Bosutinib Offers Long-Term Efficacy in CML Patients Who Failed TKI Therapy

According to a long-term follow-up analysis of a phase I/II trial, bosutinib provides durable responses and a favorable toxicity profile in patients with chronic phase chronic myeloid leukemia (CML) who are resistant/intolerant to other tyrosine kinase inhibitors (TKIs). Several baseline factors including Philadelphia chromosome–positive (Ph+) cell count were found to be predictive of outcome.

“Although many patients are successfully treated with imatinib or the second-generation TKIs dasatinib or nilotinib, some patients develop resistance or intolerance and require alternate therapy,” wrote study authors led by Jorge E. Cortes, MD, of the University of Texas MD Anderson Cancer Center in Houston. Bosutinib has activity against most BCR-ABL1 mutations that confer TKI resistance, with some exceptions.

The new analysis is of an ongoing phase I/II trial, with long-term follow-up in 119 patients who were resistant or intolerant to multiple previous TKI therapies. The results are published in the December issue of American Journal of Hematology.

The median duration of treatment was 8.6 months, and the median follow-up period was 32.7 months. The 4-year cumulative rate of confirmed complete hematologic response (CHR) was 74% in 117 evaluable patients. Fifty-two patients had a CHR at baseline, and 87% of them maintained the confirmed CHR on bosutinib; 63% of the 65 patients without a baseline CHR attained CHR during the follow-up period.

The cumulative rate of major cytogenetic response was 40%, including 32% who attained or maintained a complete cytogenetic response. Cytogenetic response rates were lower in patients aged 65 and older vs younger patients. They also appeared lower in patients who were resistant/intolerant to imatinib and resistant to dasatinib, compared to other previous treatment patterns. Median durations of CHR and cytogenetic responses were not yet reached.

The incidence of on-treatment disease progression or death at 4 years was 24%, and the 4-year overall survival rate was 78%.

Several baseline factors were associated with long-term outcomes. Ph+ ratio ≤ 35% vs ≥ 95% was prognostic of achieving major and complete cytogenetic responses by 3 and 6 months (P ≤ .0002). Patients who had no prior response to dasatinib or nilotinib had a decreased overall survival compared to others, and increased baseline basophils was a significant predictor of decreased progression-free survival (P = .0012).

The toxicity profile of bosutinib was similar to previous studies of the drug, the authors wrote. The most common non-hematologic adverse events included diarrhea (83% all grades, 9% grade 3/4), nausea (48% and 1%), and vomiting (38% and 1%). Thirty-tree patients discontinued bosutinib therapy due to adverse events, with thrombocytopenia as the most common reason.

“These findings suggest that a substantial number of patients receiving third-/fourth-line bosutinib may attain clinical benefit and that response is most likely to occur within the first year of treatment,” the authors wrote. The durable efficacy suggests that this drug “represent[s] an important treatment option for patients in this setting.”