Background
Phase 1/2, open-label, single-arm study (NCT00261846), CP-CML cohort after ≥2 prior TKIs. N=119 patients with CP-CML who had received imatinib followed by dasatinib or nilotinib, with documented resistance or intolerance to all prior lines. This cohort assessed bosutinib's activity after multiple TKI failures, addressing an unmet need for multiply pretreated CML patients prior to ponatinib or asciminib availability. Published Blood 2012.
Interventions and follow up
Regimen: Bosutinib 500 mg PO once daily in CP-CML after ≥2 prior TKIs (imatinib + dasatinib and/or nilotinib)
Primary endpoint: MCyR in CP-CML (≥2 prior TKIs)
Median follow-up: 28.5 months
Primary endpoint: MCyR in CP-CML (≥2 prior TKIs)
Median follow-up: 28.5 months
Results
MCyR: 32% (38/119)
CCyR: 24%
MMR: 14%
MCyR at 24 weeks: 27%
mPFS: 10.9 months
2-yr OS: 69%
By prior 2nd-gen TKI: prior-dasatinib MCyR 30%; prior-nilotinib MCyR 32%
CCyR: 24%
MMR: 14%
MCyR at 24 weeks: 27%
mPFS: 10.9 months
2-yr OS: 69%
By prior 2nd-gen TKI: prior-dasatinib MCyR 30%; prior-nilotinib MCyR 32%
Adverse events
Gastrointestinal/hepatic: Diarrhea any grade 81%, grade ≥3 13%; nausea 50%, vomiting 43%; ALT grade ≥3 9%; rash any grade 32%
Hematologic/other: Thrombocytopenia grade ≥3 27%, neutropenia grade ≥3 24%; pleural effusion 2%; grade ≥3 AEs 63%; dose reductions in ~50% of patients; discontinuation due to AEs 27%
Hematologic/other: Thrombocytopenia grade ≥3 27%, neutropenia grade ≥3 24%; pleural effusion 2%; grade ≥3 AEs 63%; dose reductions in ~50% of patients; discontinuation due to AEs 27%
Conclusions
Bosutinib achieved a 32% MCyR in CP-CML after failure of ≥2 prior TKIs, confirming activity in multiply pretreated patients without T315I mutation. Response rates are substantially lower than in the imatinib-only-pretreated setting (53% MCyR), with shorter PFS (mPFS 10.9 months), reflecting the more resistant biology after sequential TKI failure.
Key Limitations
Small single-arm cohort (N=119) without a randomized comparator; cross-trial comparison with ponatinib or asciminib in the ≥3rd-line setting is not valid. The cytogenetic primary endpoint (MCyR) is a surrogate, and durable molecular responses (MMR 14%) and OS were limited. T315I-mutant patients were excluded, narrowing applicability among multiply resistant patients. High GI toxicity and frequent dose reductions (~50%) affect deliverability. With subsequent approval of ponatinib and asciminib, bosutinib's role after ≥2 TKI failures has diminished.
Clinical Context
This cohort contributed to the bosutinib label across CML lines, but in the modern era asciminib (ASCEMBL) and ponatinib (OPTIC) are the preferred options after ≥2 TKI failures per ELN, given higher response rates and, for asciminib, better tolerability. Bosutinib remains useful where vascular comorbidity contraindicates ponatinib or where prior TKI intolerance rather than resistance predominates. Olverembatinib is emerging for patients failing ponatinib and asciminib. ESMO-MCBS: not assigned.