Primary myelofibrosis

Primary myelofibrosis is a clonal myeloproliferative neoplasm characterised by atypical megakaryocytic proliferation, progressive bone marrow fibrosis, extramedullary haematopoiesis, splenomegaly, and a variable propensity to transform into acute myeloid leukaemia

It is driven by somatic mutations that constitutively activate JAK-STAT signalling, most often JAK2 V617F, CALR exon 9 insertions or deletions, or MPL W515 mutations, and is classified as a myeloproliferative neoplasm rather than a myelodysplastic syndrome

Median survival is approximately 5 to 7 years overall, but ranges from more than 15 years in low-risk disease to 2 to 3 years in high-risk disease, and 10% to 20% of patients transform to acute myeloid leukaemia within a decade

Terminology and classification

• Primary myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms, alongside polycythemia vera and essential thrombocythemia, and is grouped with them in the WHO classification of haematopoietic and lymphoid tumours
• The 2022 WHO classification distinguishes pre-fibrotic primary myelofibrosis from overt primary myelofibrosis, because the two stages differ in marrow fibrosis grade, splenomegaly, and prognosis
• ICD-11 assigns the code 2A20.2 to primary myelofibrosis within the myeloproliferative neoplasm block 2A20, whereas ICD-10-CM uses D47.4 for myelofibrosis and the WHO ICD-10 uses D47.1 for chronic myeloproliferative disease
• Orphanet catalogues the disease as ORPHA:824, MONDO as MONDO:0009692, and Wikidata as Q1752571, reflecting its status as a rare haematological malignancy
• Earlier names include idiopathic myelofibrosis, agnogenic myeloid metaplasia, and chronic idiopathic myelofibrosis, all of which are now obsolete because the molecular driver is identifiable in most patients
• Secondary myelofibrosis arises after polycythemia vera or essential thrombocythemia, or in association with myelodysplastic syndromes, hairy cell leukaemia, or metastatic carcinoma, and must be distinguished from the primary form

History

• Heuck described the first probable case of myelofibrosis in 1879, reporting a patient with massive splenomegaly, anaemia, and a striking marrow appearance that he termed osteosclerosis
• In 1951 Dameshek introduced the concept of myeloproliferative disorders, grouping myelofibrosis with polycythemia vera, essential thrombocythemia, and chronic myeloid leukaemia as related clonal stem cell diseases
• Four independent groups reported the JAK2 V617F mutation in 2005, establishing the first recurrent molecular lesion in Philadelphia-negative myeloproliferative neoplasms and transforming diagnosis
• MPL W515 mutations were identified in 2006 and CALR exon 9 mutations in 2013, completing the three-driver model that now explains the molecular basis of most cases
• Ruxolitinib was approved by the United States Food and Drug Administration in 2011, the first targeted JAK1 and JAK2 inhibitor shown to reduce spleen volume and constitutional symptoms in myelofibrosis
• The 2016 and 2022 WHO classifications and the 2018 European LeukemiaNet recommendations progressively incorporated molecular data, fibrosis grading, and mutation-enhanced prognostic scores into routine practice

Epidemiology

• The annual incidence of primary myelofibrosis is approximately 0.5 to 1 per 100,000 people, with wide geographic variation that partly reflects diagnostic coding and access to haematology services
• The median age at diagnosis is 65 to 70 years, and fewer than 20% of patients are younger than 50 years at presentation
• Most series report a modest male predominance, with a male-to-female ratio of approximately 1.3 to 1.5 to 1, although some population-based studies show equal sex distribution
• Splenomegaly is present in approximately 90% of patients at diagnosis, and hepatomegaly in 40% to 50%, reflecting extramedullary haematopoiesis
• Anaemia, defined broadly as haemoglobin below 110 g/L in women and below 120 g/L in men, is present in about half of patients at diagnosis and worsens with progression
• Constitutional symptoms such as fatigue, night sweats, pruritus, fever, and weight loss affect 30% to 40% of patients and are independently associated with inferior survival
• Approximately 10% to 20% of patients transform to acute myeloid leukaemia within 10 years, and transformation is more frequent in patients with high-risk cytogenetics or TP53, ASXL1, or IDH mutations
• Thrombosis and bleeding both contribute to morbidity, with thrombosis often occurring at presentation and bleeding becoming more prominent as thrombocytopenia and splenomegaly progress

Pathophysiology

• JAK2 V617F is present in 50% to 60% of patients, CALR exon 9 mutations in 25% to 30%, MPL W515 mutations in 5% to 10%, and 10% to 15% are triple-negative and carry other, less common lesions
• All three driver mutations converge on constitutive JAK-STAT activation, which drives cytokine-independent proliferation of haematopoietic progenitors and megakaryocyte hyperplasia
• Atypical megakaryocytes release transforming growth factor beta, platelet-derived growth factor, and fibroblast growth factor, which stimulate fibroblasts and osteoblasts and produce reticulin and collagen fibrosis
• Fibrosis and osteosclerosis displace normal haematopoiesis, forcing progenitor cells into the spleen and liver, where extramedullary haematopoiesis produces splenomegaly, hepatomegaly, and a leucoerythroblastic blood picture
• The malignant clone also generates a systemic inflammatory state, with elevated interleukin-6, tumour necrosis factor alpha, and C-reactive protein contributing to fever, cachexia, pruritus, and fatigue
• Additional mutations in ASXL1, SRSF2, U2AF1, IDH1/2, EZH2, and TP53 accumulate during clonal evolution and are strongly associated with progression, blast-phase transformation, and shorter survival

