Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Abstract

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

Figure 1

Disposition of patients. Part 2 of the study enrolled a total of 115 patients who previously received imatinib and either dasatinib or nilotinib and 3 patients who previously received all 3 TKIs. *Because of logistical constraints, patients from sites in China, India, Russia, and South Africa were not assessed for molecular response.

Figure 2

Duration of MCyR while on bosutinib treatment. Duration of MCyR was based on the evaluable population; patients entering the study in cytogenetic remission (CCyR) were excluded. IM indicates imatinib; DAS, dasatinib; NI, nilotinib; and NA, not available. *Includes 2 patients: 1 patient who was nilotinib-intolerant and 1 who previously received all 3 inhibitors. †Probability of retaining response at 2 years was based on Kaplan-Meier estimates.

Figure 3

PFS while on bosutinib treatment. PFS is shown for all patients treated with bosutinib at a median follow-up of 28.5 months. Progression was determined by the investigator and defined as on-treatment transformation to accelerated or blast phase, loss of CHR, loss of MCyR with Philadelphia chromosome rate increased by 30%, doubling of white blood cell count to > 20 × 10⁹/L, or death because of any cause within 30 days of the last study dose. IM indicates imatinib; DAS, dasatinib; NI, nilotinib; and NA, not available. *Includes 3 patients who previously received all 3 inhibitors and one patient with NI intolerance. †PFS rates at 1 and 2 years were based on Kaplan-Meier estimates.

Figure 4

Overall survival is shown for all patients treated with bosutinib at a median follow-up of 28.5 months. IM indicates imatinib; DAS, dasatinib; and NI, nilotinib. *Includes 3 patients who previously received all 3 inhibitors and 1 patient with NI intolerance. †Overall survival rates at 1 and 2 years were based on Kaplan-Meier estimates.