of patients; ASXL1, DNMT3A, and TET2 are repeatedly cited as common examples (martino2024treatmentstrategiesused pages 2-4) | Reflect clonal complexity and are relevant to prognosis beyond driver status (martino2024treatmentstrategiesused pages 2-4, mora2024prognosticandpredictive pages 1-2) |
| Additional recurrent co-mutations | SRSF2, EZH2, IDH1/2, SF3B1, U2AF1, TP53 | About 80% of PMF cases carry non-driver myeloid gene variants in one 2024 review (mora2024prognosticandpredictive pages 1-2) | Splicing/epigenetic mutations are enriched in advanced or cytopenic disease and shorten survival (chifotides2023associationofmyelofibrosis pages 2-4, mora2024prognosticandpredictive pages 1-2) |
| Mutations linked to advanced disease | ASXL1, U2AF1-Q157, SRSF2 | Not primarily frequency-defined here, but identified as enriched in MF/advanced disease (martino2024treatmentstrategiesused pages 2-4) | Poorer survival and adverse-risk enrichment (martino2024treatmentstrategiesused pages 2-4, wang2025currentadvancesin pages 5-7) |
| Mutations linked to treatment resistance | RAS/CBL pathway mutations | Defined as non-driver adverse co-mutations rather than frequent drivers (martino2024treatmentstrategiesused pages 2-4, wang2025currentadvancesin pages 5-7) | Associated with ruxolitinib resistance/failure (martino2024treatmentstrategiesused pages 2-4, wang2025currentadvancesin pages 5-7) |
| Phenotype association | Myeloproliferative phenotype | Molecular profile tends to show higher JAK2 V617F burden and fewer non-driver mutations (chifotides2023associationofmyelofibrosis pages 2-4) | Typical features: larger spleen, leukocytosis, normal/mild anemia, lower fibrosis grade, better response to ruxolitinib (chifotides2023associationofmyelofibrosis pages 2-4) |
| Phenotype association | Myelodepletive / cytopenic phenotype | More often shows lower JAK2 V617F burden, greater genomic complexity, and more HMR/splicing-epigenetic mutations (chifotides2023associationofmyelofibrosis pages 2-4, reynolds2022newapproachesto pages 1-3) | Typical features: ≥2 cytopenias, transfusion dependence, moderate/severe thrombocytopenia, higher fibrosis grade, inferior survival, limited ruxolitinib response; non-myelosuppressive JAK inhibitors (momelotinib/pacritinib) are emphasized for this phenotype (chifotides2023associationofmyelofibrosis pages 2-4, reynolds2022newapproachesto pages 1-3) |
Table: This table summarizes the core genetic and molecular hallmarks of primary myelofibrosis, including driver mutation frequencies, adverse co-mutation profiles, and how molecular features map to myeloproliferative versus myelodepletive phenotypes. It is useful as a compact reference for diagnosis, prognosis, and treatment stratification.
References
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