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
Bibliographic record
Abstract
Abstract 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. Disclosures Cortes: ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent: Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Nadanaciva:Pfizer Inc: Employment. Bardy-Bouxin:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership. Leip:Pfizer Inc: Employment. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gambacorti-Passerini:Pfizer: Consultancy, Research Funding; BMS: Consultancy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".