Myelofibrosis and the myeloproliferative neoplasms

Definition and classification. Myeloproliferative neoplasms are clonal haematopoietic stem cell disorders with effective but dysregulated proliferation of one or more myeloid lineages. Philadelphia-negative: polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). Philadelphia-positive: chronic myeloid leukaemia.

Driver mutations. JAK2 V617F in 95% of PV and 50–60% of ET/PMF; JAK2 exon 12 in PV; CALR in 20–25% of ET/PMF (better prognosis); MPL in about 5%. Triple-negative PMF has the worst outcome. High-molecular-risk mutations are ASXL1, SRSF2, EZH2, IDH1/2 and U2AF1.

Polycythaemia vera. Raised haematocrit (>49% men, >48% women) with a low serum erythropoietin and JAK2 mutation. Features are aquagenic pruritus, erythromelalgia, plethora and splenomegaly. Thrombosis is the main cause of death.

Essential thrombocythaemia. Sustained platelet count ≥450 × 109/L with megakaryocytic proliferation. Causes microvascular symptoms and thrombosis, but paradoxically bleeding when platelets exceed 1000 × 109/L (acquired von Willebrand disease).

Primary myelofibrosis — clinical features. Progressive anaemia, massive splenomegaly (dragging pain, early satiety, splenic infarction), constitutional symptoms (fever, night sweats, weight loss, cachexia), bone pain, extramedullary haematopoiesis and portal hypertension.

Primary myelofibrosis — laboratory findings. Leucoerythroblastic blood picture with teardrop poikilocytes (dacrocytes), nucleated red cells and immature granulocytes; raised LDH; "dry tap" on marrow aspiration; trephine biopsy shows atypical clustered megakaryocytes with reticulin or collagen fibrosis (MF grade 1–3). WHO 5th edition (2022) separates prefibrotic from overt PMF.

Prognostic scoring. DIPSS/DIPSS-Plus — age >65, Hb <10 g/dL, WBC >25 × 109/L, circulating blasts ≥1%, constitutional symptoms, plus transfusion need, platelets <100 × 109/L and unfavourable karyotype. MIPSS70/70+ v2.0 incorporates molecular data and is used to select transplant candidates.

Complications. Progressive marrow failure and transfusion dependence, portal hypertension, splenic infarction, thrombosis, infection, and leukaemic transformation to AML in 10–20% at 10 years.

Management of PV and ET. Low-dose aspirin 75–100 mg for all unless contraindicated. PV — venesection to keep haematocrit below 45%. Cytoreduction if high risk (age >60 or prior thrombosis) — hydroxyurea first-line, interferon in younger patients, and ruxolitinib for hydroxyurea-resistant or intolerant PV. In ET, anagrelide is second-line.

Management of primary myelofibrosis. Risk-adapted — observe low-risk asymptomatic disease. For symptomatic splenomegaly or constitutional symptoms use the JAK inhibitor ruxolitinib (COMFORT-I and II: spleen and symptom reduction with a survival benefit); fedratinib after ruxolitinib failure. Allogeneic stem cell transplantation is the only curative option but is rarely feasible beyond 70 years. Supportive care includes transfusion, erythropoiesis-stimulating agents if serum EPO <500 mU/mL, danazol, splenic irradiation, and splenectomy only for refractory cases.

Cytopenia-directed JAK inhibitors — momelotinib (MOMENTUM, Lancet 2023) is approved for myelofibrosis with anaemia, improving spleen size, symptoms and transfusion independence through additional ACVR1/hepcidin inhibition; pacritinib is approved when platelets are below 50 × 109/L. NCCN MPN guidelines 2026 now contain a dedicated MF-associated anaemia algorithm listing momelotinib as a preferred regimen.

Ropeginterferon alfa-2b is approved for polycythaemia vera as a disease-modifying agent that induces molecular responses and reduces JAK2 allele burden, unlike hydroxyurea. The hepcidin mimetic rusfertide is in late-phase trials aiming to abolish phlebotomy dependence.