Replacement of hematopoietic system by allogeneic stem cell transplantation in myelofibrosis patients induces rapid regression of bone marrow fibrosis
© Kröger et al.; licensee BioMed Central Ltd. 2012
Published: 6 June 2012
Bone marrow fibrosis is a hallmark of primary and post ET/PV myelofibrosis. To investigated the impact of replacement of the hematopoietic system in myelofibrosis patients by allogeneic stem cell transplantation on bone marrow fibrosis, we studied bone marrow fibrosis on bone marrow samples from 24 patients with myelofibrosis before and after dose-reduced conditioning followed by allogeneic stem cell transplantation from related or unrelated donor. Using the European Consensus on Grading Bone Marrow Fibrosis, before allografting all patients had advanced fibrosis MF-2 (n = 13) or MF-3 (n = 11). After transplantation, a complete (MF-0) or nearly complete (MF-1) regression of bone marrow fibrosis was seen in 59 % at day +100, in 90 % at day +180, and in 100 % at day +360. No correlation between occurrence of acute graft-versus-host disease, and fibrosis regression on day +180 was seen. We conclude that dose-reduced conditioning, followed by allogeneic stem cell transplantation, resulted in a rapid resolution of bone-marrow fibrosis suggesting the bone marrow fibrogenesis is a highly dynamic rather than static process in patients with myelofibrosis.
Myelofibrosis with myeloid metaplasia (MMM) is a rare malignant hematological disease of the hematopoietic stem cells with a median age at diagnosis of 60 years. Myelofibrosis is characterized by splenomegaly, extramedullary hematopoiesis, bone marrow collagen fibrosis, and osteosclerosis . Bone marrow fibroblasts in patients with myelofibrosis are polyclonal and exhibit normal function . Clinical and preclinical observation suggested that cellular and extracellular levels of fibrogenic and angiogenic cytokines are altered in patients with myelofibrosis Conventional therapy is mainly used to control symptoms whereas no such therapy has so far shown to change the natural course of the disease. The only curative treatment option is hematopoietic stem cell transplantation . With allogeneic stem cell transplantation, about 50 % of the patients can be cured from their disease but the effect on bone marrow fibrosis has not been investigated systematically so far. Therefore we evaluated bone-marrow-fibrosis regression in patients with myelofibrosis after dose-reduced conditioning (busulfan, 10 mg/kg BW; fludarabine, 180 mg/m²; and ATG, 30 - 60 mg/kg BW), followed by allogeneic stem cell transplantation from related (n = 6) or un-related (n = 18) donor.
Methods and patients
Twenty-four patients (male: n = 16; female: n = 8) with a median age of 52 years (range, 32-63) were included. There were 16 male and 8 female patients. Diagnosis was primary myelofibrosis in 18 patients and secondary myelofibrosis in six patients; four of them developed from polycythaemia vera, and two of them from essential thrombocythaemia. Using the European Consensus on Grading . This consensus distinguishes between:
MF - 0 Scattered linear reticulin with no intersections [cross-overs] corresponding to normal bone marrow
MF - 1 Loose network of reticulin with many intersections, especially in paravascular areas
MF - 2 Diffuse and dense increase in reticulin with extensive intersections, occasionally with only focal bundles of collagen and/or focal osteosclerosis
MF - 3 Diffuse and dense increase in reticulin with extensive intersections with coarse bundles of collagen, often associated with significant osteosclerosis
Fibrosis grading was determined independently by two experienced hemato-pathologists.
All patients underwent bone marrow biopsy prior allogeneic stem cell transplantation. A first biopsy after transplantation should be performed between day +30 and day +100, a second bone marrow histology on day +180, and a third histology one year after transplantation. Patients could be included if they had at least one bone marrow histology within the first 180 days after transplantation. The study was approved by the ethic committee of Hamburg/Germany. All patients gave written informed consent for participation in the study.
n = 24
n = 22
n = 16
day +30 to day +100
11 (49 %)
2 (9 %)
13 (51 %)
7 (32 %)
2 (10 %)
9 (41 %))
9 (45 %)
6 (37 %)
4 (18 %)
9 (45 %)
10 (63 %)
This article has been published as part of Fibrogenesis & Tissue Repair Volume 5 Supplement 1, 2012: Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapies. The full contents of the supplement are available online at http://www.fibrogenesis.com/supplements/5/S1.
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