Assessment of Early Molecular Response As a Predictor of Long-Term Clinical Outcomes in the Phase 3 BELA Study

Abstract

Abstract 69 Bosutinib (BOS) is an oral, dual Src/Abl kinase inhibitor. In the randomized, phase 3 BELA trial, BOS 500 mg/d demonstrated clinical activity in newly diagnosed (≤6 mo) chronic phase chronic myeloid leukemia (CP CML) and manageable toxicity distinct from that of imatinib (IM) 400 mg/d. This analysis of the BELA trial investigated reduction in Bcr-Abl/Abl ratio at Months 3, 6, and 9 as early predictors of long-term outcomes. Baseline characteristics were well balanced between treatment arms. Dose escalation to 600 mg/d occurred in 6% of patients (pts) on BOS and 18% of pts on IM. The most common reason for BOS discontinuation was toxicity (24% vs 7% on IM), and for IM was progressive disease (13% vs 4% on BOS). Data included a minimum follow-up of 24 mo. In the intent-to-treat population, the rate of major molecular response (MMR; Bcr-Abl/Abl ratio ≤0.1% on International Scale [IS]) was higher at all time points for BOS versus IM, with a significantly shorter median time to MMR for BOS (48 wks) versus IM (73 wks; P In both arms, a Bcr-Abl/Abl ratio ≤10% versus >10% at Months 3, 6, and 9 was predictive of significantly higher cumulative rates of MMR and CCyR by both 12 mo and 24 mo (Table). The rates of MMR by 12 and 24 mo were generally highest among pts with a Bcr-Abl/Abl ratio ≤1% at Month 3, 6, and 9 in both arms. A similar trend was generally observed for on-treatment event-free survival (EFS; included death, transformation to accelerated/blast phase, increased white blood cell count without complete hematologic response [CHR], or loss of CHR or CCyR) and overall survival (OS) at 24 mo (Table). In the BOS arm, Kaplan-Meier estimates at 24 mo were significantly higher with a Bcr-Abl/Abl ratio ≤10% versus >10% for EFS at Months 3, 6, and 9, and for OS at Months 3 and 9. Furthermore, Kaplan-Meier estimates of EFS and OS at 24 mo were significantly higher for pts with Bcr-Abl/Abl ratio ≤10% versus >10% at Months 6 and 9 in the IM arm. Within each treatment arm, estimated rates of EFS and OS at 24 mo generally appeared similar for pts with reduction of Bcr-Abl/Abl ratio ≤1% versus ≤10% at early time points. In summary, a Bcr-Abl/Abl ratio ≤10% versus >10% at Months 3, 6, and 9 was associated with higher rates of MMR and CCyR by later time points in both arms. A lower Bcr-Abl ratio was also predictive of EFS after 24 mo of follow-up except for IM at Month 3, and of OS except for IM at Month 3 and BOS at Month 6. However, because of the very limited number of EFS and OS events and the relatively few pts with a Bcr-Abl/Abl ratio >10% (particularly in the BOS arm at Months 6 [n = 12] and 9 [n = 6]), longer follow-up in the BELA trial is needed to fully characterize the predictive properties of early reductions in Bcr-Abl/Abl ratio on long-term EFS and OS. Disclosures: Brummendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kantarjian:Pfizer Inc: Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Guilhot:Celgene, Bristol Myers Squibb: Consultancy. Akard:Pfizer, Novartis, Merck, Bristol Myers Squibb: Research Funding; Novartis, BMS, Eisai, Millenium, Celgene: Speakers Bureau. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.