International Journal of Hematology

, Volume 93, Issue 2, pp 243–246

Successful treatment with nilotinib after imatinib failure in a CML patient with a four-way Ph chromosome translocation and point mutations in BCR/ABL gene

  • Masaya Okada
  • Atsushi Satake
  • Katsuji Kaida
  • Kyoko Taniguchi
  • Satoshi Yoshihara
  • Kazuhiro Ikegame
  • Hiroya Tamaki
  • Toshihiro Soma
  • Yoshihiro Fujimori
  • Hiroyasu Ogawa
Case Report

Abstract

Chronic myelogenous leukemia (CML) is characterized by Philadelphia (Ph) chromosome with a chimeric gene BCR–ABL created by reciprocal t(9:22) (q34;q11) translocation. Variant Ph chromosome translocations involving chromosomes other than 9 and 22 are found in 5–10% of CML cases. We here report a CML patient who carries a four-way Ph chromosome translocation, t(9;22;15;19) (q34;q11;q15;q13). The patient was diagnosed in 1997 and initially treated with hydroxyurea. In 2002, treatment with imatinib, a selective BCR–ABL tyrosine kinase inhibitor (TKI), was started but Ph-positive chromosomes remained at the levels of 42–65%, indicating imatinib failure. In 2006, the point mutations of F359I and L387M were detected in BCR/ABL gene, which may be related to imatinib failure. Treatment with nilotinib, a TKI with high target specificity, was then started which resulted in durable major molecular response. Administration of nilotinib offered an effective treatment in a CML patient with variant Ph chromosome translocations and BCR–ABL point mutations after imatinib failure.

Keywords

Chronic myelogenous leukemia Variant Philadelphia chromosome Point mutation Nilotinib 

