Results from a phase 1/phase 2 study showed that the
dual Sarcoma/Abelson tyrosine kinase inhibitor bosutinib was associated with
high response rates and a tolerable safety profile in patients with
chronic-phase chronic myeloid leukemia.
Researchers enrolled 200 patients with
imatinib-resistant CML and 88 with imatinib-intolerant disease into the study.
Patients were assigned to 500 mg daily bosutinib. Eligible patients had
undergone previous therapy with imatinib, but no other exposure to a TKI.
At 24 weeks, 31% of patients had major cytogenetic
response, the primary endpoint of the study. One-third of imatinib-resistant
patients and 27% of imatinib-intolerant patients had major cytogenetic response
After a median follow-up of 24.2 months, 86% of patients
had complete hematologic response, 53% had a major cytogenetic response and 41%
had a complete cytogenetic response. Almost two-thirds of patients who had
complete cytogenetic response also had a major molecular response. Of 141
evaluable patients, 78% had complete hematologic response during the study.
One-fourth of patients who did not have complete
cytogenetic response on imatinib responded to bosutinib, as did 41% of patients
who did not have major cytogenetic response on imatinib. Researchers observed
responses across all BCR-ABL mutations, except T315I.
Median time to major cytogenetic response was 12.3 weeks
overall; 13.1 weeks in the imatinib-resistant group and 12.1 weeks in the
imatinib-intolerant group. Dose intensities of at least 350 mg daily bosutinib
were associated with higher rates of major cytogenetic response.
Two-year PFS was 79% and 2-year OS was 92%.
The most common treatment-related adverse event was mild
to moderate diarrhea (84%). Grade-3/grade-4 non-hematologic adverse events
observed in more than 2% of patients included diarrhea (9%), rash (9%) and