Clinical features

• The commonest presenting symptoms are fatigue, exertional dyspnoea, abdominal fullness from splenomegaly, early satiety, weight loss, night sweats, and pruritus after bathing
• Massive splenomegaly may cause left upper quadrant pain, hiccups, portal hypertension with varices and ascites, and splenic infarction
• Pallor, tachycardia, and fatigue reflect anaemia, while petechiae, ecchymoses, and mucosal bleeding reflect thrombocytopenia or platelet dysfunction
• Peripheral blood shows teardrop-shaped red cells, nucleated red cells, immature granulocytes, and sometimes circulating blasts, producing the classic leucoerythroblastic picture
• Gout, infections, thrombosis, and bleeding are frequent complications, and portal hypertension may dominate the late clinical course in patients with massive splenomegaly
• Disease progression may be marked by increasing splenomegaly, worsening cytopenias, rising blast count, new high-risk mutations, or transformation to acute myeloid leukaemia

Diagnosis

• Diagnosis requires a bone marrow biopsy showing megakaryocytic proliferation and atypia, with reticulin or collagen fibrosis graded according to the European consensus, together with a clonal driver mutation or an abnormal karyotype
• The 2022 WHO criteria require at least one major criterion, namely megakaryocytic proliferation and atypia with fibrosis, a clonal JAK2, CALR, or MPL mutation, or an abnormal karyotype, plus at least one minor criterion
• Minor criteria include anaemia not explained by another cause, leukocytosis above 11 by 10 to the ninth per litre, palpable splenomegaly, elevated lactate dehydrogenase, and leucoerythroblastosis
• Molecular testing for JAK2, CALR, and MPL is essential at diagnosis, and next-generation sequencing panels add prognostic information from ASXL1, SRSF2, U2AF1, IDH1/2, EZH2, and TP53
• The differential diagnosis includes chronic myeloid leukaemia, which is excluded by absence of BCR-ABL1
• Risk stratification uses the International Prognostic Scoring System and its dynamic variants, and the mutation-enhanced MIPSS70 plus version 2.0 and GIPSS scores, which incorporate karyotype, driver mutation, and high-risk mutations

Management

• Low-risk and asymptomatic patients are managed with observation, because early intervention has not been shown to prolong survival in this group
• Symptomatic intermediate-risk and high-risk patients receive JAK inhibitors, beginning with ruxolitinib, which reduces spleen volume and improves constitutional symptoms and quality of life
• Fedratinib was approved in 2019, pacritinib in 2022 for patients with thrombocytopenia, and momelotinib in 2023 for patients with anaemia, expanding options for those who cannot tolerate or do not respond to ruxolitinib
• Imetelstat, a telomerase inhibitor, was approved in 2024 for transfusion-dependent anaemia in lower-risk myelofibrosis, and represents the first agent specifically targeting the anaemia of this disease
• Hydroxyurea, interferon alfa, and danazol are used for cytoreduction, control of thrombocytosis, or anaemia, while lenalidomide may benefit patients with del(5q) or anaemia
• Allogeneic haematopoietic stem cell transplantation is the only potentially curative therapy and is offered to eligible patients with intermediate-2 or high-risk disease, generally younger than 70 years with a suitable donor
• Splenectomy, splenic irradiation, and radiotherapy for extramedullary haematopoiesis are reserved for mechanical symptoms, refractory splenomegaly, or palliation, and carry substantial perioperative risk
• Supportive care includes transfusion, erythropoiesis-stimulating agents in selected patients with low endogenous erythropoietin, antimicrobial prophylaxis, vaccination, and management of thrombosis and bleeding risk

Research and controversies

• The optimal timing of allogeneic transplantation in intermediate-risk disease remains debated, because transplant-related mortality must be weighed against the risk of progression and leukaemic transformation
• JAK inhibitor resistance and persistence of the malignant clone mean that no current drug modifies the natural history of the disease, and combination strategies with BET, BCL-2, or PI3K inhibitors are under investigation
• The MIPSS-M score, published in 2022, integrates clinical, cytogenetic, and molecular variables and appears to outperform earlier scores, but it has not yet been validated prospectively in all treatment settings
• Whether pre-fibrotic primary myelofibrosis should be treated like essential thrombocythemia or like overt myelofibrosis is unresolved, and trials have historically enrolled mainly overt disease
• Novel agents targeting anaemia, fibrosis, and the inflammatory microenvironment, including activin receptor ligand traps and telomerase inhibition, are being tested with the aim of modifying rather than merely palliating the disease