Predictors of Response Duration and Survival with Second-Line Bosutinib Therapy in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Prior Imatinib

Bosutinib (BOS), a Src/Abl tyrosine kinase inhibitor (TKI), is approved for adults with Philadelphia chromosome-positive (Ph+) CML that is resistant/intolerant to prior therapy. In this retrospective analysis, baseline and on-treatment characteristics of chronic phase (CP) CML pts receiving second-line BOS following imatinib resistance (IM-R) or intolerance (IM-I) in an ongoing open-label, phase 1/2 study and a long-term extension study were examined to identify potential predictors of duration of major cytogenetic response (MCyR), overall survival (OS), and progression-free survival (PFS), using a backward-elimination multivariate Cox regression model.

A total of 284 (IM-R, n=195; IM-I, n=89) pts who received BOS starting at 500 mg/d were included in this analysis. Median (range) age was 53 (18‒91) y; time from CML diagnosis was 3.7 (0.1‒15.1) y; treatment duration was 25.6 (0.2‒106.7) mo; follow-up duration was 53.7 (0.5‒106.8) mo. For the last enrolled patient, time from first BOS dose was ≥6 y.

After ≥6 y of follow-up, median MCyR duration and OS were not yet reached. Kaplan-Meier estimated probability of maintaining MCyR at 6 y was 71%, OS rate was 83%, and cumulative incidence of on-treatment disease progression or death was 21%. Several factors were identified as predictive of MCyR duration, OS or PFS, including baseline Ph+ ratio ≥95% vs ≤35% and MCyR by week 12, which were significant predictors of all 3. Other significant predictors of decreased OS included: age ≥65, BOS-sensitive mutations vs no mutations and higher peripheral blood (PB) blasts at baseline (all P ≤0.031; Table). Other significant predictors of decreased PFS included: higher PB blasts and no dose reduction to 400 mg/d due to AEs (all P ≤0.025; Table). Prior IM response or resistance did not predict long-term outcomes, nor did any treatment-emergent adverse events examined except for abnormal liver function test (LFT), which was predictive of increased OS.

In conclusion, pts with CP CML resistant/intolerant to IM treated with BOS were identified as having an increased risk of poorer outcomes if they had the following characteristics: baseline Ph+ ratio ≥95% vs ≤35%, higher PB blasts at baseline or no MCyR by week 12. Having a better understanding of factors that may be predictive of long-term patient outcomes with TKI therapies may aid healthcare providers in the future selection of optimal treatment regimens for pts with Ph+ CML.

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