Bosutinib Approved for Previously Treated CML

Jorge E. Cortes, MD

The FDA has approved bosutinib (Bosulif) for the treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) who are intolerant or who have become resistant to prior therapy.

Bosutinib is a dual tyrosine kinase inhibitor (TKI) of the SRC and ABL signaling pathways believed to be responsible for the development of resistance to imatinib (Gleevec), another TKI that is considered a standard of care for many Ph+ CML patients, according to Pfizer Inc, which developed Bosulif.

“Bosulif is an important new addition to the CML treatment landscape,” said Jorge E. Cortes, MD, deputy chair and professor of medicine in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, and a lead investigator of the study, in a statement. “Despite recent advances, an unmet need remains for many CML patients who are refractory to one or more tyrosine kinase inhibitors.”

The approval of bosutinib was based on the results of the ongoing Study 200 trial, the FDA said. In that study, more than 500 patients with imatinib-resistant or —intolerant Ph+ CML were enrolled. Patients had either chronic, blast phase, or accelerated phase disease and had been previously treated with imatinib or imatinib followed by dasatinib and/or nilotinib, both forms of TKI therapy.

The FDA reported that the percentage of patients with chronic phase CML who had been previously treated with only imatinib (n = 266) and who achieved a major cytogenetic response (MCyR) increased as the study continued.

At 24 weeks’ follow-up, 33.8% (95% CI, 28.2-39.9) achieved MCyR, according to results that Pfizer released. After a minimum follow-up of 23 months, 53.4% of patients achieved an MCyR, and of those patients, 52.8% experienced an MCyR lasting at least 18 months.

For patients with chronic phase CML who had been previously treated with imatinib and at least one other TKI (n = 108), the MCyR by 24 weeks was 26.9% (95% CI, 18.8-36.2). The minimum follow-up in this group was 13 months, and after that time, 32.4% of these patients achieved a MCyR. Of those patients, 51.4% of them had an MCyR of at least 9 months.

The study also found that 33% of CML patients with accelerated phase CML had blood counts that returned to a normal range and 55% of patients achieved normal blood counts with no evidence of leukemia within the first 48 weeks of treatment. Among patients with blast phase CML, 15% of patients had blood counts return to normal, and 28% had normal blood counts with no evidence of leukemia during the first 48 weeks of treatment.

Richard Pazdur, MD

In the study, 16 patients (4%) experienced transformation from the chronic phase to the advanced or blast phase, Pfizer said.

The most common adverse reactions (ARs) of any grade in chronic phase patients included diarrhea (84%), nausea (46%), abdominal pain (40%), thrombocytopenia (40%) and vomiting (37 %), with ARs of grade 3 or higher including thrombocytopenia (26%), neutropenia (11%), diarrhea (9%), anemia (9%) and rash (8%).

The data provided by the FDA and Pfizer on Tuesday were updated results from a study that was published in the journal Blood in 2011, a Pfizer spokeswoman said.

“With the approval of tyrosine kinase inhibitors, we are seeing improvements in the treatment of CML based on a better understanding of the molecular basis of the disease,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, in a statement. “These improvements have been observed in chronic and accelerated phases of CML.”

Cortes JE, Kantarjian HM, Brümmendorf T, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive CML patients with resistance or intolerance to imatinib. Blood. 2011 Oct;118(17):4567-4576.