Bosutinib (Bosulif) demonstrated “acceptable safety with manageable toxicities” in a phase I/II study among patients with chronic-phase chronic myeloid leukemia (CML) or advanced Philadelphia chromosome–positive leukemia (accelerated-phase/blast-phase CML or acute lymphoblastic leukemia). Patients had resistance/intolerance to imatinib (Gleevec) and possibly other tyrosine kinase inhibitors such as dasatinib (Sprycel) and nilotinib (Tasigna). “Our findings support the continued clinical development of bosutinib as monotherapy for the treatment of [Philadelphia chromosome–positive] CML patients,” concluded the researchers, led by Hagop M. Kantarjian, MD, of The University of Texas MD Anderson Cancer Center, Houston, in Blood.
The first phase of the trial was a dose-escalation study that established a recommended dose of bosutinib at 500 mg/d in primarily imatinib-resistant chronic-phase CML patients, the researchers explained. The phase II safety and efficacy evaluation permitted dose escalation to 600 mg/d “for lack of efficacy,” defined as complete hematologic response not reached by week 8 or complete cytogenetic response not reached by week 12, if no drug-related grade 3/4 adverse event occurred.
The three patient cohorts included second-line chronic-phase CML (n = 286), third/fourth–line chronic-phase CML (n = 118), and advanced leukemia (n = 166). All patients were at least 18 years old and resistant to full-dose imatinib or intolerant to any dose of imatinib. Patients in the third/fourth–line cohort were resistant to dasatinib at 100 mg/d or nilotinib at 800 mg/d and/or intolerant to any dose of dasatinib; patients in the advanced leukemia cohort may also have been resistant or intolerant to dasatinib and/or nilotinib, the researchers reported. The median duration of bosutinib treatment was 11.1 months (range, 0.03–83.4 months).
“Treatment-emergent adverse events in each cohort were primarily gastrointestinal,” the investigators stated. Diarrhea occurred in 86% of the second-line cohort, 83% of the third/fourth–line cohort, and 74% of the advanced leukemia cohort; nausea occurred in 46%, 48%, and 48% of the respective cohorts; and vomiting in 37%, 38%, and 43%.
“Diarrhea presented early, with few (8%) patients experiencing grade 3/4 events; dose reduction due to diarrhea occurred in 6% of affected patients. Grade 3/4 myelosuppression … [was] reported in 41% of patients; among affected patients, 46% and 32% were managed with bosutinib interruption and dose reduction, respectively. Alanine aminotransferase elevation … occurred in 17% of patients, including 7% with grade 3/4 events; among patients managed with dose interruption, bosutinib rechallenge was successful in 74%,” the researchers reported. “Additional experience with bosutinib treatment may further improve the management of observed toxicities,” the authors added.
A total of 44 deaths occurred within 30 days of the last bosutinib dose. Most (32) deaths occurred among patients in the advanced disease cohort. Common reasons for death included CML disease progression and adverse events considered by the investigators to be unrelated to bosutinib, such as pneumonia/pneumonitis and cardiac events. The three deaths that were attributed to adverse events considered related to bosutinib were from lower gastrointestinal hemorrhage with thrombocytopenia, myocardial infarction, and acidosis with respiratory failure complicated by sepsis. ■
Kantarjian HM, et al: Blood. December 17, 2013 (early release online).