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Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia

Leukemia volume 18, pages 1340–1346 (2004)Cite this article

Abstract

Imatinib mesylate (Gleevec®), an inhibitor of the BCR-ABL tyrosine kinase, was introduced recently into the therapy of chronic myeloid leukemia (CML). Several cases of emergence of clonal chromosomal abnormalities after therapy with imatinib have been reported, but their incidence, etiology and prognosis remain to be clarified. We report here a large series of 34 CML patients treated with imatinib who developed Philadelphia (Ph)-negative clones. Among 1001 patients with Ph-positive CML treated with imatinib, 34 (3.4%) developed clonal chromosomal abnormalities in Ph-negative cells. Three patients were treated with imatinib up-front. The most common cytogenetic abnormalities were trisomy 8 and monosomy 7 in twelve and seven patients, respectively. In 15 patients, fluorescent in situ hybridization with specific probes was performed in materials archived before the initiation of imatinib. The Ph-negative clone was related to previous therapy in three patients, and represented a minor pre-existing clone that expanded after the eradication of Ph-positive cells with imatinib in two others. However, in 11 patients, the new clonal chromosomal abnormalities were not detected and imatinib may have had a direct effect. No myelodysplasia was found in our cohort. With a median follow-up of 24 months, one patient showed CML acceleration and two relapsed.

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References

  1. Champlin RE, Golde DW . Chronic myelogenous leukemia: recent advances. Blood 1985; 65: 1039–1047.

    CAS  PubMed  Google Scholar 

  2. Shtivelman E, Lifshitz B, Gale RP, Canaani E . Fused transcript of ABL and BCR genes in chronic myelogenous leukemia. Nature 1985; 315: 550–554.

    Article  CAS  Google Scholar 

  3. Kantarjian H, Sawyers C, Hochlaus 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  Google Scholar 

  4. O'Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F et al. IRIS Investigators. 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  Google Scholar 

  5. Casali M, Truglio F, Milone G, Di Raimondo F, Parinello G, Maserati E et al. Trisomy 8 in Philadelphia chromosome (Ph 1)-negative cells in the course of Ph1-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1992; 4: 269–270.

    Article  CAS  Google Scholar 

  6. Bilhou-Nabera C, Marit G, Devianne I, Viard F, Salzes S, Montastruc M et al. A second case of trisomy 8 in Philadelphia chromosome (Ph)-negative cells during the course of Ph-positive chronic myelocytic leukemia. Genes Chromosomes Cancer 1993; 4: 255–256.

    Article  Google Scholar 

  7. Ariyama T, Inazawa J, Uemura Y, Kakazu N, Maekawa T, Urase FK et al. Clonal origin of Philadelphia chromosome negative cells with trisomy 8 appearing during the course of α-interferon therapy for Ph positive chronic myelocytic leukemia. Cancer Genet Cytogenet 1995; 81: 20–23.

    Article  CAS  Google Scholar 

  8. Ohtuska E, Kikuchi H, Abe Y, Moriyama K, Ohno E, Hirota K et al. Acute myeloblastic leukemia without Philadelphia chromosome developing after interferon therapy for chronic myelocytic leukemia with Philadelphia chromosome. Br J Haematol 1995; 90: 951–953.

    Article  Google Scholar 

  9. Izumi T, Imagawa S, Hatatake H, Miura Y, Ariyama T, Inazawa J et al. Philadelphia chromosome-negative cells with trisomy 8 after busulfan and interferon treatment of Ph1-positive chronic myelogenous leukemia. Int J Hematol 1996; 64: 73–77.

    Article  CAS  Google Scholar 

  10. Fayad L, Kantarjian H, O'Brien S, Seong D, Keating M, Talpaz M . Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia 1997; 11: 767–771.

    Article  CAS  Google Scholar 

  11. Marktel S, Bua M, Marin D, Chase A, Udom C, Armstrong L et al. Emergence of additional chromosomal abnormalities following treatment with STI571 (Imatinib Mesylate) for Philadelphia positive chronic myeloid leukemia in chronic phase. Blood 2001; 98: 617a (abstr.).

