Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up

Abstract

Bosutinib is an orally active, dual Src/Abl tyrosine kinase inhibitor for treatment of chronic myeloid leukemia (CML) following resistance/intolerance to prior therapy. Here, we report the data from the 2-year follow-up of a phase 1/2 open-label study evaluating the efficacy and safety of bosutinib as second-line therapy in 288 patients with chronic phase CML resistant (n = 200) or intolerant (n = 88) to imatinib. The cumulative response rates to bosutinib were as follows: 85% achieved/maintained complete hematologic response, 59% achieved/maintained major cytogenetic response (including 48% with complete cytogenetic response), and 35% achieved major molecular response. Responses were durable, with 2-year estimates of retaining response >70%. Two-year probabilities of progression-free survival and overall survival were 81% and 91%, respectively. The most common toxicities were primarily gastrointestinal adverse events (diarrhea [84%], nausea [45%], vomiting [37%]), which were primarily mild to moderate, typically transient, and first occurred early during treatment. Thrombocytopenia was the most common grade 3/4 hematologic laboratory abnormality (24%). Outcomes were generally similar among imatinib-resistant and imatinib-intolerant patients and did not differ with age. The longer-term results of the present analysis confirm that bosutinib is an effective and tolerable second-line therapy for patients with imatinib-resistant or imatinib-intolerant chronic phase CML. ClinicalTrials.gov Identifier: NCT00261846.

Figure 1

Cumulative incidence curve for time to response adjusting for the competing risk of treatment discontinuation without response. Time to CHR (A), MCyR (B), and MMR (D) was calculated among evaluable patients with a valid baseline assessment from the start date of therapy until the first date of attained/maintained response (confirmed for CHR and unconfirmed for MCyR and MMR) or last nonmissing assessment date for those without a response or discontinuation. All treated patients were evaluable for MMR except patients from sites in China, India, Russia, and South Africa, who were not assessed for molecular response. (C) Rates of MCyR, including PCyR and CCyR, were cumulative by the defined time points for evaluable patients (IM-R, n = 186; IM-I, n = 80) who had an adequate baseline cytogenetic assessment and maintained/achieved their response. Abbreviations: CCyR, complete cytogenetic response; CHR, complete hematologic response; IM-I, imatinib intolerant; IM-R, imatinib resistant; MCyR, major cytogenetic response; MMR, major molecular response; PCyR, partial cytogenetic response.

Figure 2

Duration of CHR (A), MCyR (B), and MMR (C). Duration of response was calculated among responders from the first date of response until confirmed loss of response, treatment discontinuation due to progressive disease or death, or death within 30 days of the last dose; patients without events were censored at their last assessment visit. The probability of retaining response at 2 years was based on Kaplan–Meier estimates. Abbreviations: CHR, complete hematologic response; IM-I, imatinib intolerant; IM-R, imatinib resistant; MCyR, major cytogenetic response; MMR, major molecular response.

Figure 3

PFS (A) and OS (B). PFS was calculated for the all-treated population from the start date of therapy until treatment discontinuation due to disease progression (as assessed by the investigator; including transformation to AP or BP CML) or death, or death within 30 days of the last dose; patients without events were censored at their last assessment visit. OS was calculated for the all-treated population from the start date of therapy to the date of death due to any cause; patients without events were censored at the last contact (patients were followed up for 2 years after treatment discontinuation). PFS and OS at 1 and 2 years were based on Kaplan–Meier estimates. Abbreviations: AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; IM-I, imatinib intolerant; IM-R, imatinib resistant; OS, overall survival; PFS, progression-free survival.