Abstract
A clinicopathological study was conducted on 351 bone marrow trephine biopsies derived from 124 patients with chronic myeloid leukemia (CML) at standardized endpoints before and after allogeneic bone marrow transplantation (BMT). The purpose was to investigate quantitative changes of the nucleated erythroid precursor cell population and other associated features such as resident bone marrow macrophages and myelofibrosis and to elucidate their relevance on engraftment parameters. Monoclonal antibodies were applied for the identification of erythroid precursors and the labeling of mature macrophages; argyrophilic (reticulin-collagen) fibers were demonstrated by a silver impregnation technique. Following morphometric analysis of the pregraft bone marrow specimens statistical evaluation was in line with an adverse correlation between early to moderate reticulin fibrosis and amount of erythropoiesis. Moreover, a significant relationship was calculable between numbers of erythroid precursors and CD68+ macrophages. After myelo-ablative therapy and BMT a pronounced decrease in cellularity and in the quantity of erythropoiesis was found. Comparable with the pregraft samples, a significant association between erythroid precursors and macrophages could be determined in the regenerating donor bone marrow. A pretransplant relevant reduction of the red cell lineage and a manifest (reticulin) myelofibrosis indicating an advanced stage of disease were accompanied by a significant delay to reach transfusion independence. This result was further supported by comparable findings in trephine biopsies performed in the early post-transplant period (second month after BMT). Corresponding examinations revealed an enhancement of fiber density and a decrease in erythropoiesis in those patients who did not conform with the usually accepted criteria for successful engraftment. In conclusion, compelling evidence has been produced that a significantly reduced amount of erythroid precursors, which is usually associated with myelofibrosis in the pretransplant bone marrow, exerts an impairment to undisturbed hematopoietic reconstitution. Moreover, a close spatial and numerical relationship between the erythroid lineage and resident (mature) macrophages is observable, in particular in the state of regeneration after BMT.
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References
Appelbaum FR, Clift R, Radich J, Anasetti C, Buckner CD . Bone marrow transplantation for chronic myelogenous leukemia Semin Oncol 1995 22: 405–441
Clift RA, Anasetti C . Allografting for chronic myeloid leukaemia Baillière's Clin Haematol 1997 10: 319–336
Goldman JM, Szydlo R, Horowitz MM, Gale RP, Ash AC, Atkinson K, Dicke KA, Gluckman E, Herzig RH, Marmont A, Masaoka T, McGlave PB, Messner H, O'Reilly RJ, Reiffers J, Rimm AA, Speck B, Veum-Stone JA, Wingard JR, Zwaan FE, Bortin MM . Choise of pretransplant treatment and timing of transplants for chronic myelogenous leukemia in chronic phase Blood 1993 82: 2235–2238
Savage DG, Szydlo RM, Chase A, Apperley JF, Goldman JM . Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse Br J Haematol 1997 99: 30–35
Gale RP, Hehlmann R, Zhang MJ, Hasford J, Goldman JM, Heimpel H, Hochhaus A, Klein JP, Kolb HJ, McGlave PB, Passweg J, Rowlings PA, Sobocinski KA, Horowitz MM, and the German CML Study Group . Survival with bone marrow transplantation versus hydroxyurea or interferon for chronic myelogenous leukemia Blood 1998 91: 1810–1819
Cortes J, Kantarjian HM, Giralt S, Talpaz M . Natural history and staging of chronic myelogenous leukaemia Baillière's Clin Haematol 1997 10: 277–290
Muehleck SD, McKenna RW, Arthur DC, Parkin JL, Brunning RD . Transformation of chronic myelogenous leukemia: clinical, morphologic and cytogenic features Am J Clin Pathol 1984 82: 1–14
Thiele J, Hoefer M, Kvasnicka HM, Bertsch HP, Zankovich R, Fischer R . Erythropoiesis in CML – immunohistomorphometric quantification, PCNA-reactivity, and influence on survival Hematol Pathol 1993 7: 239–249
