Relevance and dynamics of myelofibrosis regarding hematopoietic reconstitution after allogeneic bone marrow transplantation in chronic myelogenous leukemia – a single center experience on 160 patients

Abstract

Summary:A retrospective single center study was performed on 516 trephine biopsies derived from 160 patients with stable phase Ph + -CML and allogeneic BMT. Following morphometric quantification of reticulin-collagen fibers we tried to elucidate (1) the dynamics of bone marrow fibrosis in the post-transplant period; and (2) the influence of manifest myelofibrosis on relevant engraftment parameters. An evaluation of fiber density at standardized endpoints after BMT was carried out on a selected cohort of 124 patients (399 biopsy specimens). A manifest myelofibrosis (more than a three-fold increase compared to the normal fiber content) before BMT was found in 26% of our patients. Concentrating on bone marrow areas with reconstituting hematopoiesis, several findings emerged. Pretransplant myelofibrosis was associated with an initial regression following BMT, but insidiously recurred in the areas of regenerating hematopoiesis or developed in a few patients without increased pregraft fibers during the post-transplant period (mean observation time more than 4 months). Severe acute GVHD (grades III and IV) was significantly correlated with a greater amount of reticulin fibers in the early post-transplant period (9 to 30 days after BMT). Regarding engraftment parameters, a significant delay was detectable in the time to achieve transfusion independence for the patients with manifest myelofibrosis compared to those without pretransplant fiber increase. Bone Marrow Transplantation (2000) 26, 275-281.

Stromal SPARC contributes to the detrimental fibrotic changes associated with myeloproliferation whereas its deficiency favors myeloid cell expansion

“…[3][4][5][6]16 Moreover, stromal alterations may render the HSC niche unfit for HSC seeding (supplemental Figure 1) and negatively impact the outcome of allogeneic stem cell transplantation. 17,18 Thus, BM stroma involvement in myeloid malignancies is an integral part of the disease manifestations impacting the outcome. However, little is known about the nature of stromaintrinsic factors and their role in BM stromal changes and myeloid clone progression.…”

Hematologic aspects of myeloablative therapy and bone marrow transplantation

“…An increase in reticulin fibers and the development of myelofibrosis is also seen in patients treated with busulfan, and particularly interferon-alfa (IFN-alfa), while a regression of myelofibrosis occurs with hydroxyurea treatment (50,147). There is usually an initial regression of myelofibrosis after BMTx, but it often recurs in the areas of regenerating hematopoiesis, and is associated with the presence of atypical dwarf megakaryocytes, severe acute GVHD, and a significant delay in the time to achieve transfusion independence (183). De novo post-BMTx myelofibrosis also develops in a few patients.…”

Morphology of the bone marrow after stem cell transplantation

“…The development and severity of acute GVHD correlates significantly with the number of CD45RO lymphocytes in the marrow 83 . In chronic myeloid leukaemia, severe acute GVHD also correlates with a larger amount of reticulin fibres in the early PT period and with a delay in achieving transfusion independence 32 . Patchy regeneration of megakaryocytes occurs (Figure 2c), including dysplastic megakaryocytes 24,77 .…”

“…Therefore, an acellular or hypocellular BM and a high degree of reticulin-collagen fibrosis are signs of late or failing engraftment after transplantation. 20,21,24,[30][31][32] The regeneration of haematopoiesis Speed and quality of haematopoietic regeneration are variable and generally depend on the nature of the underlying disease and on the type of conditioning regimen and method of transplantation. Usually, BM reconstitution is better and faster when a non-myeloablative treatment is applied compared with aggressive myeloablative strategies, where severe immunosuppression, slower haematopoietic regeneration and longer lasting pancytopenia are seen.…”

“…In the following hours the number of donor cells in the endosteal region decreases and the proportion of cells in the central regions increases. 32,69 The distribution of the progenitor cells can be visualized by immunohistochemical CD34 staining, where they are differentiated from endothelial cells by their histological characteristics, including distribution (histotopography). 26,27,70,71 The induced BM changes become more evident at the end of the first week.…”