The FDA approved the second-generation TKI bosutinib as a treatment for patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) following resistance of intolerance to prior therapy in September 2012. Bosutinib was explored in patients who had received prior treatment with imatinib or imatinib followed by dasatinib and/or nilotinib, notes Elias Jabbour, MD.

The approval for bosutinib was based on a single-arm, open-label study of 546 patients with CML, with 503 evaluable in the efficacy analysis. In patients with chronic phase (CP) CML, 233 had received prior imatinib and 108 had received prior imatinib followed by dasatinib and/or nilotinib.

In patients who received prior imatinib alone, the major cytogenetic response (MCyR) at 24 weeks was 33.8%. In patients treated with multiple prior TKIs, the MCyR was 26.9% at 24 weeks. In total, at any time during trial, 52.8% of patients with CP CML treated with imatinib alone experienced a MCyR and 51.4% treated with multiple TKIs experienced a MCyR.

Bosutinib's safety profile differentiates it from other TKIs used to treat CML, notes Jabbour. In general, bosutinib is associated with less myelosuppression. The most common all-grade adverse events (>20% of patients) in the clinical trial were diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, and fatigue. Serious adverse events included anaphylactic shock, myelosuppression, diarrhea, fluid retention, hepatoxicity, and rash.

Severe diarrhea generally occurs early following treatment with bosutinib and can be managed by adding an antidiarrheal therapy or by pausing treating for a few days and then resuming with the same dose, Jabbour notes. For recurring or persistent diarrhea, the dose can be reduced to 400 mg per day (the recommended dose is 500 mg daily with food). A similar treatment pause or dose reduction can be utilized for addressing potential liver dysfunction associated with bosutinib, Jabbour notes.