Bosutinib in imatinib-resistant/intolerant chronic CML

CML cells

Chicago—The investigational tyrosine kinase inhibitor bosutinib was effective in patients with chronic-phase chronic myelogenous leukemia (CML) who failed on previous therapy with imatinib—current first-line therapy for this hematologic cancer. Half of the patients who were either imatinib-resistant or imatinib-intolerant achieved a complete cytogenetic response (CCyR) with bosutinib, according to a study presented at the 2010 annual meeting of ASCO. A second study showed that bosutinib was also effective as third-line therapy in chronic phase CML, after failure on imatinib and second-line dasatinib.

Bosutinib’s achievements in these trials is impressive. Accrual is now under way for a phase 3 study of bosutinib versus imatinib in newly diagnosed chronic phase CML patients.

“We see very good activity for bosutinib in both second- and third-line therapy, with high levels of response,” said Jorge E. Cortes, MD, from MD Anderson Cancer Center in Houston, Texas. These studies also show acceptable toxicities, making this drug a contender for a major role in the treatment of CML, he said. Dr Cortes was lead author of the study in the second-line setting and coauthor of the study in the third-line setting.

Bosutinib is 30 times more potent than imatinib. This drug inhibits BCR-ABL signaling in CML cells and is active against all imatinib-resistant mutations, with the exception of the T315-I clone.

At ASCO, Dr Cortes presented results of a multicenter phase 1/2 study in patients who failed prior imatinib therapy. Phase 1 was a dose-finding study that included 18 patients treated with bosutinib at 400, 500, or 600 mg/day. The phase 2 trial included 276 patients treated with bosutinib 500 mg/day. Median age was 52 years, median time since diagnosis was 4 years, and patients had been on prior imatinib therapy for a median of 2.3 years. Seventy percent of the patients were imatinib-resistant, and 30% were imatinib-intolerant.

Median duration of bosutinib therapy was 13.7 months, with a median follow-up of almost 3 years. Of these, 75% had some dose interruptions and 45% required dose reductions. The dose of bosutinib was escalated to 600 mg in 33 patients (22%).

Of the 109 patients evaluable for best response, overall response was seen in 102 (94%) and complete hematologic response was observed in 99 (91%). Of the 214 patients analyzed for cytogenetic response (CyR), major CyR was observed in 136 (64%), and complete CyR was seen in 106 (50%). Of the 151 patients evaluated for molecular response, a major molecular response was seen in 79 patients (51%) and a complete molecular response was seen in 49 (32%).

Response rates were higher in patients who were intolerant to imatinib than in those who were resistant. Time to achieve a major CyR was about 6 months, but responses continued to improve over time, Dr Cortes said, and have continued well into the second and third years of therapy.

At 2 years, median progression-free survival was 77% in imatinib-resistant patients and 86% in imatinib-intolerant patients. “The majority of patients are still alive,” Dr Cortes said.

Treatment-emergent adverse events included diarrhea in 84% (grade 3 or 4, 9%); rash in 34% (grade 3 or 4, 9%), nausea in 44% (grade 3 or 4, 2%), and vomiting in 36% (grade 3 or 4, 3%). Fluid retention was uncommon and pleural effusion occurred in 3%. The rates of grade 3 or 4 myelosuppression were: thrombocytopenia, 24%; neutropenia, 16%; and anemia, 12%.

A related study presented at a poster session by second author Hanna J. Khoury, MD, of Winship Cancer Institute at Emory University in Atlanta, Georgia, showed that bosutinib was effective and well tolerated as third-line therapy in 90 chronic phase CML patients who failed both first-line imatinib and second-line dasatinib. In imatinib- and dasatinib- resistant patients, a complete CyR was reported in 6 (22%) of 27 evaluable patients; a complete hematologic response was reported in 18 (86%) of 21 evaluable patients; and a major molecular response was observed in 6 (27%) of 22 evaluable patients. Cytogenetic and molecular response rates were higher in the 23 patients who were intolerant to both drugs.

The starting dose of bosutinib was 500 mg/day, and the dose was escalated to 600 mg if required. Median duration of treatment was 6.1 months in this ongoing phase 2 trial. Thus far, 3 patients have died and 14 have progressed. Median overall survival in patients who failed on both imatinib and dasatinib was 36.3 months. Responses were seen in patients with common BCR-ABL mutations, but not in those with T315I.