    Google Scholar 

  12. Gambarcoti-Passeri C, Giudici G, le Coutre P, Bungaro S, Pogliani EM, Kreuzer KA et al. Non random chromosomal abnormalities in Ph-negative bone marrow (BM) cells from CML patients achieving major cytogenetic response (MCR) with STI571 (GleevecTM). Blood 2001; 98: 257b (abstr.).

    Article  Google Scholar 

  13. Meunier V, Giraudier S, Van den Akker J, Perot C, Jouault H, Caron-Servan B et al. Treatment with STI571 (Novartis) in chronic myeloid leukemia (CML): unexpected hematological findings in a series of 26 patients. Blood 2001; 98: 263b (abstr.).

    Google Scholar 

  14. Braziel R, Launder M, Druker B, Olson S, Magenis E, Mauro M et al. Hematopathologic and cytogenetic findings in imatinib mesylate-treated chronic myelogenous leukemia patients: 14 months experience. Blood 2002; 100: 435–441.

    Article  CAS  Google Scholar 

  15. Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K . Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia 2002; 16: 1390–1393.

    Article  CAS  Google Scholar 

  16. Bumm T, Müller C, Al-Ali HF, Krohn K, Shepherd P, Schmidt E et al. Emergence of clonal cytogenetic abnormalities in Ph-negative cells in some CML patients in cytogenetic remission to imatinib but restoration of polyclonal hematopoiesis in the majority. Blood 2003; 101: 1941–1949.

    Article  CAS  Google Scholar 

  17. Feldman E, Najfeld V, Schuster M, Roboz G, Chadburn A, Goodman O et al. The emergence of Philadelphia chromosome (Ph) negative trisomy 8 cells in patients treated with imatinib mesylate: clinical evidence for a multistep pathogenesis. Blood 2002; 100: 2299 (abstr.).

    Google Scholar 

  18. Meeus P, Demuynck H, Martiat P, Michaux L, Wouters E, Hagemeijer A . Sustained, clonal karyotype abnormalities in the Philadelphia chromosome negative cells of CML patients successfully treated with Imatinib. Leukemia 2003; 17: 465–467.

    Article  CAS  Google Scholar 

  19. Schoch C, Haferlach T, Kern W, Schnittgers S, Berger U, Hehlmann R et al. Occurence of additional chromosome aberrations in chronic myeloid leukemia patients treated with imatinib mesylate. Leukemia 2003; 17: 461–463.

    Article  CAS  Google Scholar 

  20. O'Dwyer M, Gatter K, Loriaux M, Druker B, Olson S, Magenis E et al. Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate. Leukemia 2003; 17: 481–487.

    Article  CAS  Google Scholar 

  21. McMullin M, Humphreys M, Byrne J, Russel N, Cuthbert R, O'Dwyer M . Chromosomal abnormalities in Ph− cells of patients on imatinib. Blood 2003; 102: 2700–2701.

    Article  Google Scholar 

  22. Medina J, Kantarajian H, Talpaz M, O'Brien S, Garcia-Manero G, Giles F et al. Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during Imatinib Mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase. Cancer 2003; 98: 1905–1911.

    Article  CAS  Google Scholar 

  23. Sehested J . A simple method for R-banding of human chromosomes, showing a pH-dependent connection between R and G bands. Humangentik 1975; 21: 55–58.

    Google Scholar 

  24. Wiktor A, Rybicki B, Prao Z, Shurafa M, Barthel B, Maeda K et al. Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 2000; 27: 11–16.

    Article  CAS  Google Scholar 

  25. Maserati E, Aprili F, Vinante F, Locatelli F, Amendola G, Zatterale A et al. Trisomy 8 in myelodysplasia and acute leukaemia is constitutional in 15–20% of cases. Genes Chromosomes Cancer 2002; 33: 93–97.

    Article  CAS  Google Scholar 

  26. Chandley AC, Hargreave TB, Fletcher JM, Soos M, Axworthy D, Price WH . Trisomy 8. Report of a mosaic human male with near-normal phenotype and normal IQ, ascertained through infertility. Hum Genet 1980; 55: 31–38.

    Article  CAS  Google Scholar 

  27. Baskaran R, Wood LD, Whitaker LL, Canman CE, Morgan SE, Xu Y et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 1997; 387: 516–519.

