International Journal of Hematology

, Volume 89, Issue 3, pp 332–341 | Cite as

Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia

  • Hisashi Sakamaki
  • Ken-ichi Ishizawa
  • Masafumi Taniwaki
  • Shin Fujisawa
  • Yasuo Morishima
  • Kensei Tobinai
  • Masaya Okada
  • Kiyoshi Ando
  • Noriko Usui
  • Shuichi Miyawaki
  • Atae Utsunomiya
  • Nobuhiko Uoshima
  • Tadashi Nagai
  • Tomoki Naoe
  • Toshiko Motoji
  • Itsuro Jinnai
  • Mitsune Tanimoto
  • Yasushi Miyazaki
  • Kazunori Ohnishi
  • Shinsuke Iida
  • Shinichiro Okamoto
  • Taku Seriu
  • Ryuzo Ohno
Original Article


A phase 1/2 study was conducted to assess the safety and efficacy of dasatinib in Japanese patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) resistant or intolerant to imatinib. In phase 1, 18 patients with chronic phase (CP) CML were treated with dasatinib 50, 70, or 90 mg twice daily to evaluate safety. Dasatinib ≤ 90 mg twice daily was well tolerated. In phase 2, dasatinib 70 mg was given twice daily to CP-CML patients for 24 weeks and to CML patients in accelerated phase (AP)/blast crisis (BC) or Ph+ ALL for 12 weeks. In the CP-CML group (n = 30) complete hematologic response was 90% and major cytogenetic response (MCyR) 53%. In the AP/BC-CML group (n = 11) major hematologic response (MaHR) was 64% and MCyR 27%, whereas in the Ph+ ALL group (n = 13) MaHR was 38% and MCyR 54%. Dasatinib was well tolerated and most of the nonhematologic toxicities were mild or moderate. Dasatinib therapy resulted in high rates of hematologic and cytogenetic response, suggesting that dasatinib is promising as a new treatment for Japanese CML and Ph+ ALL patients resistant or intolerant to imatinib.


