Читать книгу Haematology - Barbara J. Bain, Irene Roberts - Страница 14

5 Primary myelofibrosis

A 40‐year‐old man underwent allogeneic stem cell transplantation for JAK2‐mutated primary myelofibrosis. His disease has recurred, and now 7 years later, he has been enrolled into a phase 1 clinical trial. He has massive splenomegaly which causes abdominal discomfort and early satiety but his blood counts are reasonably well preserved: Hb 126 g/l, WBC 5.3 × 10⁹/l, neutrophils 4.1 × 10⁹/l and platelets 348 × 10⁹/l. A bone marrow trephine biopsy was taken as a baseline at enrolment and the sections are illustrated above. On H&E staining the marrow showed marked hypercellularity, approaching 100%, largely due to a marked increase in large pleomorphic megakaryocytes (top images ×50 objective). These showed inevitable gross clustering. There was a marked increase in stainable reticulin to grade 3/3 with the reticulin fibres often laid down circumferentially around the megakaryocytes (bottom left). There was a marked increase in marrow sinusoids (note the CD34 expression by the endothelial cells) and the megakaryocytes showed aberrant CD34 expression (CD34, bottom centre, immunoperoxidase). The variation in megakaryocyte size is also illustrated here with giant forms being common, though much smaller forms are also evident (CD42b, bottom right, immunoperoxidase).

Primary myelofibrosis is a myeloproliferative neoplasm characterised by megakaryocyte proliferation, associated progressive bone marrow fibrosis/osteosclerosis and a propensity to evolve to acute myeloid leukaemia. Due to compromise of the bone marrow compartment, extramedullary haemopoiesis follows with involvement of the liver and particularly the spleen. Progressive bone marrow fibrosis causes bone marrow failure which is further compounded by hypersplenism. Patients develop abdominal pain and early satiety due to splenomegaly together with night sweats, fatigue and weight loss from the catabolic effect of the disease. Treatments such as ruxolitinib, a JAK‐STAT pathway inhibitor, are useful for splenic symptoms and sweats. Ruxolitinib prolongs survival in myelofibrosis but the only potential curative treatment is allogeneic bone marrow transplantation. There is an unmet need for effective treatment of myelofibrosis.

The blood film can show important features (images above ×100), but these are not specific for the diagnosis which is based on bone marrow assessment. Note the teardrop poikilocytes and the macrothrombocytes with abnormal granulation. Platelet morphology is consistently abnormal in myelofibrosis. Myelofibrosis can also develop as a secondary phenomenon in other myeloproliferative neoplasms and the clinical consequences are similar to those described above, often with a loss of proliferative behaviour of the disorder with progressive splenomegaly and cytopenias.

MCQ

1 Molecular mechanisms underlying primary myelofibrosis include:BCR‐ABL1CALR mutationJAK2 V617FJAK2 exon 12 mutationMPL mutationFor answers and discussion, see page 206.