Recognise marrow fibrosis and extramedullary haematopoiesis, distinguish prefibrotic and secondary disease, quantify molecular risk and integrate symptom control with early curative transplant assessment.
Primary myelofibrosis ranges from a prefibrotic proliferative phase to overt fibrotic marrow failure. Diagnosis integrates marrow morphology, fibrosis grade, blood findings, driver mutation and exclusion of secondary causes. JAK2, CALR and MPL overlap with ET and PV and therefore cannot determine subtype alone. Triple-negative disease requires expert morphology and broader genetics because it includes higher-risk PMF and mimics. A dry aspirate is a clue, not the diagnosis; a high-quality trephine is essential.
The characteristic blood film is leucoerythroblastic, with teardrop red cells, nucleated red cells, immature granulocytes and sometimes giant abnormal platelets. Anaemia is multifactorial: ineffective production, splenic sequestration, haemolysis, bleeding, inflammation, renal disease and nutrient deficiency all contribute. Splenic haematopoiesis causes early satiety, pain and portal complications. Systemic cytokines cause drenching sweats, fever, weight loss, pruritus, fatigue and bone pain. A validated MPN symptom score helps quantify change beyond spleen size.
Most primary myelofibrosis carries acquired JAK2, CALR or MPL activation in a haematopoietic stem-cell clone, with additional mutations shaping progression.
Abnormal megakaryocytes and monocytes release inflammatory and fibrogenic mediators that remodel marrow stroma even though fibroblasts themselves are usually non-clonal.
The same fibrotic phenotype can evolve from polycythaemia vera or essential thrombocythaemia; prior counts and marrow determine whether disease is primary, post-PV or post-ET.
Dense abnormal megakaryocyte clusters and granulocytic proliferation define prefibrotic disease before collagen fibrosis and advanced marrow failure become established.
Reticulin and collagen deposition distort marrow niches, producing ineffective haematopoiesis, dry tap, cytopenia and release of immature blood cells.
Spleen and liver resume blood-cell production, causing massive splenomegaly, portal hypertension, early satiety, infarction and occasional paraspinal or other masses.
Cytokines cause cachexia, sweats, fever, pruritus and bone pain, while adverse subclones can transform to acute myeloid leukaemia.
Teardrops, nucleated red cells, immature myeloid cells and giant platelets indicate marrow distortion or extramedullary production and require urgent cause assessment.
Early satiety, abdominal distension, pain and cachexia reflect extramedullary haematopoiesis; sudden pain may be infarction.
Sweats, fever, weight loss, pruritus, fatigue and bone pain may be severe despite relatively stable blood counts.
Dyspnoea, infection and bleeding correspond to anaemia, neutropenia and thrombocytopenia but competing causes must be sought.
Rising circulating blasts, rapid count decline, severe systemic symptoms or new tissue masses needs same-day specialist escalation.
Metastatic cancer, lymphoma, infection, autoimmune myelofibrosis, hairy-cell leukaemia and metabolic bone disease can produce fibrosis without a classical MPN clone.
Earlier erythrocytosis, thrombocytosis and diagnostic marrow establish evolution from another MPN rather than de novo primary disease.
CML, MDS with fibrosis, chronic myelomonocytic leukaemia and acute panmyelosis require BCR-ABL1, morphology, flow, cytogenetic and molecular integration.
Severe infection, haemorrhage, haemolysis and metastatic infiltration can release immature myeloid and nucleated red cells without primary myelofibrosis.
Anaemia, infection and bleeding worsen as effective marrow is lost and can be amplified by splenic sequestration, inflammation and treatment.
Pain, infarction, early satiety, malnutrition, portal hypertension, varices and splanchnic thrombosis arise from extramedullary haematopoiesis and altered flow.
MPN thrombophilia coexists with thrombocytopenia, platelet dysfunction, varices and treatment-related bleeding, requiring individual antithrombotic decisions throughout the disease course.
Accelerated blasts and AML carry poor prognosis and need urgent intensive, lower-intensity, transplant or trial planning according to fitness.
The malignant clone is haematopoietic; cytokine-driven non-clonal stromal cells lay down much of the marrow fibrosis.
A dry aspirate and driver mutation cannot distinguish prefibrotic, overt and secondary myelofibrosis without architecture.
Spleen and symptoms can improve without eradication of the clone or elimination of future blast transformation.
Rapid cytokine rebound can cause severe symptom recurrence and haemodynamic or respiratory deterioration.
Good symptom control does not remove adverse molecular risk or the need for early curative assessment.
Diagnosing primary MF from fibrosis without excluding metastatic, inflammatory and other myeloid causes.
Using a driver mutation instead of marrow morphology to assign subtype.
Treating anaemia without checking bleeding, haemolysis and deficiency.
Equating spleen response with cure.
Stopping ruxolitinib suddenly without a taper plan.
Delaying transplant referral until blast transformation.
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A fit adult has newly diagnosed high-risk primary myelofibrosis with adverse molecular features and symptomatic splenomegaly. Which principle should guide the initial plan?
National guidance is shown before implementation-dependent detail. Typical adult dose examples remain subject to patient factors, contraindications and the live BNF or specialist protocol. Source check completed 27 Aug 2026; clinical approval remains outstanding.
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JAK inhibitors mainly improve spleen and symptoms; they are not proven curative and can worsen anaemia or thrombocytopenia. Ruxolitinib dosing is based on platelets and adjusted for cytopenia, renal or hepatic function and interacting medicines. Momelotinib has an anaemia-directed advantage in the commissioned population. Hydroxycarbamide can control proliferative counts but is less effective for broad symptom burden. Anaemia care includes cause correction, individualised transfusion and selected ESA, danazol or other specialist options. Splenectomy and splenic radiotherapy are high-risk, selected interventions rather than routine alternatives.
Reduce the platelet-based start by about 50% in severe renal impairment or any hepatic impairment; ESRD dosing is post-haemodialysis only. Reduce the unit dose 50% with strong CYP3A inhibitors or fluconazole and avoid fluconazole above 200 mg daily. Monitor FBC every 2 to 4 weeks initially, infection and skin, taper when possible, and avoid use in pregnancy or breastfeeding.
No renal adjustment is required above 15 mL/min, but ESRD has not been studied. Monitor FBC, liver tests, infection, neuropathy, cardiovascular events, thrombosis and BCRP substrates; avoid strong CYP3A4 inducers. Pregnancy and breastfeeding are contraindicated, and systemic hormonal contraception needs an added barrier during treatment and for 1 week after.
Adjust for renal impairment, monitor cytopenia, ulcers and skin cancer, avoid pregnancy and breastfeeding and discuss fertility and alternative interferon strategies where relevant.
Plan rate and diuresis for TACO risk, maintain antibody history and consider iron overload only in the context of cumulative burden, expected survival and transplant plan.