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Chronic Myeloproliferative Disorders

Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia

Leukemia volume 21, pages 2420–2427 (2007)Cite this article

Abstract

In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF). Whether the unfavorable prognosis of MF is also reversed and whether imatinib guarantees against evolution of MF are unclear as yet. Fifty-nine patients with Ph+ CML treated with ⩾400 mg imatinib/day were examined for MF in 6- to 12-month intervals. Imatinib effectively reversed initial MF (P<0.0005). However, during a follow-up period of up to 4.8 years, small foci with abnormal fiber increase (FFI) emerged in 8 of 30 pretreated and 6 of 29 non-pretreated patients. Patients with FFI showed a significantly lower probability of achieving a complete cytogenetic or major molecular response (36 versus 81%; P<0.007). During the further follow up, 57% of patients with FFI but none of the other patients suffered from full-blown MF (P=0.00005). None of the patients with FFI or MF showed a Janus kinase-2 mutation (V617F). Evolutions of FFI and MF were independent significant predictors of imatinib failure (P=0.0031), accelerated phase and death of patients (P=0.0001; multivariate analyses). Imatinib effectively reverses initial MF in CML, but neither eliminates its unfavorable prognosis nor guarantees completely against new evolution of MF.

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References

  1. Hahn EA, Glendenning GA, Sorensen MV, Hudgens SA, Druker BJ, Guilhot F et al. Quality of life in patients with newly diagnosed chronic phase chronic myeloid leukemia on imatinib versus interferon alfa plus low-dose cytarabine: results from the IRIS Study. J Clin Oncol 2003; 21: 2138–2146.

    Article  CAS  PubMed  Google Scholar 

  2. Hughes TP, Kaeda J, Branford S, Rudzki Z, Hochhaus A, Hensley ML et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med 2003; 349: 1423–1432.

    Article  CAS  PubMed  Google Scholar 

  3. Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002; 346: 645–652.

    Article  CAS  PubMed  Google Scholar 

  4. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  5. Buchdunger E, Cioffi CL, Law N, Stover D, Ohno-Jones S, Druker BJ et al. Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors. J Pharmacol Exp Ther 2000; 295: 139–145.

    CAS  PubMed  Google Scholar 

  6. Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ et al. Inhibition of the Abl protein-tyrosine kinase in vitro and in vivo by a 2-phenylaminopyrimidine derivative. Cancer Res 1996; 56: 100–104.

    CAS  PubMed  Google Scholar 

  7. Daniels CE, Wilkes MC, Edens M, Kottom TJ, Murphy SJ, Limper AH et al. Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. J Clin Invest 2004; 114: 1308–1316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kimura A, Katoh O, Hyodo H, Kuramoto A, Satow Y . Platelet derived growth factor expression, myelofibrosis and chronic myelogenous leukemia. Leuk Lymphoma 1995; 18: 237–242.

    Article  CAS  PubMed  Google Scholar 

  9. 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  PubMed  Google Scholar 

  10. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Lazzarino M, Morra E, Castello A, Inverardi D, Coci A, Pagnucco G et al. Myelofibrosis in chronic granulocytic leukaemia: clinicopathologic correlations and prognostic significance. Br J Haematol 1986; 64: 227–240.

    Article  CAS  PubMed  Google Scholar 

  13. Kvasnicka HM, Thiele J, Schmitt-Graeff A, Diehl V, Zankovich R, Niederle N et al. Bone marrow features improve prognostic efficiency in multivariate risk classification of chronic-phase Ph(1+) chronic myelogenous leukemia: a multicenter trial. J Clin Oncol 2001; 19: 2994–3009.

    Article  CAS  PubMed  Google Scholar 

  14. Beham-Schmid C, Apfelbeck U, Sill H, Tsybrovsky O, Hofler G, Haas OA et al. Treatment of chronic myelogenous leukemia with the tyrosine kinase inhibitor STI571 results in marked regression of bone marrow fibrosis. Blood 2002; 99: 381–383.

    Article  CAS  PubMed  Google Scholar 

  15. Bueso-Ramos CE, Cortes J, Talpaz M, O'Brien S, Giles F, Rios MB et al. Imatinib mesylate therapy reduces bone marrow fibrosis in patients with chronic myelogenous leukemia. Cancer 2004; 101: 332–336.

