Long-term treatment with bosutinib in a phase 1/2 study in Japanese chronic myeloid leukemia patients resistant/intolerant to prior tyrosine kinase inhibitor treatment

Abstract

This long-term follow-up of a completed phase 1/2 study assessed the safety and efficacy of bosutinib in Japanese Philadelphia chromosome-positive, chronic phase (CP) or advanced phase (ADV) chronic myeloid leukemia patients who were resistant/refractory or intolerant to prior tyrosine kinase inhibitor treatment. This analysis included 63 patients with a median bosutinib follow-up of 132 weeks (range 3‒372). In the CP second-line (2L) cohort, the cumulative major cytogenetic response (MCyR) and major molecular response (MMR) rates throughout the study were 73 and 53%, respectively. In the CP third-line (3L) cohort, the cumulative MCyR and MMR rates throughout the study were 70 and 40%, respectively. Of the eight ADV patients, MCyR was attained or maintained by 50% of patients, and complete hematologic response was attained or maintained by 25% of patients. Progression-free survival rate and overall survival rate at 96 weeks were, respectively, 91 and 98% in CP2L, 88 and 100% in CP3L, and 33 and 50% in ADV patients. The most common adverse events (>50%) reported were diarrhea (95%), nasopharyngitis (57%), and rash (57%). Bosutinib demonstrated durable efficacy and a manageable tolerability profile over long-term use in Japanese patients.

ClinicalTrials.gov: NCT00811070.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    BOSULIF® bosutinib. New York: Pfizer Labs, Pfizer Inc; 2016.

  2. 2.

    Redaelli S, Boschelli F, Perini P, Pirola A, Viltadi M, Gambacorti-Passerini C. Synergistic activity of the Src/Abl inhibitor bosutinib in combination with imatinib. Leukemia. 2010;24:1223–7.

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Blay JY, von Mehren M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin Oncol. 2011;38(Suppl 1):S3–9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Gnoni A, Marech I, Silvestris N, Vacca A, Lorusso V. Dasatinib: an anti-tumour agent via Src inhibition. Curr Drug Targets. 2011;12:563–78.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Gambacorti-Passerini C, Tornaghi L, Cavagnini F, Rossi P, Pecori-Giraldi F, Mariani L, et al. Gynaecomastia in men with chronic myeloid leukaemia after imatinib. Lancet. 2003;361:1954–6.

    Article  PubMed  Google Scholar 

  6. 6.

    Bartolovic K, Balabanov S, Hartmann U, Komor M, Boehmler AM, Buhring HJ, et al. Inhibitory effect of imatinib on normal progenitor cells in vitro. Blood. 2004;103:523–9.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Brummendorf TH, Cortes JE, Khoury HJ, Kantarjian HM, Kim DW, Schafhausen P, et al. Factors influencing long-term efficacy and tolerability of bosutinib in chronic phase chronic myeloid leukaemia resistant or intolerant to imatinib. Br J Haematol. 2016;172:97–110.

    Article  PubMed  Google Scholar 

  8. 8.

    Cortes JE, Kantarjian HM, Brummendorf TH, Kim DW, Turkina AG, Shen ZX, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011;118:4567–76.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Cortes JE, Kim DW, Kantarjian HM, Brummendorf TH, Dyagil I, Griskevicius L, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: results from the BELA trial. J Clin Oncol. 2012;30:3486–92.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brummendorf TH, et al. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015;90:755–68.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012;119:3403–12.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, et al. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol. 2015;101:154–64.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Redaelli S, Mologni L, Rostagno R, Piazza R, Magistroni V, Ceccon M, et al. Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol. 2012;87:E125–8.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27:469–71.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Gambacorti-Passerini C, Brummendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: minimum 24-month follow-up. Am J Hematol. 2014;89:732–42.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Caldemeyer L, Dugan M, Edwards J, Akard L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr Hematol Malig Rep. 2016;11:71–9.

    Article  PubMed  Google Scholar 

  17. 17.

    Chai-Adisaksopha C, Lam W, Hillis C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk Lymphoma. 2016;57:1300–10.

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Douxfils J, Haguet H, Mullier F, Chatelain C, Graux C, Dogne JM. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. 2016;2:625–32.

    Article  Google Scholar 

  19. 19.

    Guignabert C, Phan C, Seferian A, Huertas A, Tu L, Thuillet R, et al. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J Clin Invest. 2016;126:3207–18.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Sprycel® dasatinib. Princeton: Bristol-Myers Squibb; 2015.

  21. 21.

    Tasigna® nilotinib East. Hanover: Novartis Pharmaceuticals Corporation; 2015.

  22. 22.

    Sakamaki H, Ishizawa K, Taniwaki M, Fujisawa S, Morishima Y, Tobinai K, et al. Phase 1/2 clinical study of dasatinib in Japanese patients with chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Int J Hematol. 2009;89:332–41.

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Usuki K, Tojo A, Maeda Y, Kobayashi Y, Matsuda A, Ohyashiki K, et al. Efficacy and safety of nilotinib in Japanese patients with imatinib-resistant or -intolerant Ph+ CML or relapsed/refractory Ph+ ALL: a 36-month analysis of a phase I and II study. Int J Hematol. 2012;95:409–19.

    CAS  Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was sponsored by Pfizer Inc. The authors thank Emiko Ohki and Hiroko Godai, of Pfizer Inc, for their contributions. Editorial support was provided by Anny Wu, PharmD, of Complete Healthcare Communications, LLC, and was funded by Pfizer Inc.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Naoto Takahashi.

Ethics declarations

Conflict of interest

Dr. Takahashi reports grants and personal fees from Pfizer and Novartis and grants from Otsuka Pharmaceutical during the conduct of the study. Dr. Nakaseko reports grants and personal fees from Pfizer and Bristol-Myers Squibb during the conduct of the study. Dr. Kobayashi reports grants from Pfizer, Astellas Pharma, Amgen Astellas BioPharma, Otsuka Pharmaceuticals, and Ariad Pharmaceuticals during the conduct of the study. Drs. Ono, Koide, and Fujii are employees of Pfizer Japan. Drs. Miyamura and Ohnishi have nothing to disclose.

Electronic supplementary material

About this article

Verify currency and authenticity via CrossMark

Cite this article

Takahashi, N., Nakaseko, C., Kobayashi, Y. et al. Long-term treatment with bosutinib in a phase 1/2 study in Japanese chronic myeloid leukemia patients resistant/intolerant to prior tyrosine kinase inhibitor treatment. Int J Hematol 106, 398–410 (2017). https://doi.org/10.1007/s12185-017-2239-8

Download citation

Keywords

  • Bosutinib
  • Long term
  • Chronic myeloid leukemia
  • Japan
  • Tyrosine kinase inhibitor