01OverviewDefinition, clinical context and the essential points that orientate the chapter.
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.
Prognosis drives curative planning. DIPSS uses age, haemoglobin, leukocytes, circulating blasts and symptoms; DIPSS-plus and molecular systems add platelets, transfusion, karyotype and adverse mutations. Scores inform but do not replace transplant assessment. Suitable higher-risk adults should see a transplant service early for donor and comorbidity work-up. Waiting for JAK-inhibitor failure may lose the curative window. Conversely, stable lower-risk asymptomatic disease may be observed without exposing a person to treatment harm.
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.
Key points
- Suspect myelofibrosis with massive splenomegaly, constitutional symptoms, anaemia, teardrop cells, nucleated red cells, left-shifted granulocytes, raised LDH or a dry marrow aspirate.
- First-line assessment is FBC and expert film, reticulocytes, haemolysis, iron, B12 and folate, renal, liver, urate and LDH plus examination of spleen, liver, symptoms and thrombosis.
- Confirm with bone-marrow trephine for atypical megakaryocytes and fibrosis, cytogenetics and JAK2, CALR and MPL testing; exclude BCR-ABL1 and secondary fibrosis.
- Distinguish prefibrotic primary myelofibrosis from essential thrombocythaemia because marrow architecture, progression risk and treatment counselling differ.
- Use DIPSS, DIPSS-plus or molecularly informed scores together with symptoms, transfusion dependence, blasts, comorbidity and transplant fitness.
- Allogeneic stem-cell transplantation is the only established curative treatment and should be assessed early for suitable intermediate-2, high-risk or adverse molecular disease.
- Ruxolitinib is NICE commissioned for intermediate-2 or high-risk disease-related splenomegaly or symptoms; starting dose is platelet dependent and abrupt withdrawal can cause severe rebound.
- Momelotinib is NICE commissioned for intermediate-2 or high-risk disease with moderate to severe anaemia in defined JAK-inhibitor-naive or ruxolitinib-exposed adults.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Driver-mutated myeloid clone
Most primary myelofibrosis carries acquired JAK2, CALR or MPL activation in a haematopoietic stem-cell clone, with additional mutations shaping progression.
Clonal cytokine dysregulation
Abnormal megakaryocytes and monocytes release inflammatory and fibrogenic mediators that remodel marrow stroma even though fibroblasts themselves are usually non-clonal.
Primary and secondary forms
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.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Atypical megakaryocyte proliferation
Dense abnormal megakaryocyte clusters and granulocytic proliferation define prefibrotic disease before collagen fibrosis and advanced marrow failure become established.
- 2Progressive stromal fibrosis
Reticulin and collagen deposition distort marrow niches, producing ineffective haematopoiesis, dry tap, cytopenia and release of immature blood cells.
- 3Extramedullary haematopoiesis
Spleen and liver resume blood-cell production, causing massive splenomegaly, portal hypertension, early satiety, infarction and occasional paraspinal or other masses.
- 4Inflammatory and clonal progression
Cytokines cause cachexia, sweats, fever, pruritus and bone pain, while adverse subclones can transform to acute myeloid leukaemia.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
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.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
First-line blood and reversible-cause panelFirst stepFirst line - Why
- Recognise the phenotype and identify treatable contributors to cytopenia.
- Interpretation and limitations
- Use FBC, expert film, reticulocytes, bilirubin, LDH, haptoglobin, iron, B12, folate, renal, liver and inflammatory context; compare historical PV or ET counts.
- 02
Confirmatory marrow trephineConfirmatory - Why
- Define megakaryocyte atypia, cellularity, reticulin or collagen fibrosis, blasts and alternative infiltration.
- Interpretation and limitations
- Prefibrotic PMF has atypical clustered megakaryocytes with granulocytic proliferation and little fibrosis; overt disease has higher-grade fibrosis and often a dry aspirate.
- 03
Driver, cytogenetic and myeloid testing - Why
- Establish clonality, exclude CML and classify diagnostic and prognostic molecular risk.
- Interpretation and limitations
- Test JAK2, CALR and MPL plus BCR-ABL1 exclusion; use karyotype and a myeloid panel for adverse mutations and possible germline clues.
- 04
Risk and transplant assessment - Why
- Estimate mortality and transformation risk and identify a curative window.
- Interpretation and limitations
- Calculate an age-appropriate validated score and document transfusion, blasts, platelets, karyotype, mutations, symptoms, performance, comorbidity and donor options.
- 05
Spleen and portal assessment - Why
- Measure symptomatic extramedullary disease and detect infarction, thrombosis or portal hypertension.
- Interpretation and limitations
- Use examination and ultrasound or CT when anatomy changes management; sudden pain, falling haemoglobin or instability requires emergency imaging.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Secondary marrow fibrosis
Metastatic cancer, lymphoma, infection, autoimmune myelofibrosis, hairy-cell leukaemia and metabolic bone disease can produce fibrosis without a classical MPN clone.
Post-PV or post-ET myelofibrosis
Earlier erythrocytosis, thrombocytosis and diagnostic marrow establish evolution from another MPN rather than de novo primary disease.
Other myeloid neoplasm
CML, MDS with fibrosis, chronic myelomonocytic leukaemia and acute panmyelosis require BCR-ABL1, morphology, flow, cytogenetic and molecular integration.
Reactive leucoerythroblastosis
Severe infection, haemorrhage, haemolysis and metastatic infiltration can release immature myeloid and nucleated red cells without primary myelofibrosis.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01Suspected myelofibrosisConfirm architecture and cloneFirst stepLeucoerythroblastosis, teardrops, splenomegaly or unexplained cytopenia suggests fibrotic marrow disease.+
- 1Assess reversible cytopenia causes, symptoms, spleen, thrombosis and prior PV or ET phenotype.
