A 54-year-old previously fit insurance salesman presents with lethargy, weight loss and night sweats. Blood tests reveal haemoglobin 7.5 g/dl, white blood cell count 19 × 109/l and platelets 846 × 109/l. The blood film is reported as being leukoerythroblastic with 2% circulating blasts; bone marrow aspirate and trephine are subsequently reported as primary myelofibrosis (PMF).
What should the initial management plan be?
Is he a candidate for a bone marrow transplant?
A leukoerythroblastic blood film, in which immature white cell precursors (including blasts) and nucleated red blood cells are seen, is highly indicative of an infiltrative process affecting the bone marrow. The differential diagnosis includes malignancy (both haematological and secondary bone marrow involvement from non-haematological malignancy), infection involving the bone marrow (for example tuberculosis) and myelofibrosis. The patient mentions a nagging abdominal pain he has had for several months and clinical examination reveals an enlarged spleen that stretches to the umbilicus. Causes of such gross splenomegaly are few, and myelofibrosis would be the most likely diagnosis. The patient underwent a bone marrow examination and the diagnosis was confirmed.
Primary myelofibrosis is a clonal myeloproliferative neoplasm characterized by the proliferation of mainly megakaryocytic and granulocytic elements in the bone marrow, associated with reactive deposition of bone marrow connective tissue (although an early pre-fibrotic phase is also recognized) and with extramedullary haematopoiesis. The incidence is approximately 1 new case per 100 000 population per year. The median age at diagnosis is 65 years, while only 22% of cases are in individuals <56 years and 11% in those <46 years. Diagnosis may follow incidental blood count abnormalities but patients may also present with symptomatic splenomegaly, constitutional symptoms, bone pain, gout secondary to hyperuricaemia or symptoms related to bone marrow failure. Most patients have splenomegaly, which may be massive, and nearly half have hepatomegaly. Most are anaemic, while platelet and leukocyte counts may be low, normal or raised. A blood film typically shows a leukoerythroblastic picture with teardrop poikilocytes. Folate levels may be low due to increased cell turnover. Median survival is 4 years but there is considerable variation between individuals. Causes of death include infection, bleeding, thrombosis (arterial/venous) or transformation to acute myeloid leukaemia, which occurs in nearly 20% of cases.1
Prognostic scoring systems have been used to help identify candidates for allogeneic bone marrow transplantation (alloBMT) and divide patients into low, intermediate and high risk (Table 24.1). Allogeneic BMT represents the only curative treatment and by replacing the abnormal stem cell clone with normal donor haematopoietic precursors, the stimulus for reactive marrow fibrosis is removed. For conventional myeloablative alloBMT, the transplant-related mortality (TRM) of 30% is significant, with a 5-year survival of only 30%–50%, although the majority of these patients are disease free. Better outcome has been associated with younger age, busulphan/cyclophosphamide conditioning and the absence of markers of advanced disease (e.g. absence of circulating blasts, less marrow fibrosis). A sibling donor appeared superior to an unrelated donor in some but not all studies. Pre-transplant splenectomy has been used for patients with severe marrow fibrosis or massive splenomegaly in an attempt to reduce their risk of delayed or failed engraftment. This procedure remains contentious, however, because of the operative mortality risk.
Table 24.1Prognostic scoring systems for PMF |Favorite Table|Download (.pdf) Table 24.1 Prognostic scoring systems for PMF
|System ||Adverse factor (each scores 1) ||Score ||Median survival (months) ||Risk |
|Dupriez (Lille system)6 ||Leukocytes <4 or >30 × 109/l ||0 ||93 ||Low |
|All ages, n = 195, median OS ...|