CML Ph+ ALL Dasatinib Imatinib resistant Imatinib intolerant 


  1. 1.
    Wong S, Witte ON. The BCR-ABL story: bench to bedside and back. Annu Rev Immunol. 2004;22:247–306. doi:10.1146/annurev.immunol.22.012703.104753.PubMedCrossRefGoogle Scholar
  2. 2.
    Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038–42. doi:10.1056/NEJM200104053441402.PubMedCrossRefGoogle Scholar
  3. 3.
    Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;344:1031–7. doi:10.1056/NEJM200104053441401.PubMedCrossRefGoogle Scholar
  4. 4.
    Kantarjian HM, O’Brien S, Cortes JE, et al. Treatment of Philadelphia chromosome-positive, accelerated-phase chronic myelogenous leukemia with imatinib mesylate. Clin Cancer Res. 2002;8:2167–76.PubMedGoogle Scholar
  5. 5.
    Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408–17. doi:10.1056/NEJMoa062867.PubMedCrossRefGoogle Scholar
  6. 6.
    Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80. doi:10.1126/science.1062538.PubMedCrossRefGoogle Scholar
  7. 7.
    Shah NP, Nicoll JM, Nagar B, et al. Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia. Cancer Cell. 2002;2:117–25. doi:10.1016/S1535-6108(02)00096-X.PubMedCrossRefGoogle Scholar
  8. 8.
    Hochhaus A, Hughes T. Clinical resistance to imatinib: mechanisms and implications. Hematol Oncol Clin North Am. 2004;18:641–56. doi:10.1016/j.hoc.2004.03.001.PubMedCrossRefGoogle Scholar
  9. 9.
    Hochhaus A, Kreil S, Corbin AS, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190–6. doi:10.1038/sj.leu.2402741.PubMedCrossRefGoogle Scholar
  10. 10.
    Illmer T, Schaich M, Platzbecker U, et al. P-glycoprotein-mediated drug efflux is a resistance mechanism of chronic myelogenous leukemia cells to treatment with imatinib mesylate. Leukemia. 2004;18:401–8. doi:10.1038/sj.leu.2403257.PubMedCrossRefGoogle Scholar
  11. 11.
    Thomas J, Wang L, Clark RE, Pirmohamed M. Active transport of imatinib into and out of cells: implications for drug resistance. Blood. 2004;104:3739–45. doi:10.1182/blood-2003-12-4276.PubMedCrossRefGoogle Scholar
  12. 12.
    Dai Y, Rahmani M, Corey SJ, Dent P, Grant SA. Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2. J Biol Chem. 2004;279:34227–39. doi:10.1074/jbc.M402290200.PubMedCrossRefGoogle Scholar
  13. 13.
    Donato NJ, Wu JY, Stapley J, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101:690–8. doi:10.1182/blood.V101.2.690.PubMedCrossRefGoogle Scholar
  14. 14.
    O’Hare T, Walters DK, Stoffregen EP, et al. In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants. Cancer Res. 2005;65:4500–5. doi:10.1158/0008-5472.CAN-05-0259.PubMedCrossRefGoogle Scholar
  15. 15.
    Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401. doi:10.1126/science.1099480.PubMedCrossRefGoogle Scholar
  16. 16.
    Burgess MR, Skaggs BJ, Shah NP, Lee FY, Sawyers CL. Comparative analysis of two clinically active BCR-ABL kinase inhibitors reveals the role of conformation-specific binding in resistance. Proc Natl Acad Sci USA. 2005;102:3395–400. doi:10.1073/pnas.0409770102.PubMedCrossRefGoogle Scholar
  17. 17.
    Talpaz M, Shah NP, Kantarjian H, et al. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 2006;354:2531–41. doi:10.1056/NEJMoa055229.PubMedCrossRefGoogle Scholar
  18. 18.
    Kantarjian H, Pasquini R, Hamerschlak N, et al. Dasatinib or high-dose imatinib for chronic-phase chronic myeloid leukemia after failure of first-line imatinib: a randomized phase 2 trial. Blood. 2007;109:5143–50. doi:10.1182/blood-2006-11-056028.PubMedCrossRefGoogle Scholar
  19. 19.
    Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109:2303–9. doi:10.1182/blood-2006-09-047266.PubMedCrossRefGoogle Scholar
  20. 20.
    Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. 2007;109:4143–50. doi:10.1182/blood-2006-09-046839.PubMedCrossRefGoogle Scholar
  21. 21.
    Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. 2007;109:3207–13. doi:10.1182/blood-2006-09-046888.PubMedCrossRefGoogle Scholar
  22. 22.
    Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110:2309–15. doi:10.1182/blood-2007-02-073528.PubMedCrossRefGoogle Scholar
  23. 23.
    Mauro MJ, Baccarani M, Cervantes F, et al. Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C). J Clin Oncol. 2008;26(Suppl 18):7009a.Google Scholar
  24. 24.
    Guilhot F, Chastang C, Michallet M, et al. Interferon alfa-2b combined with cytarabine versus interferon alone in chronic myelogenous leukemia. French Chronic Myeloid Leukemia Study Group. N Engl J Med. 1997;337:223–9. doi:10.1056/NEJM199707243370402.PubMedCrossRefGoogle Scholar
  25. 25.
    The Italian Cooperative Study Group on Chronic Myeloid Leukemia. Interferon alfa-2a as compared with conventional chemotherapy for the treatment of chronic myeloid leukemia. N Engl J Med. 1994;330:820–5. doi:10.1056/NEJM199403243301204.CrossRefGoogle Scholar
  26. 26.
    Baccarani M, Saglio G, Goldman J, 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. doi:10.1182/blood-2006-02-005686.PubMedCrossRefGoogle Scholar
  27. 27.
    Lombardo LJ, Lee FY, Chen P, et al. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61. doi:10.1021/jm049486a.PubMedCrossRefGoogle Scholar
  28. 28.
    Morishima Y, Ogura M, Nishimura M, et al. Efficacy and safety of imatinib mesylate for patients in the first chronic phase of chronic myeloid leukemia: results of a Japanese phase II clinical study. Int J Hematol. 2004;80:261–6. doi:10.1532/IJH97.04074.PubMedCrossRefGoogle Scholar
  29. 29.
    Matsuo E, Miyazaki Y, Tsutsumi C, et al. Imatinib provides durable molecular and cytogenetic responses in a practical setting for both newly diagnosed and previously treated chronic myelogenous leukemia: a study in Nagasaki prefecture, Japan. Int J Hematol. 2007;85:132–9. doi:10.1532/IJH97.06157.PubMedCrossRefGoogle Scholar
  30. 30.
    Sugita J, Tanaka J, Kurosawa M, et al. Effects of the mean daily doses of imatinib during the first year on survival of patients with chronic myeloid leukemia in Japan: a study of the Hokkaido Hematology Study Group. Eur J Haematol. 2008;80:160–3.PubMedGoogle Scholar
  31. 31.
    Miyazawa K, Nishimaki J, Katagiri T, et al. Thrombocytopenia induced by imatinib mesylate (Glivec) in patients with chronic myelogenous leukemia: is 400 mg daily of imatinib mesylate an optimal starting dose for Japanese patients? Int J Hematol. 2003;77:93–5. doi:10.1007/BF02982610.PubMedCrossRefGoogle Scholar
  32. 32.
    Shah NP, Kantarjian HM, Kim DW, et al. Intermittent target inhibition with dasatinib 100 mg once daily preserves efficacy and improves tolerability in imatinib-resistant and intolerant chronic-phase chronic myeloid leukemia. J Clin Oncol. 2008;26:3204–12. doi:10.1200/JCO.2007.14.9260.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2009