- 2Obtain trephine with expert morphology, fibrosis grade, blasts, cytogenetics, JAK2, CALR, MPL and broader myeloid testing.
- 3Exclude secondary fibrosis and classify prefibrotic, overt primary or post-PV or post-ET disease.
02Newly risk-classified diseaseProtect the transplant windowDiagnosis and molecular risk are available before prolonged symptom-directed treatment.+
- 1Use a validated prognostic score with comorbidity, symptoms and patient goals.
- 2Refer suitable intermediate-2, high-risk or molecularly adverse disease early for allogeneic transplant and donor assessment.
- 3Use JAK inhibition, supportive care or trial as symptom control or a bridge without allowing response to postpone curative review indefinitely.
03Symptomatic spleen or cytokinesUse commissioned JAK inhibitionIntermediate-2 or high-risk disease causes clinically important splenomegaly or constitutional symptoms.+
- 1Assess platelets, anaemia, infection, renal and hepatic function, TB and viral risk and interacting medicines.
- 2Start ruxolitinib at the platelet-defined dose or momelotinib in the NICE anaemia-defined population.
- 3Measure symptom and spleen response by 24 weeks, adjust for cytopenia and taper rather than stopping abruptly when switching or discontinuing.
04Worsening anaemiaDefine mechanism before treatingHaemoglobin falls, transfusion need increases or fatigue worsens.+
- 1Assess bleeding, haemolysis, iron, B12, folate, renal function, inflammation, spleen, medicines and clonal progression.
- 2Use individualised red-cell transfusion and selected ESA, danazol, momelotinib or trial according to erythropoietin, risk and contraindications.
- 3Reassess marrow, transplant timing and JAK-inhibitor dose when blasts, cytopenia or spleen also progress.
Key medicines and prescribing safety4 treatments · regimens, roles and cautions+
Ruxolitinib
Start orally twice daily by platelet count: 20 mg above 200 × 10⁹/L, 15 mg at 100 to 200 × 10⁹/L, 10 mg at 75 to below 100 × 10⁹/L and 5 mg at 50 to below 75 × 10⁹/L; do not start below 50 × 10⁹/L.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.
Momelotinib
Give 200 mg orally once daily while benefit persists; start 150 mg once daily in severe Child-Pugh C hepatic impairment, reduce toxicity doses in 50 mg steps and discontinue if 100 mg once daily is not tolerated.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.
Hydroxycarbamide
Start commonly at 500 mg orally once daily and titrate with FBC to control proliferative leukocytosis, thrombocytosis or spleen symptoms while avoiding worsening anaemia and thrombocytopenia.Adjust for renal impairment, monitor cytopenia, ulcers and skin cancer, avoid pregnancy and breastfeeding and discuss fertility and alternative interferon strategies where relevant.
Red-cell transfusion
Use an individual symptom and haemoglobin plan, commonly one unit followed by reassessment in a stable non-bleeding adult, with more urgent component support dictated by physiology and active bleeding.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.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Marrow-failure cytopenia
Anaemia, infection and bleeding worsen as effective marrow is lost and can be amplified by splenic sequestration, inflammation and treatment.
Massive spleen and portal disease
Pain, infarction, early satiety, malnutrition, portal hypertension, varices and splanchnic thrombosis arise from extramedullary haematopoiesis and altered flow.
Thrombosis and bleeding
MPN thrombophilia coexists with thrombocytopenia, platelet dysfunction, varices and treatment-related bleeding, requiring individual antithrombotic decisions throughout the disease course.
Blast-phase transformation
Accelerated blasts and AML carry poor prognosis and need urgent intensive, lower-intensity, transplant or trial planning according to fitness.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- Track FBC, blood film, symptoms, spleen, transfusion, weight and performance at a frequency set by risk and treatment; counts alone do not measure JAK-inhibitor benefit.
- During ruxolitinib or momelotinib initiation, check FBC and infection frequently, then monitor renal, liver and interaction changes throughout treatment.
- Use a validated symptom score and consistent spleen measure at baseline and about 24 weeks to decide whether commissioned therapy provides meaningful benefit.
- Repeat marrow and molecular assessment for rising blasts, new cytopenia, loss of response or transplant planning and refer blast-phase disease urgently.
- Revisit transplant fitness and donor options after clinical change, not only after complete JAK-inhibitor failure.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
Fibroblasts are reactive
The malignant clone is haematopoietic; cytokine-driven non-clonal stromal cells lay down much of the marrow fibrosis.
Trephine is indispensable
A dry aspirate and driver mutation cannot distinguish prefibrotic, overt and secondary myelofibrosis without architecture.
JAK response is mainly clinical
Spleen and symptoms can improve without eradication of the clone or elimination of future blast transformation.
Do not stop ruxolitinib abruptly
Rapid cytokine rebound can cause severe symptom recurrence and haemodynamic or respiratory deterioration.
Transplant timing is separate
Good symptom control does not remove adverse molecular risk or the need for early curative assessment.
11Common pitfallsFrequent interpretation and management errors.
- 01
Diagnosing primary MF from fibrosis without excluding metastatic, inflammatory and other myeloid causes.
- 02
Using a driver mutation instead of marrow morphology to assign subtype.
- 03
Treating anaemia without checking bleeding, haemolysis and deficiency.
- 04
Equating spleen response with cure.
- 05
Stopping ruxolitinib suddenly without a taper plan.
- 06
Delaying transplant referral until blast transformation.