    Article  CAS  Google Scholar 

  28. Kharbanda S, Pandey P, Jin S, Inoue S, Bharti A, Yuan ZM et al. Functional interaction between DNA-PK and c-Abl in response to DNA damage. Nature 1997; 386: 732–735.

    Article  CAS  Google Scholar 

  29. Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 1997; 387: 520–523.

    Article  CAS  Google Scholar 

  30. Yuan ZM, Huang Y, Ishiko T, Nakada S, Utsugisawa T, Kharbanda S et al. Regulation of Rad51 function by c-Abl in response to DNA damage. J Biol Chem 1998; 273: 3799–3802.

    Article  CAS  Google Scholar 

  31. Chen G, Yuan SS, Liu W, Xu Y, Trujillo K, Song B et al. Radiation-induced assembly of Rad21 and rad52 combination complex requires ATM and c-Abl. J Biol Chem 1999; 274: 12748–12752.

    Article  CAS  Google Scholar 

  32. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG, Levrero M et al. The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 1999; 399: 806–809.

    Article  CAS  Google Scholar 

  33. Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY et al. p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 1999; 399: 814–817.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Jeanne Ong for FISH illustrations and the cytologist for the morphologic review: I Garcia, A Bourguignat, C Arnoulet, C Maurice, C Garabedian, D Sainty, C Fourcade, D Lusina, M Godard, E Duchayne, R Garand, F Accard, K Maloum and M Maynadier.

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Authors and Affiliations

  1. Cytogenetic and Clinical Departments, Hôpital André Mignot, Versailles, France

    C Terre, J N Bastie & S Castaigne

  2. Cytogenetic and Clinical Departments, Hôpital Avicenne, Bobigny, France

    V Eclache & G L Roux

  3. Cytogenetic and Clinical Departments, Hôpital St-Louis, Paris, France

    P Rousselot & O Maarek

  4. Cytogenetic and Clinical Departments, Hôpital Henri Mondor, Créteil, France

    M Imbert, Y Yacouben & S Giraudier

  5. Cytogenetic and Clinical Departments, Hôpital Edouard Herriot, Lyon, France

    C Charrin & F Nicolini

  6. Cytogenetic and Clinical Departments, Hôpital de Hautepierre, Strasbourg, France

    C Gervais, F Maloisel, V Leymarie & M Lessard

  7. Cytogenetic and Clinical Departments, Institut Paoli-Calmettes, Marseille, France

    M J Mozziconacci, M Lafage-Pochitaloff & N Vey

  8. Cytogenetic and Clinical Departments, Cerba, Cergy-Pontoise, France

    H Mossafa

  9. Cytogenetic and Clinical Departments, Hôpital Pontchaillou, Rennes, France

    N Auger

  10. Cytogenetic and Clinical Departments, Hôpital Purpan, Toulouse, France

    N Dastugue, G Laurent & C Recher

  11. Cytogenetic and Clinical Departments, Hôpital Hôtel-Dieu, Nantes, France

    P Talmant & M Vigier

  12. Cytogenetic and Clinical Departments, Hôpital St-Antoine, Paris, France

    J Van den Akker

  13. Cytogenetic and Clinical Departments, Hôpital Kremlin-Bicêtre, Kremlin-Bicêtre, France

    C Leonard

  14. Cytogenetic and Clinical Departments, Hôpital Pitié-Salpétrière, Paris, France

    F N'Guyen Khac & J P Vernant

  15. Cytogenetic and Clinical Departments, Hôpital du Bocage, Dijon, France

    F Mugneret & B Salles

  16. Cytogenetic and Clinical Departments, Hôpital Hôtel-Dieu, Paris, France

    F Viguié & J Roussi

  17. Cytogenetic and Clinical Departments, Hôpital Necker, Paris, France

    G Flandrin

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  1. C Terre
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On behalf of France Intergroupe pour la Leucemie Myeloide Chronique (FILMC)

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Correspondence to C Terre.

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Terre, C., Eclache, V., Rousselot, P. et al. Report of 34 patients with clonal chromosomal abnormalities in Philadelphia-negative cells during imatinib treatment of Philadelphia-positive chronic myeloid leukemia. Leukemia 18, 1340–1346 (2004). https://doi.org/10.1038/sj.leu.2403399

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  • DOI: https://doi.org/10.1038/sj.leu.2403399

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