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Erythropoietic Reconstitution, Macrophages and Reticulin Fibrosis

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Erythropoietic Reconstitution, Macrophages and Reticulin Fibrosis Leukemia (2000) 14, 1378–1385 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation J Thiele1, HM Kvasnicka1, DW Beelen2, B Pilgram1, A Rose1, L-D Leder3 and UW Schaefer2 Institutes of Pathology, Universities of 1Cologne, Cologne and 3Essen, Essen; and 2Department of Bone Marrow Transplantation, University of Essen, Essen, Germany A clinicopathological study was conducted on 351 bone mar- ated or blastic phases,7 some data have been accumulated row trephine biopsies derived from 124 patients with chronic that histopathology may offer supportive evidence. Follow-up myeloid leukemia (CML) at standardized endpoints before and after allogeneic bone marrow transplantation (BMT). The pur- studies on bone marrow histopathology together with clinical pose was to investigate quantitative changes of the nucleated observations were in keeping with the finding that reduction erythroid precursor cell population and other associated fea- in erythropoiesis8 and extent of myelofibrosis9–12 may serve as tures such as resident bone marrow macrophages and myelo- valid parameters for the assessment of disease progression. fibrosis and to elucidate their relevance on engraftment para- Both variables have been shown to be significantly correlated meters. Monoclonal antibodies were applied for the and to exert a predictive value for survival.8,9,11,12 Contrasting identification of erythroid precursors and the labeling of mature the overall progress which has been achieved during the last macrophages; argyrophilic (reticulin-collagen) fibers were 2,13–18 demonstrated by a silver impregnation technique. Following decade concerning BMT in CML, hardly any information morphometric analysis of the pregraft bone marrow specimens exists about bone marrow morphology following marrow- statistical evaluation was in line with an adverse correlation ablative pretransplant regimens and the regeneration of hema- between early to moderate reticulin fibrosis and amount of topoiesis. In particular, this lack of knowledge applies to erythropoiesis. Moreover, a significant relationship was calcu- erythroid precursors in the pre- and post-transplant period and lable between numbers of erythroid precursors and CD68؉ macrophages. After myelo-ablative therapy and BMT a pro- the problem whether a greatly reduced erythropoiesis before nounced decrease in cellularity and in the quantity of erythro- BMT exerts a relevant influence on engraftment. Because poiesis was found. Comparable with the pregraft samples, a there is clear-cut evidence for an important functional role of significant association between erythroid precursors and the central resident (mature) macrophages of erythroblastic macrophages could be determined in the regenerating donor islets in iron turnover, hemoglobin synthesis, erythropoietin bone marrow. A pretransplant relevant reduction of the red cell production and phagocytosis of the expelled erythroblastic lineage and a manifest (reticulin) myelofibrosis indicating an 19 advanced stage of disease were accompanied by a significant nuclei, this cell lineage deserves special attention in the con- delay to reach transfusion independence. This result was text of erythropoietic regeneration. For this reason, the pur- further supported by comparable findings in trephine biopsies pose of the present study was focused on histopathology performed in the early post-transplant period (second month characterizing the reconstitution of erythropoiesis including after BMT). Corresponding examinations revealed an enhance- the macrophage population and associated changes of the ment of fiber density and a decrease in erythropoiesis in those fiber content during the critical phase of marrow engraftment patients who did not conform with the usually accepted criteria for successful engraftment. In conclusion, compelling evidence in CML. To elucidate the putative impact of these features on has been produced that a significantly reduced amount of BMT biology, appropriate analysis was carried out by histoch- erythroid precursors, which is usually associated with myelo- emical and morphometric methods on repeatedly performed fibrosis in the pretransplant bone marrow, exerts an impair- bone marrow trephine biopsies at standardized endpoints ment to undisturbed hematopoietic reconstitution. Moreover, a accompanied by corresponding clinical data. close spatial and numerical relationship between the erythroid lineage and resident (mature) macrophages is observable, in particular in the state of regeneration after BMT. Leukemia (2000) 14, 1378–1385. Materials and methods Keywords: erythropoiesis; macrophages; myelofibrosis; bone marrow biopsy; bone marrow transplantation; CML Patients The series considered for study was based on a retrospective Introduction evaluation of 124 patients presenting with first chronic (stable) phase of Philadelphia chromosome-positive (Ph1ϩ) CML. Stem cell and bone marrow transplantation (BMT) is generally Patients received unmanipulated marrow grafts from HLA- believed to be the only form of therapy with the option to identical family or alternate donors at a single referral trans- cure chronic myelogenous leukemia (CML).1,2 However, plantation center following standard procedures.14 Details among other factors, outcome determined as capacity for regarding, clinical findings and treatment characteristics are unsupported hematopoietic reconstitution at day 30 following summarized in Table 1. As may be easily derived from Table 1 BMT is significantly influenced by progression of disease at homogeneity of our cohort concerning specifications of cer- onset and thus timing.3–5 Regarding staging of chronic phase tain characteristics is established by showing about 80% sib- CML indicating a certain progress4–6 or definition of acceler- ling donors, in more than 70% an identical HLA constellation and the same conditioning regimen in 90% of patients. Endpo- int of hematological reconstitution with normal graft function was assumed if patients achieved transplant-derived absolute Correspondence: J Thiele, Institute of Pathology, University of × 9 Cologne, Joseph-Stelzmannstr. 9, D-50924 Cologne, Germany; neutrophil counts greater than 0.5 10 /l and self-sustaining 9 Fax: +49–0221–4786360 thrombocyte counts greater than 20.0 × 10 /l until day 30 fol- Received 10 March 2000; accepted 21 March 2000 lowing BMT. Delayed engraftment was diagnosed if these Erythropoiesis and BMT in CML J Thiele et al 1379 Table 1 Characteristics of 123 CML patients with allogeneic BMT for 3–4 days in 10% buffered ethylene-diamine tetra-acetic under study acid (EDTA), pH 7.2, paraffin embedding, and employment of several routine staining techniques, involving Giemsa, PAS Median age (years) 35 (periodic acid Schiff reagent), naphthol-AS-D-chloroacetate range (15–55) Gender (M/F) 73/51 esterase, Perls’ reaction for iron and finally a silver impreg- Sokal index-risk groups, n (%) nation method (Gomori’s technique) for the assessment of low 106 (85) argyrophilic (reticulin-collagen) fiber density. For specific intermediate 11 (9) staining of nucleated erythroid precursor cells the monoclonal high 7 (6) antibody Ret40f (anti-glycophorin C) was used20 and for the Median interval from diagnosis to BMT (months) 20 CD68ϩ mature-resident macrophage population PG-M .21 range 5–133 1 Relation – Donors, n (%) Monoclonal antibodies and other reagents were purchased sibling 97 (79) from Dako-Diagnostica (Hamburg, Germany). Details of stain- unrelated 26 (21) ing procedures (APAAP-method) were reported in a previous Median donor age (years) 37 communication.12,21 range 18–66 Gender of donor (F/M) 64/59 Donor/recipient sex, n M → F34 F → M20Morphometry Predominant pretransplant therapya, n (%) hydroxyurea (HU) 89 (72) interferon-␣ (IFN-␣) 62 (50) Following immunostaining and silver impregnation morpho- busulfan (BU) 43 (35) metric analysis was performed by two manual optic plan- HLA constellation, n (%) HLA identical 90 (73) imeters (MOP-A-MO1-Kontron and VIDAS-Zeiss-Kontron, 1 MM 34 (27) Carl Zeiss, Oberkochen, Germany) with a standard program Conditioning regimen, n (%) set (Kontron software, Kontron, Eching, Germany) on large tre- (Cy 60 mg/kg/day ×2) phine biopsies with an artefact-free mean marrow area of dose of TBI × 2 1 (1) 14.5 4.8 mm . Frequencies of erythroid precursors and 8.6 Gy 60 Colbalt 2 7 (6) macrophages were calculated per square millimeter (mm ) 4 × 2.5 Gy LINAC 116 (93) 4 × 2.5 Gy 60 Cobalt total marrow area by regarding the age- or therapy-related adi- GVHD prophylaxis, n(%) pose tissue and also per hematopoiesis (cellularity). After sil- MTX alone 9 (8) ver impregnation procedures density of argyrophilic (reticulin- sMTX + CyA 98 (79) collagen) fibers was determined by the point-intersection CyA 4 (3) method using an ocular grid. Thus the amount of fibers was + CyA BMA031 12 (10) expressed as intersections (i) per area (mm2) of total bone mar- ABO-blood group constellation, n (%) matched 73 (59) row and also per hematopoietic tissue (cellularity). Reference mismatched to cellularity was necessary to focus on the areas relevant for minor 24 (19) hematopoietic reconstitution and further to avoid the major 27 (22) erroneous impression of a significant reduction of these vari- Marrow cell dose ables due to the expansion of adipose tissue or interstitial × 8 graft size ( 10 /kg nucleated cells) median 2.3 edema. This feature was prominent
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