Lazzarino M, Morra E, Castello A, Inverardi D, Coci A, Pagnuco G, Magrini U, Bernasconi C . Myelofibrosis in chronic granulocytic leukemia. Clinical pathologic correlations and prognostic significance Br J Haematol 1986 64: 227–240
Dekmezian R, Kantarjian HM, Keating M, Talpaz M, McCredie KB, Freireich EJ . The relevance of reticulin stain-measured fibrosis at diagnosis in chronic myelogenous leukaemia Cancer 1987 57: 1739–1743
Buhr T, Choritz H, Georgii A . The impact of megakaryocyte proliferation for the evolution of myelofibrosis. Histological follow-up study in 186 patients with chronic myeloid leukemia Virchows Arch A Pathol Anat 1992 420: 473–478
Thiele J, Kvasnicka HM, Fischer R . Bone marrow histopathology in chronic myelogenous leukemia (CML) – evaluation of distinctive features with clinical impact Histol Histopathol 1999 14: 1241–1256
Gratwohl A, Hermans J, Niederwieser D, Frassoni F, Arcese W, Gahrton G, Bandini G, Carreras E, Vernant JP, Bosi A, de Witte T, Fibbe WE, Zwaan F, Michallet M, Ruutu T, Devergie A, Iriondo A, Apperley J, Reiffers J, Speck B, Goldman JM for the Chronic Leukemia Working Party of the European Group for Bone Marrow Transplantation . Bone marrow transplantantion for chronic myeloid leukemia: long-term results Bone Marrow Transplant 1993 12: 509–516
Beelen DW, Graeven U, Elmaagacli AH, Niederle N, Kloke O, Opalka B, Schaefer UW . Prolonged administration of interferon-α in patients with chronic-phase Philadelphia chromosome-positive chronic myelogenous leukemia before allogeneic bone marrow transplantation may adversely affect transplant outcome Blood 1995 36: 2981–2990
Lamparelli T, Van Lint MT, Gualandi F, Occhini D, Barbanti M, Sacchi N, Ficai G, Ghinatti C, Ferrara GB, Delfino L, Pozzi S, Morabito A, Zikos P, Vitale V, Corvo R, Frassoni F, Bacigalupo A . Bone marrow transplantation for chronic myeloid leukemia (CML) from unrelated and sibling donors: single center experience Bone Marrow Transplant 1997 20: 1057–1062
Van Rhee F, Szydlo RM, Hermans J, Devergy A, Frassoni F, Arcese W, de Witte T, Kolb HJ, Niederwieser D, Jacobson N, Gahrton G, Bandini G, Carreras E, Bacigalupo A, Michallet M, Ruutu T, Reiffers J, Goldman JM, Apperley J, Gratwohl A for the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation . Long-term results after allogeneic bone marrow transplantation for chronic myelogenous leukemia in chronic phase: a report from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Bone Marrow Transplant 1997 20: 553–560
Dini G, Lamparelli T, Rondelli R, Lanino E, Barbanti M, Costa C, Manfredini L, Guidi S, Rosti G, Alessandrino EP, Locatelli F, Marenco P, Soligo D, Di Bartolomeo P, Aversa F, La Nasa G, Busca A, Majolino I, De Laurenzi A, Bacigalupo A . Unrelated donor marrow transplantation for chronic myelogenous leukaemia Br J Haematol 1998 102: 544–552
Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift AR, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C . Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia New Engl J Med 1998 338: 962–968
Vogt C, Pentz S, Rich IN . A role for the macrophage in normal hematopoiesis. III. In vitro and in vivo erythropoietin gene expression in macrophages detected by in situ hybridization Exp Hematol 1989 17: 391–397
Gatter KC, Cordell JL, Turley H, Heryet A, Kiefer N, Anstee DJ, Mason DJ . The immunohistological detection of platelet, megakaryocytes and thrombi in routinely processed specimens Histopathology 1988 13: 257–267
Thiele J, Braeckel C, Wagner S, Falini B, Dienemann D, Stein H, Fischer R . Macrophages in normal human bone marrow and chronic myeloproliferative disorders: an immunohistochemical and morphometric study by a new monoclonal antibody (PG-M1) on trephine biopsies Virchows Arch A Pathol Anat 1992 421: 33–39
Bauermeister DE . Quantitation of bone marrow reticulin: a normal range Am J Clin Pathol 1971 56: 24–31
