Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myelodysplasias

Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes

Leukemia volume 22, pages 313–322 (2008)Cite this article

Abstract

Marrow fibrosis (MF) has rarely been studied in myelodysplastic syndromes (MDS). There are no data on occurrence and significance of MF in the context of the World Health Organization (WHO) classification of disease. In total, 349 bone marrow biopsies from 200 patients with primary MDS were examined for MF and its prognostic relevance. MF correlated with multilineage dysplasia, more severe thrombopenia, higher probability of a clonal karyotype abnormality, and higher percentages of blasts in the peripheral blood (P<0.002). Its frequency varied markedly between different MDS types ranging from 0 (RARS) to 16% (RCMD, RAEB, P<0.007). Two patients with MF showed a Janus kinase-2 mutation (V617F). Patients with MF suffered from marrow failure significantly earlier with shortening of the survival time down to 0.5 (RAEB-1/-2), and 1–2 (RCMD, RA) years in median (P<0.00005). The prognostic relevance of MF was independent of the International Prognostic Scoring System and the classification of disease. Conclusion: The risk of MF Differs markedly between various subtypes of MDS. MF indicates an aggressive course with a significantly faster progression to fatal marrow failure and should therefore be considered in diagnosis, prognosis and treatment of disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Castro-Malaspina H, Jhanwar SC . Properties of myelofibrosis-derived fibroblasts. Prog Clin Biol Res 1984; 154: 307–322.

    CAS  Google Scholar 

  2. Kimura A, Nakata Y, Hyodo H, Kuramoto A, Satow Y . Platelet-derived growth factor expression in accelerated and blastic phase of chronic myelogenous leukaemia with myelofibrosis. Br J Haematol 1994; 86: 303–307.

    Article  CAS  Google Scholar 

  3. Reilly JT, Barnett D, Dolan G, Forrest P, Eastham J, Smith A . Characterization of an acute micromegakaryocytic leukaemia: evidence for the pathogenesis of myelofibrosis. Br J Haematol 1993; 83: 58–62.

    Article  CAS  Google Scholar 

  4. Kimura A, Katoh O, Hyodo H, Kuramoto A . Transforming growth factor-beta regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts. Br J Haematol 1989; 72: 486–491.

    Article  CAS  Google Scholar 

  5. Georgii A, Buesche G, Kreft A . The histopathology of chronic myeloproliferative diseases. Baillieres Clin Haematol 1998; 11: 721–749.

    Article  CAS  Google Scholar 

  6. Buesche G, Hehlmann R, Hecker H, Heimpel H, Heinze B, Schmeil A et al. Marrow fibrosis, indicator of therapy failure in chronic myeloid leukemia—prospective long-term results from a randomized-controlled trial. Leukemia 2003; 17: 2444–2453.

    Article  CAS  Google Scholar 

  7. Buesche G, Ganser A, Schlegelberger B, von Neuhoff N, Gadzicki D, Hecker H et al. Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia. Leukemia 2007; e-pub ahead of print 6 September : doi:10.1038/sj.leu.2404917.

    Article  CAS  Google Scholar 

  8. Brunning RD, Bennett JM, Flandrin G, Matutes E, Head D, Vardiman JW et al. Myelodysplastic syndromes. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001. pp 61–74.

    Google Scholar 

  9. Germing U, Gattermann N, Strupp C, Aivado M, Aul C . Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000; 24: 983–992.

    Article  CAS  Google Scholar 

  10. Nosslinger T, Reisner R, Koller E, Gruner H, Tuchler H, Nowotny H et al. Myelodysplastic syndromes, from French-American-British to World Health Organization: comparison of classifications on 431 unselected patients from a single institution. Blood 2001; 98: 2935–2941.

    Article  CAS  Google Scholar 

  11. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  Google Scholar 

  12. Lambertenghi-Deliliers G, Annaloro C, Oriani A, Soligo D, Pozzoli E, Polli EE . Prognostic relevance of histological findings on bone marrow biopsy in myelodysplastic syndromes. Ann Hematol 1993; 66: 85–91.

    Article  CAS  Google Scholar 

  13. Maschek H, Georgii A, Kaloutsi V, Werner M, Bandecar K, Kressel MG et al. Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 1992; 48: 208–214.

    Article  CAS  Google Scholar 

  14. Cunningham I, MacCallum SJ, Nicholls MD, Byth K, Hewson JW, Arnold B et al. The myelodysplastic syndromes: an analysis of prognostic factors in 226 cases from a single institution. Br J Haematol 1995; 90: 602–606.

