Rapid Regression of Bone Marrow Fibrosis after Dose-Reduced Allogeneic Stem Cell Transplantation in Patients with Myelofibrosis.

Abstract

Myelofibrosis with myeloid metaplasia [MMM] is a myeloproliferative disease of which bone marrow histology is characterized by substantial collagen fibrosis and osteosclerosis. Bone marrow histology changes in MMM are reactive and cytokine mediated. Studies suggested a pathogenic role of transforming growth factor β [TGF-β], platelet derived growth factor, and basic fibroblast growth factor. In the current study we investigated the dynamic and kinetic of fibrosis regression in 18 patients with myelofibrosis who underwent allogeneic stem cell transplantation after a dose-reduced conditioning. The conditioning regimen consisted of Busulfan 10 mg/kg, Fludarabin 180 mg/m2, and Antithymocyte globulin 30 – 60 mg/kg followed by peripheral stem cell transplantation (SCT). 18 patients with a median age of 45 [range 35 to 64] were included and bone marrow histology was investigated prior SCT, between day+30 and +40 after engraftment, on day+100, and 1 year after stem cell transplantation. The grading of myelofibrosis [MF] was performed according to the recently published European Consensus on Grading Bone Marrow Fibrosis [Thiele et al., Haematologica 2005; 90:1125–1132]. This consensus distinguishes between:MF - 0 Scattered linear reticulin with no intersections [cross-overs] corresponding to normal bone marrowMF - 1 Loose network of reticulin with many intersections, especially in perivascular areasMF - 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosisMF - 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosisAt time of transplantation all patients suffered from advanced myelofibrosis 2° [39 %] or 3° [61 %], resulting in a median MF grade of 3 [range 2–3]. After engraftment on day+30 a regression of MF grade to a median of 2 [range 0–3] was observed. Grade 2 or less was observed in 80 % and grade 1 or 0 in 40 % of the patients. On day+100 the median grade of MF was 1 [range 0–3] and 93 % of the patients had an MF-grade of 2 or less, while 73 % of the patients had MF grade-1 or 0. One year after transplantation the median MF-grade was 0 [range 0–2] and 100 % of the patients had a MF-grade of 2 or less and 92 % of the patients had MF grade 1 or 0. We conclude that allogeneic stem cell transplantation after a dose-reduced conditioning induces a rapid and nearly complete regression of bone marrow fibrosis within the first year after transplantation.