Bosutinib for the treatment of Philadelphia chromosome-positive leukemias

Abstract

Introduction: Bosutinib is a dual ABL1 and SRC third-generation tyrosine kinase inhibitor (TKI) indicated for the treatment of patients with chronic myelogenous leukemia (CML) resistant or intolerant to other BCR-ABL1 inhibitors. Bosutinib is active against leukemia cells expressing imatinib-resistant BCR-ABL1 mutations. Mechanistically, this agent may also be beneficial for Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) because in preclinical animal models, SRC accelerates ALL disease development.

Areas covered: Here, we review the current scientific and medical literature on the role of bosutinib for the treatment of CML. We address the unique therapeutic advantages of this agent, specifically its ability to inhibit mutant BCR-ABL1 kinases conferring resistance to other TKIs and its unique safety profile consisting of mainly manageable self-limited diarrhea, not cardiovascular, side effects. Long-term toxicities reported with dasatinib, nilotinib and ponatinib have not been described with bosutinib. Lastly, we present preclinical data demonstrating that bosutinib inhibits a broader range of tyrosine kinases than any other TKI, including those implicated in acute leukemia.

Expert opinion: We propose that future studies should explore the use of bosutinib in Ph+ ALL due to its multi-kinase inhibitory activity and its relatively long-term safety compared with other second- and third-generation TKIs.

Keywords:

• acute lymphoblastic leukemia
• bosutinib
• chronic myeloid leukemia
• Philadelphia chromosome

Acknowledgments

Unfortunately, M Wetzler passed away during the preparation of this manuscript. Because he had contributed significantly to its writing, he is still listed as an author.

Declaration of interest

This work was supported partially by grants from the National Cancer Institute Grant CA16056, the Szefel Foundation, Roswell Park Cancer Institute, the Leonard S LuVullo Endowment for Leukemia Research, the Nancy C Cully Endowment for Leukemia Research, the Babcock Family Endowment and the Heidi Leukemia Research Fund, Buffalo, NY. ES Wang is also supported by Cancer Clinical Investigator Team Leadership Award (CCITLA) awarded by National Cancer Institute through a supplement to P30CA016056. EA Griffiths and ES Wang have served as consultants for Ariad. M Wetzler served as consultant for Novartis, Ariad and Teva. He was the principal investigator of clinical trials with Bristol-Myers Squibb and Teva. C Varallo-Rodriguez, CW Freyer and EP Ontiveros have no financial relationships to report.