    Article  CAS  PubMed  Google Scholar 

  16. Frater JL, Tallman MS, Variakojis D, Druker BJ, Resta D, Riley MB et al. Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). Bone marrow histopathology and correlation with genetic status. Am J Clin Pathol 2003; 119: 833–841.

    Article  PubMed  Google Scholar 

  17. Hasserjian RP, Boecklin F, Parker S, Chase A, Dhar S, Zaiac M et al. ST1571 (imatinib mesylate) reduces bone marrow cellularity and normalizes morphologic features irrespective of cytogenetic response. Am J Clin Pathol 2002; 117: 360–367.

    Article  CAS  PubMed  Google Scholar 

  18. Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood 2004; 103: 473–478.

    Article  CAS  PubMed  Google Scholar 

  19. Thiele J, Kvasnicka HM, Schmitt-Graeff A, Kriener S, Engels K, Staib P et al. Effects of the tyrosine kinase inhibitor Imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia. Histol Histopathol 2004; 19: 1277–1288.

    CAS  PubMed  Google Scholar 

  20. Kantarjian H, Bueso-Ramos CE, Talpaz M, O'Brien S, Giles F, Faderl S et al. Significance of myelofibrosis in early chronic-phase, chronic myelogenous leukemia on imatinib mesylate therapy. Cancer 2005; 104: 777–780.

    Article  CAS  PubMed  Google Scholar 

  21. Kantarjian H, Bueso-Ramos CE, Talpaz M, O'Brien S, Giles F, Rios MB et al. The degree of bone marrow fibrosis in chronic myelogenous leukemia is not a prognostic factor with imatinib mesylate therapy. Leuk Lymphoma 2005; 46: 993–997.

    Article  CAS  PubMed  Google Scholar 

  22. Buesche G, Freund M, Hehlmann R, Georgii A, Ganser A, Hecker H et al. Treatment intensity significantly influencing fibrosis in bone marrow independently of the cytogenetic response—meta-analysis of the long-term results from two prospective controlled trials on chronic myeloid leukemia. Leukemia 2004; 18: 1460–1467.

    Article  CAS  PubMed  Google Scholar 

  23. Berger U, Engelich G, Reiter A, Hochhaus A, Hehlmann R, German CML Study Group. Imatinib and beyond—the new CML study IV. A randomized controlled comparison of imatinib vs imatinib/interferon-alpha vs imatinib/low-dose AraC vs imatinib after interferon-alpha failure in newly diagnosed chronic phase chronic myeloid leukemia. Ann Hematol 2004; 83: 258–264.

    Article  CAS  PubMed  Google Scholar 

  24. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. J Natl Cancer Inst 1998; 90: 850–858.

    Article  CAS  PubMed  Google Scholar 

  25. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE et al. Prognostic discrimination in ‘good-risk’ chronic granulocytic leukemia. Blood 1984; 63: 789–799.

    CAS  PubMed  Google Scholar 

  26. Vardiman JW, Imbert M, Pierre R, Brunning RD, Thiele J, Flandrin G . Chronic myelogenous leukemia. 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 20–26.

    Google Scholar 

  27. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006; 108: 1809–1820.

    Article  CAS  PubMed  Google Scholar 

  28. 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  PubMed  PubMed Central  Google Scholar 

  29. 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  PubMed  Google Scholar 

  30. Hedeker D, Gibbons RD . Mixreg: a computer program for mixed-effects regression analysis with autocorrelated errors. Comput Methods Programs Biomed 1996; 49: 229–252.

    Article  CAS  PubMed  Google Scholar 

  31. Hochhaus A, Kreil S, Corbin AS, La Rosee P, Muller MC, Lahaye T et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 2002; 16: 2190–2196.

    Article  CAS  PubMed  Google Scholar 

  32. Chu S, Xu H, Shah NP, Snyder DS, Forman SJ, Sawyers CL et al. Detection of BCR-ABL kinase mutations in CD34+ cells from chronic myelogenous leukemia patients in complete cytogenetic remission on imatinib mesylate treatment. Blood 2005; 105: 2093–2098.

