Baseline Predictors of Response to Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib Plus Dasatinib and/or Nilotinib.

Abstract 2793

Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated the activity and tolerability of BOS 500 mg/d in Philadelphia chromosome–positive (Ph+) leukemia following prior TKI exposure. The current analysis investigated baseline characteristics as predictors of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), and 2-year Kaplan- Meier–estimated progression-free survival (PFS) and overall survival (OS).

All included patients had chronic phase (CP) chronic myeloid leukemia (CML), had developed resistance/intolerance to prior imatinib, and were also either dasatinib resistant (n = 38), dasatinib intolerant (n = 50), nilotinib resistant (n = 27), nilotinib intolerant (n = 1), or resistant/intolerant to dasatinib and nilotinib (n = 3). Median follow-up was 31.4 mo (range, 0.3–66.0 mo). A summary of results is provided in the Table .

Longer time since CML diagnosis versus shorter time (median time 6.61 years) was associated with greater OS (2-y probability, 90% vs 79%; log-rank P= 0.0435); however, no association with MCyR, CCyR, or PFS was observed.

A lower percentage of Ph+ cells (<95% Ph+ cells vs ≥95% Ph+ cells) at baseline was significantly associated with a higher rate of MCyR (76% vs 23%; P <0.001) and CCyR (65% vs 14%; P <0.001), as well as PFS (2-y probability, 83% vs 68%; log-rank P = 0.0181); no association with OS was observed.

Resistance versus no resistance (ie, only intolerance) to prior TKIs was not significantly associated with response or survival, although a numeric trend toward lower rates of MCyR (39% vs 50%) and CCyR (28% vs 50%), as well as 2-y probabilities of PFS (72% vs 89%) and OS (82% vs 91%) among resistant patients was observed.

Prior response of at least a minor cytogenetic response (MiCyR) versus no response to first-line imatinib was associated with a higher rate of MCyR (49% vs 28%; P= 0.0375) and a numeric trend toward a higher rate of CCyR (39% vs 20%) on BOS; no trend for PFS or OS was observed. Prior response of at least MiCyR versus no response to second-line dasatinib/nilotinib was associated with higher rates of MCyR (56% vs 19%; P<0.001) and CCyR (48% vs 7%; P<0.001), as well as PFS (2-y probability, 80% vs 64%; log-rank P= 0.0180) and OS (2-y probability, 89% vs 77%; log-rank P= 0.0285) on BOS.

While baseline demographic characteristics showed a numerical trend toward lower response and/or survival rates with age ≥65 y and female gender, no trends were statistically significant. There was also no predictive effect for presence of a Bcr-Abl kinase domain mutation at baseline or CP status at onset of imatinib therapy.

In conclusion, most evaluated baseline characteristics appeared not to be predictive of response and/or survival on BOS in patients with CP CML and resistance/intolerance to multiple prior TKIs, although at least MiCyR to prior dasatinib/nilotinib and lower percentage of Ph+ cells at baseline were found to be consistently predictive of better outcomes on BOS.