    Article  CAS  Google Scholar 

  15. Cassano E, Giordano M, Riccardi A, Coci A, Cazzola M . Myelodysplastic syndromes: a multiparametric study of prognostic factors and a proposed scoring system. Haematologica 1990; 75: 141–145.

    CAS  Google Scholar 

  16. Ohyashiki K, Sasao I, Ohyashiki JH, Murakami T, Iwabuchi A, Tauchi T et al. Clinical and cytogenetic characteristics of myelodysplastic syndromes developing myelofibrosis. Cancer 1991; 68: 178–183.

    Article  CAS  Google Scholar 

  17. Rios A, Canizo MC, Sanz MA, Vallespi T, Sanz G, Torrabadella M et al. Bone marrow biopsy in myelodysplastic syndromes: morphological characteristics and contribution to the study of prognostic factors. Br J Haematol 1990; 75: 26–33.

    Article  CAS  Google Scholar 

  18. Verhoef GE, De Wolf-Peeters C, Ferrant A, Deprez S, Meeus P, Stul M et al. Myelodysplastic syndromes with bone marrow fibrosis: a myelodysplastic disorder with proliferative features. Ann Hematol 1991; 63: 235–241.

    Article  CAS  Google Scholar 

  19. Marisavljevic D, Rolovic Z, Cemerikic V, Boskovic D, Colovic M . Myelofibrosis in primary myelodysplastic syndromes: clinical and biological significance. Med Oncol 2004; 21: 325–331.

    Article  CAS  Google Scholar 

  20. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. [published erratum appears in Blood 1998; 91: 1100] Blood 1997; 89: 2079–2088.

    CAS  Google Scholar 

  21. Thiele J, Vardiman JW, Pierre R, Brunning RD, Imbert M, Flandrin G . Chronic idiopathic myelofibrosis. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds). World Health Organization Classification of Tumours Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon, 2001. pp 35–38.

    Google Scholar 

  22. Verburgh E, Achten R, Maes B, Hagemeijer A, Boogaerts M, De Wolf-Peeters C et al. Additional prognostic value of bone marrow histology in patients subclassified according to the International Prognostic Scoring System for myelodysplastic syndromes. J Clin Oncol 2003; 21: 273–282.

    Article  CAS  Google Scholar 

  23. Buesche G, Georgii A, Duensing A, Schlue J, Kreipe HH . Evaluating the volume ratio of bone marrow affected by fibrosis—a parameter crucial for the prognostic significance of marrow fibrosis in chronic myeloid leukemia. Hum Pathol 2003; 34: 391–401.

    Article  Google Scholar 

  24. Metzke-Heidemann S, Harder L, Gesk S, Schoch R, Jenisch S, Grote W et al. Integration of amplified BCR/ABL fusion genes into the short arm of chromosome 17 as a novel mechanism of disease progression in chronic myeloid leukemia. Genes Chromosomes Cancer 2001; 31: 10–14.

    Article  CAS  Google Scholar 

  25. Mitelman F, (ed)., ISCN (1995). An International System for Human Cytogenetic Nomenclature. Karger: Basel, Switzerland, 1995.

    Google Scholar 

  26. Bock O, Neuse J, Hussein K, Brakensiek K, Buesche G, Buhr T et al. Aberrant collagenase expression in chronic idiopathic myelofibrosis is related to the stage of disease but not to the JAK2 mutation status. Am J Pathol 2006; 169: 471–481.

    Article  CAS  Google Scholar 

  27. Gattermann N, Billiet J, Kronenwett R, Zipperer E, Germing U, Nollet F et al. High frequency of the JAK2 V617F mutation in patients with thrombocytosis (platelet count&gt;600 × 109/l) and ringed sideroblasts more than 15% considered as MDS/MPD, unclassifiable. Blood 2007; 109: 1334–1335.

    Article  CAS  Google Scholar 

  28. Ingram W, Lea NC, Cervera J, Germing U, Fenaux P, Cassinat B et al. The JAK2 V617F mutation identifies a subgroup of MDS patients with isolated deletion 5q and a proliferative bone marrow. Leukemia 2006; 20: 1319–1321.

    Article  CAS  Google Scholar 

  29. Steensma DP, Dewald GW, Lasho TL, Powell HL, McClure RF, Levine RL et al. The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both ‘atypical’ myeloproliferative disorders and myelodysplastic syndromes. Blood 2005; 106: 1207–1209.

    Article  CAS  Google Scholar 

  30. Ohyashiki K, Aota Y, Akahane D, Gotoh A, Miyazawa K, Kimura Y et al. The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients. Leukemia 2005; 19: 2359–2360.