Martin PJ . Determinants of engraftment after allogeneic marrow transplantation Blood 1992 79: 1647–1650
Salomon O, Lapidot T, Terenzi A, Lubin I, Rabi I, Reisner Y . Induction of donor-type chimerism in murine recipients of bone marrow allografts by different radiation regimens currently used in treatment of leukemia patients Blood 1990 76: 1872–1878
Domenech J, Roingeard F, Hérault O, Truglio D, Desbois I, Colombat P, Binet C . Changes in functional capacity of marrow stromal cells after autologous bone marrow transplantation Leuk Lymphoma 1998 29: 533–546
Rajantie J, Sale GE, Deeg HJ, Amos D, Appelbaum F, Storb R, Clift RA, Buckner CD . Adverse effect of severe marrow fibrosis on hematologic recovery after chemoradiotherapy and allogeneic bone marrow transplantation Blood 1986 67: 1693–1697
Soll E, Massumoto C, Clift RA, Buckner CD, Appelbaum FR, Storb R, Sale G, Hackman R, Martin P . Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment Blood 1995 86: 4667–4673
Liesveld JL, Winslow JM, Kempski MC, Ryan DH, Brennan JK, Abboud CN . Adhesive interactions of normal and leukemic human CD34+ myeloid progenitors: role of marrow stromal, fibroblast, and cytomatrix components Exp Hematol 1991 19: 63–70
Wilson JG, Tavassoli M . Microenvironmental factors involved in the establishment of erythropoiesis in bone marrow Ann NY Acad Sci 1994 718: 271–284
Obinata M, Okuyama R, Matsuda KI, Koguma M, Yanai N . Regulation of myeloid and lymphoid development of hematopoietic stem cells by bone marrow stromal cells Leuk Lymphoma 1998 29: 61–69
Breton-Gorius J, Vuillet-Gaugler MH, Coulombel L, Guichard J, Teillet F, Vainchenker W . Association between erythroid progenitors and bone marrow macrophages Blood Cells 1991 17: 127–146
Hanspal M . Importance of cell–cell interactions in regulation of erythropoiesis Curr Opin Hematol 1997 4: 142–147
Gregory CJ, Eaves AC . Three stages of erythropoietic progenitor cell differentiation distinguished by a number of physical and biologic properties Blood 1978 51: 527–537
Rich IN . A role for the macrophage in normal hemopoiesis. II. Effect of varying physiological oxygen tensions on the release of hemopoietic growth factors from bone-marrow-derived macrophages in vitro Exp Hematol 1986 14: 746–751
Wang CQ, Udupa KB, Lipschitz DA . The role of macrophages in the regulation of erythroid colony growth in vitro Blood 1992 80: 1702–1709
Kelley LL, Koury MJ, Bondurant MC, Koury ST, Sawyer ST, Wickrema A . Survival or death of individual proerythroblasts results from differing erythropoietin sensitivities: a mechanism for controlled rates of erythrocyte production Blood 1993 82: 2340–2352
Ponka P, Beaumont C, Richardson DR . Function and regulation of transferrin and ferritin Semin Hematol 1998 35: 35–54
Golde DW, Burgaleta C, Sparkes RS, Cline MJ . The Philadelphia chromosome in human macrophages Blood 1977 49: 367–370
Thiele J, Schmitz B, Fuchs R, Kvasnicka HM Lorenzen J, Fischer R . Detection of the bcr/abl gene in bone marrow macrophages in CML and alterations during interferon therapy – a fluorescence in situ hybridization study on trephine biopsies J Pathol 1998 186: 331–335
Bhatia R, McGlave BM, Dewald GW, Blazar BR, Verfaillie CM . Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages Blood 1995 85: 3636–3645
Acknowledgements
We are greatly indebted to Mrs B Rosenbach, Mrs M Wonschick and Mrs H Tilemann for their excellent technical assistance. This work was supported by a grant from the Dr M Scheel Foundation for Cancer Research (70–2134-Th1).
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Thiele, J., Kvasnicka, H., Beelen, D. et al. Erythropoietic reconstitution, macrophages and reticulin fibrosis in bone marrow specimens of CML patients following allogeneic transplantation. Leukemia 14, 1378–1385 (2000). https://doi.org/10.1038/sj.leu.2401838
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DOI: https://doi.org/10.1038/sj.leu.2401838
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