    Article  CAS  PubMed  Google Scholar 

  33. Lahaye T, Riehm B, Berger U, Paschka P, Muller MC, Kreil S et al. Response and resistance in 300 patients with BCR-ABL-positive leukemias treated with imatinib in a single center. Cancer 2005; 103: 1659–1669.

    Article  PubMed  Google Scholar 

  34. Wendel HG, de Stanchina E, Cepero E, Ray S, Emig M, Fridman JS et al. Loss of p53 impedes the antileukemic response to BCR-ABL inhibition. Proc Natl Acad Sci USA 2006; 103: 7444–7449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Frank O, Brors B, Fabarius A, Li L, Haak M, Merk S et al. Gene expression signature of primary imatinib-resistant chronic myeloid leukemia patients. Leukemia 2006; 20: 1400–1407.

    Article  CAS  PubMed  Google Scholar 

  36. Villuendas R, Steegmann JL, Pollan M, Tracey L, Granda A, Fernandez-Ruiz E et al. Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach. Leukemia 2006; 20: 1047–1054.

    Article  CAS  PubMed  Google Scholar 

  37. Hussein K, Bock O, Seegers A, Flasshove M, Hennecke F, Buesche G et al. Myelofibrosis evolving during imatinib treatment of a chronic myeloproliferative disorder with co-existing BCR-ABL translocation and JAK2V617F mutation. Blood 2007; 109: 4106–4107 (letter).

    Article  CAS  PubMed  Google Scholar 

  38. Kronenwett R, Graf T, Neumann F, Pechtel S, Steidl U, Diaz-Blanco E et al. Absence of the JAK2 mutation V617F in CD34+ hematopoietic stem and progenitor cells from patients with BCR-ABL-positive CML in chronic phase and blast crisis. Leuk Res 2006; 30: 1323–1324.

    Article  CAS  PubMed  Google Scholar 

  39. Cortes JE, Talpaz M, Giles F, O'Brien S, Rios MB, Shan J et al. Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy. Blood 2003; 101: 3794–3800.

    Article  CAS  PubMed  Google Scholar 

  40. Marktel S, Marin D, Foot N, Szydlo R, Bua M, Karadimitris A et al. Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression. Haematologica 2003; 88: 260–267.

    CAS  PubMed  Google Scholar 

  41. Mohamed AN, Pemberton P, Zonder J, Schiffer CA . The effect of imatinib mesylate on patients with Philadelphia chromosome-positive chronic myeloid leukemia with secondary chromosomal aberrations. Clin Cancer Res 2003; 9: 1333–1337.

    CAS  PubMed  Google Scholar 

  42. Cortes J, Talpaz M, O'Brien S, Jones D, Luthra R, Shan J et al. Molecular responses in patients with chronic myelogenous leukemia in chronic phase treated with imatinib mesylate. Clin Cancer Res 2005; 11: 3425–3432.

    Article  CAS  PubMed  Google Scholar 

  43. Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.

    Article  CAS  PubMed  Google Scholar 

  44. Buesche G, Hehlmann R, Ganser A, Hecker H, Hochhaus A, Heimpel H et al. In CML, marrow fibrosis relapses or emerges in 5–6% of patients per year-independently indicating imatinib failure and shortened survival time of patients. Blood 2006; 108: 2195 (abstract).

    Google Scholar 

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Acknowledgements

We thank our clinical colleagues for their support in recruiting and validating data on cytogenetic±molecular response and course of disease, Dr R Hehlmann and Dr A Hochhaus for helpful comments and discussion of the data and M Engel, R Lohmann, M Markwart and S Schröter for their excellent technical assistance. This study was supported by a grant (Bu1103/2-1) from the Deutsche Forschungsgemeinschaft, Bonn, Germany

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Authors and Affiliations

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

    G Buesche, O Bock, B Frye & H Kreipe

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

    A Ganser

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

    B Schlegelberger, N von Neuhoff & D Gadzicki

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

    H Hecker

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  1. G Buesche
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Correspondence to G Buesche.

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

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Buesche, G., Ganser, A., Schlegelberger, B. et al. Marrow fibrosis and its relevance during imatinib treatment of chronic myeloid leukemia. Leukemia 21, 2420–2427 (2007). https://doi.org/10.1038/sj.leu.2404917

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