    Article  CAS  Google Scholar 

  31. Cermak J, Vitek A, Michalova K . Combined stratification of refractory anemia according to both WHO and IPSS criteria has a prognostic impact and improves identification of patients who may benefit from stem cell transplantation. Leuk Res 2004; 28: 551–557.

    Article  Google Scholar 

  32. Hellstrom-Lindberg E . Update on supportive care and new therapies: immunomodulatory drugs, growth factors and epigenetic-acting agents. Hematology (Am Soc Hematol Educ Program) 2005; 2005: 161–166.

    Article  Google Scholar 

  33. Dredge K, Horsfall R, Robinson SP, Zhang LH, Lu L, Tang Y et al. Orally administered lenalidomide (CC-5013) is anti-angiogenic in vivo and inhibits endothelial cell migration and Akt phosphorylation in vitro. Microvasc Res 2005; 69: 56–63.

    Article  CAS  Google Scholar 

  34. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352: 549–557.

    Article  CAS  Google Scholar 

  35. Stadler M, Germing U, Kliche KO, Josten KM, Kuse R, Hofmann WK et al. A prospective, randomised, phase II study of horse antithymocyte globulin vs rabbit antithymocyte globulin as immune-modulating therapy in patients with low-risk myelodysplastic syndromes. Leukemia 2004; 18: 460–465.

    Article  CAS  Google Scholar 

  36. Alvi S, Shaher A, Shetty V, Henderson B, Dangerfield B, Zorat F et al. Successful establishment of long-term bone marrow cultures in 103 patients with myelodysplastic syndromes. Leuk Res 2001; 25: 941–954.

    Article  CAS  Google Scholar 

  37. Flores-Figueroa E, Gutierrez-Espindola G, Montesinos JJ, Arana-Trejo RM, Mayani H . In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome. Leuk Res 2002; 26: 677–686.

    Article  CAS  Google Scholar 

  38. Borojevic R, Roela RA, Rodarte RS, Thiago LS, Pasini FS, Conti FM et al. Bone marrow stroma in childhood myelodysplastic syndrome: composition, ability to sustain hematopoiesis in vitro, and altered gene expression. Leuk Res 2004; 28: 831–844.

    Article  CAS  Google Scholar 

  39. Buesche G, Georgii A, Kreipe HH . Diagnosis and quantification of bone marrow fibrosis are significantly biased by the pre-staining processing of bone marrow biopsies. Histopathology 2006; 48: 133–148.

    Article  CAS  Google Scholar 

  40. Germing U, Hildebrandt B, Pfeilstocker M, Nosslinger T, Valent P, Fonatsch C et al. Refinement of the international prognostic scoring system (IPSS) by including LDH as an additional prognostic variable to improve risk assessment in patients with primary myelodysplastic syndromes (MDS). Leukemia 2005; 19: 2223–2231.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the numerous clinical colleagues in Germany who supported these evaluations by sending and validating the clinical and hematologic data of their patients who had been recruited into this study. We furthermore thank Dr Peter Greenberg for his valuable comments, Dr Hans-Jörg Maschek for helpful discussion of controversial cases, and Michael Engel, Regina Lohmann, Marita Markwart, Gabriele Bauerschaper and Sabine Schröter for their excellent technical assistance.

Author information

Authors and Affiliations

  1. Institut für Pathologie, Medizinische Hochschule Hannover, Hannover, Germany

    G Buesche, H Teoman, O Bock, A Georgii & H Kreipe

  2. Institut für Pathologie, Universitätsklinikum Hamburg-Eppendorf, Ha, m, burg, Germany

    W Wilczak

  3. Klinik für Hämatologie, Hämostaseologie und Onkologie, Medizinische Hochschule Hannover, Hannover, Germany

    A Ganser

  4. Institut für Biometrie, Medizinische Hochschule Hannover, Hannover, Germany

    H Hecker

  5. Institut für Zell- und Molekularpathologie, Medizinische Hochschule Hannover, Hannover, Germany

    L Wilkens, G Göhring & B Schlegelberger

  6. Institut für Pathologie, Universität Bern, Bern, Switzerland

    L Wilkens

Authors
  1. G Buesche
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. H Teoman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Wilczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Ganser
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H Hecker
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L Wilkens
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G Göhring
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. B Schlegelberger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. O Bock
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Georgii
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. H Kreipe
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G Buesche.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Buesche, G., Teoman, H., Wilczak, W. et al. Marrow fibrosis predicts early fatal marrow failure in patients with myelodysplastic syndromes. Leukemia 22, 313–322 (2008). https://doi.org/10.1038/sj.leu.2405030

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2405030

Keywords

This article is cited by

Search

Advanced search

Quick links