Bosutinib for Previously Treated Patients with Philadelphia Chromosome-Positive Leukemia: ≥8-Year Update of a Phase 1/2 Study

Introduction: Bosutinib is approved for use in patients with Philadelphia chromosome–positive (Ph+) chronic, accelerated or blast phase (CP, AP or BP) chronic myeloid leukemia (CML) that is resistant or intolerant to prior therapy, and in patients with newly diagnosed Ph+ CP CML.

Methods: A phase 1/2 study (NCT00261846) evaluated bosutinib at a starting dose of 500 mg/day in patients with CP CML resistant or intolerant to imatinib (CP2L), resistant or intolerant to imatinib + dasatinib and/or nilotinib (CP3L), or with AP/BP CML or Ph+ acute lymphoblastic leukemia with prior tyrosine kinase inhibitor (TKI) therapy (ADV). Here we report an ≥8-year update of this phase 1/2 study and its ongoing extension study (NCT01903733).

Results: Forty-one of 284 (14%) CP2L patients were still on bosutinib after ≥9 years and 8/119 (7%) CP3L and 4/167 (2%) ADV patients after ≥8 years. The most common reason for treatment discontinuation was disease progression/lack of efficacy in CP2L (27%), CP3L (42%) and ADV (50%) patients; the last dose before discontinuation was ≥500 mg/day in 70 (25%), 28 (24%) and 46 (28%) patients, respectively. Seventy-four CP2L patients discontinued bosutinib since Year 5 and 21 CP3L and 13 ADV patients since Year 4. In CP2L patients, median (range) follow-up was 54 (1–155) months, treatment duration 26 (<1–155) months and dose intensity 437 (87–599) mg/day; responses were durable (Table) and overall survival (OS; 95% CI) was 74% (67–80) at 9 years vs 84% (79–88) at 5 years. In CP3L and ADV patients, respectively, median (range) treatment duration was 9 (<1–148) and 4 (<1–147) months and dose intensity 427 (65–577) and 453 (26–594) mg/day. In CP3L, AP CML and BP CML patients, respectively, median (range) follow-up was 34 (<1–148), 29 (<1–147) and 10 (<1–131) months; OS (95% CI) was 69% (58–80), 55% (42–68) and 23% (7–38) at 8 years vs 78% (70–86), 59% (47–71) and 23% (7–38) at 4 years. Fifty-five CP2L, 29 CP3L and 98 ADV patients died on study (10, 3 and 2 since the 4/5-year reports); 15, 5 and 3 had on-treatment transformations to AP/BP (none since the 4/5-year reports). Across cohorts, the most common new treatment-emergent adverse events since Year 5 were pleural effusion (n=18), arthralgia (n=14), anemia (n=13), increased blood creatinine (n=13) and pneumonia (n=13).

Conclusions: Bosutinib demonstrated long-term efficacy and no new safety signals in patients with CML after ≥8 years, further supporting bosutinib use after prior TKIs.