References

  1. 1.
    Sawyers CL. Chronic myeloid leukemia. N Engl J Med. 1999;340:1330–40.CrossRefPubMedGoogle Scholar
  2. 2.
    De Braekeleer M. Variant Philadelphia translocations in chronic myeloid leukemia. Cytogenet Cell Genet. 1987;44:215–22.CrossRefPubMedGoogle Scholar
  3. 3.
    Ishihara T, Minamihisamatsu M. The Philadelphia chromosome. Considerations based on studies of variant Ph translocations. Cancer Genet Cytogenet. 1988;32:75–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Johansson B, Fioretos T, Mitelman F. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia. Acta Haematol. 2002;107:76–94.CrossRefPubMedGoogle Scholar
  5. 5.
    O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervanteset 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.CrossRefPubMedGoogle Scholar
  6. 6.
    Druker B, Guilhot F, O’Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17.CrossRefPubMedGoogle Scholar
  7. 7.
    Silver RT, Talpaz M, Sawyers CL, Druker BJ, Hochhaus A, Schiffer CA, et al. Four years of follow-up of 1027 patients with late chronic phase (L-CP), accelerated phase (AP), or blast crisis (BC) chronic myeloid leukemia (CML) treated with imatinib in three large phase II trials. Blood. 2004;104:11a (abstract).Google Scholar
  8. 8.
    Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR–ABL. Br J Cancer. 2006;94:1765–9.CrossRefPubMedGoogle Scholar
  9. 9.
    Kantarjian H, Giles F, Wunderle L, Cowan-Jacob S, Ray A, Griffin JD. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354:2542–51.CrossRefPubMedGoogle Scholar
  10. 10.
    Kantarjian HM, Giles F, Gattermann N, Bhalla K, Alimena G, Palandri F, et al. Nilotinib (formerly AMN107), a highly selective BCR–ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110:3540–6.CrossRefPubMedGoogle Scholar
  11. 11.
    le Coutre P, Ottmann OG, Giles F, Kim DW, Cortes J, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR–ABL tyrosine kinase inhibitor, is active in patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia. Blood. 2008;111:1834–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Tojo A, Usuki K, Urabe A, Maeda Y, Kobayashi Y, Jinnai I, et al. A phase I/II study of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL. Int J Hematol. 2009;89:679–88.CrossRefPubMedGoogle Scholar
  13. 13.
    Cang S, Liu D. P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. J Hematol Oncol. 2008;1:15.CrossRefPubMedGoogle Scholar
  14. 14.
    Jabbour E, Kantarjian HM, Jones D, Shan J, O’Brien S, Reddy N, et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood. 2009;113:2154–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good risk” chronic granulocytic leukemia. Blood. 1984;63:789–99.PubMedGoogle Scholar
  16. 16.
    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;108:1809–20.CrossRefPubMedGoogle Scholar
  17. 17.
    Mitelman F, Johansson B, Mertens F. Mitelman database of chromosome aberrations in cancer. 2010. http://cgap.nci.nih.gov/Chromosomes/Mitelman.
  18. 18.
    Mkrtchyan H, Ghazaryan S, Avetisyan G, Hovhannisyan A, Muradyan L, Daghbashyan S, et al. Novel complex t(V;9;22) rearrangements in three cases with chronic myeloid leukemia and a rare translocation in a case with classical Philadelphia chromosome. Oncol Rep. 2008;20:99–104.PubMedGoogle Scholar
  19. 19.
    El-Zimaity MM, Kantarjian H, Talpaz M, O’Brien S, Giles F, Garcia-Manero G, et al. Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome. Br J Haematol. 2004;125:187–95.CrossRefPubMedGoogle Scholar
  20. 20.
    Zhao Y, Wu G, Wu K, Liu L, Cao W, Yu X, et al. Simultaneous occurrence of variant Philadelphia translocations and ABL mutations in two patients with chronic myeloid leukemia. Leuk Res. 2009;33:e85–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Buda G, Orciuolo E, Cecconi N, Galimberti S, Cervetti G, Petrini M. Poor prognosis chronic myeloid leukemia with a complex variant Philadelphia translocation, t(9;10;22)(q34;q24;q11). Leuk Res. 2007;31:1765–6.CrossRefPubMedGoogle Scholar
  22. 22.
    Tan J, Cang S, Seiter K, Primanneni S, Ahmed N, Mathews T, et al. t(3;9;22) 3-way chromosome translocation in chronic myeloid leukemia is associated with poor prognosis. Cancer Invest. 2009;27:718–22.CrossRefPubMedGoogle Scholar
  23. 23.
    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;101:3794–800.CrossRefPubMedGoogle Scholar
  24. 24.
    O’Dwyer ME, Mauro MJ, Kurilik G, Mori M, Balleisen S, Olson S, et al. The impact of clonal evolution on response to imatinib mesylate (STI571) in accelerated phase CML. Blood. 2002;100:1628–33.CrossRefPubMedGoogle Scholar
  25. 25.
    Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41.CrossRefPubMedGoogle Scholar
  26. 26.
    Barańska M, Lewandowski K, Gniot M, Iwoła M, Lewandowska M, Komarnicki M. Dasatinib treatment can overcome imatinib and nilotinib resistance in CML patient carrying F359I mutation of BCR–ABL oncogene. J Appl Genet. 2008;49:201–3.CrossRefPubMedGoogle Scholar
  27. 27.
    Jakubowska J, Czyz M. Novel inhibitors of BCR–Abl. Postepy Hig Med Dosw. 2006;60:697–706 (Polish, online).Google Scholar
  28. 28.
    von Bubnoff N, Manley PW, Mestan J, Sanger J, Peschel C, Duyster J. BCR–Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. 2006;108:1328–33.CrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2011

Authors and Affiliations

  • Masaya Okada
    • 1
  • Atsushi Satake
    • 1
  • Katsuji Kaida
    • 1
  • Kyoko Taniguchi
    • 1
  • Satoshi Yoshihara
    • 1
  • Kazuhiro Ikegame
    • 1
  • Hiroya Tamaki
    • 1
    • 2
  • Toshihiro Soma
    • 1
  • Yoshihiro Fujimori
    • 2
  • Hiroyasu Ogawa
    • 1
    • 2
  1. 1.Division of Hematology, Department of Internal MedicineHyogo College of MedicineNishinomiyaJapan
  2. 2.Laboratory of Cell Transplantation, Institute for Advanced Medical SciencesHyogo College of MedicineNishinomiyaJapan

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