Background
Phase 1/2, open-label, single-arm study (NCT00261846). N=288 patients with CP-CML resistant or intolerant to imatinib (prior 1L imatinib only; no prior 2nd-generation TKI). Bosutinib is a dual Src/Abl TKI with reduced KIT and PDGFR off-target binding compared with imatinib, explaining its distinct toxicity profile. This study established bosutinib's efficacy in imatinib-resistant/intolerant CML and supported FDA approval. Primary results Blood 2011; extended 4-year follow-up Am J Hematol 2014.
Interventions and follow up
Regimen: Bosutinib 500 mg PO once daily, continuous, in CP-CML after imatinib failure/intolerance
Primary endpoint: MCyR (major cytogenetic response) in CP-CML
Median follow-up: 24.2 months (primary); 48 months (Am J Hematol 2014)
Primary endpoint: MCyR (major cytogenetic response) in CP-CML
Median follow-up: 24.2 months (primary); 48 months (Am J Hematol 2014)
Results
MCyR: 53% (Blood 2011); 59% by 48 months (Am J Hematol 2014)
CCyR: 41% (primary); 50% at 4 years
MMR: 26% (primary); 40% at 4 years
Median time to MCyR: 12.3 weeks
PFS: 2-yr 79%; 4-yr 57%
OS: 4-yr 84%
By prior status: imatinib-resistant MCyR 47%; imatinib-intolerant MCyR 73%
CCyR: 41% (primary); 50% at 4 years
MMR: 26% (primary); 40% at 4 years
Median time to MCyR: 12.3 weeks
PFS: 2-yr 79%; 4-yr 57%
OS: 4-yr 84%
By prior status: imatinib-resistant MCyR 47%; imatinib-intolerant MCyR 73%
Adverse events
Gastrointestinal/hepatic: Diarrhea any grade 84%, grade ≥3 9%, the dominant toxicity, mostly early and manageable; nausea 46%, vomiting 37%; ALT grade ≥3 9%, AST grade ≥3 5%, requiring hepatotoxicity monitoring
Hematologic/other: Thrombocytopenia grade ≥3 25%, neutropenia grade ≥3 17%; rash any grade 36%, grade ≥3 8%; pleural effusion <2% (contrast dasatinib ~30%); no significant QT prolongation; discontinuation due to AEs 24%
Hematologic/other: Thrombocytopenia grade ≥3 25%, neutropenia grade ≥3 17%; rash any grade 36%, grade ≥3 8%; pleural effusion <2% (contrast dasatinib ~30%); no significant QT prolongation; discontinuation due to AEs 24%
Conclusions
Bosutinib achieved a 53% MCyR and 41% CCyR in imatinib-resistant or intolerant CP-CML with a 4-year PFS of 57%, supporting its approval as a 2nd-line CML option. Gastrointestinal toxicity (diarrhea 84%) is the primary management challenge but is rarely treatment-limiting. Better cytogenetic responses were seen in imatinib-intolerant than imatinib-resistant patients.
Key Limitations
Single-arm phase 1/2 without a randomized comparator; response rates cannot be directly contrasted with dasatinib or nilotinib in the 2nd-line setting. The cytogenetic primary endpoint (MCyR) is a surrogate; molecular endpoints (MMR) and long-term OS matured in later follow-up. Heterogeneity between imatinib-resistant and imatinib-intolerant subgroups complicates interpretation of pooled response. High early diarrhea rates drive dose modifications and discontinuations (24%), and BCR-ABL mutation status at baseline influenced response but was incompletely characterized for all patients.
Clinical Context
This trial supported FDA approval of bosutinib (September 2012) for CP, accelerated, or blast-phase CML resistant or intolerant to prior therapy. Bosutinib is an established 2nd-line option alongside dasatinib and nilotinib, with a differentiated toxicity profile (more GI, less pleural effusion than dasatinib, fewer vascular events than nilotinib/ponatinib), useful in patients with pulmonary or cardiovascular comorbidity. After ≥2 TKI failures, asciminib (ASCEMBL) and ponatinib (OPTIC) are preferred per ELN. ESMO-MCBS: not assigned.