Authors and Affiliations

  • Hisashi Sakamaki
    • 1
  • Ken-ichi Ishizawa
    • 2
  • Masafumi Taniwaki
    • 3
  • Shin Fujisawa
    • 4
  • Yasuo Morishima
    • 5
  • Kensei Tobinai
    • 6
  • Masaya Okada
    • 7
  • Kiyoshi Ando
    • 8
  • Noriko Usui
    • 9
  • Shuichi Miyawaki
    • 10
  • Atae Utsunomiya
    • 11
  • Nobuhiko Uoshima
    • 12
  • Tadashi Nagai
    • 13
  • Tomoki Naoe
    • 14
  • Toshiko Motoji
    • 15
  • Itsuro Jinnai
    • 16
  • Mitsune Tanimoto
    • 17
  • Yasushi Miyazaki
    • 18
  • Kazunori Ohnishi
    • 19
  • Shinsuke Iida
    • 20
  • Shinichiro Okamoto
    • 21
  • Taku Seriu
    • 22
  • Ryuzo Ohno
    • 23
  1. 1.Department of HematologyMetropolitan Komagome HospitalTokyoJapan
  2. 2.Tohoku UniversitySendaiJapan
  3. 3.Kyoto Prefectural University of MedicineKyotoJapan
  4. 4.Yokohama City University Medical CenterYokohamaJapan
  5. 5.Aichi Cancer CenterNagoyaJapan
  6. 6.National Cancer CenterTokyoJapan
  7. 7.Hyogo Medical UniversityNishinomiyaJapan
  8. 8.Tokai UniversityIseharaJapan
  9. 9.Jikei University School of MedicineTokyoJapan
  10. 10.Saiseikai Maebashi HospitalMaebashiJapan
  11. 11.Jiaikai Imamura Hospital Branch HospitalKagoshimaJapan
  12. 12.Matsushita Memorial HospitalMoriguchiJapan
  13. 13.Jichi Medical SchoolShimotsukeJapan
  14. 14.Nagoya UniversityNagoyaJapan
  15. 15.Tokyo Women’s Medical UniversityTokyoJapan
  16. 16.Saitama Medical UniversityIrumaJapan
  17. 17.Okayama UniversityOkayamaJapan
  18. 18.Nagasaki UniversityNagasakiJapan
  19. 19.Hamamatsu University School of MedicineHamamatsuJapan
  20. 20.Nagoya City UniversityNagoyaJapan
  21. 21.Keio UniversityTokyoJapan
  22. 22.Bristol-Myers K.K.TokyoJapan
  23. 23.Aichi Shukutoku UniversityNagoyaJapan

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