Assessment of Early Molecular Response As a Predictor of Long-Term Clinical Outcomes in the Phase 3 BELA Study
Authors: Brümmendorf Tim H , Kantarjian Hagop M. , Gambacorti-Passerini Carlo , Guilhot Francois , Akard Luke , Doshi Vaishali , Lipton Jeff H , Pavlov Dmitri , Gogat Karin , Duvillie Ladan , Shapiro Mark , Cortes Jorge E 
Published: October 2019

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 <0.001). Among pts with molecular assessment at each time point, the rate of Bcr-Abl/Abl ratio ≤10% on the IS was significantly higher with BOS versus IM at Month 3 (86% vs 65%; P <0.001), Month 6 (94% vs 82%; P <0.001), and Month 9 (97% vs 90%; P = 0.01); a similar trend was observed for pts with Bcr-Abl/Abl ratio ≤1% at each time point (Table).
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.
Bcr-Abl/Abl ratio on IS at Month 3 BOS (n = 208) IM (n = 223) ≤1% (n = 81) ≤10%a (n = 179) >10% (n = 29) P valueb ≤1% (n = 39) ≤10%a (n = 146) >10% (n = 77) P valueb MMR     By 12 mo 82% 56% 17% <0.001 72% 46% 5% <0.001     By 24 mo 91% 74% 21% <0.001 85% 69% 17% <0.001 CCyR     By 12 mo 100% 95% 48% <0.001 92% 93% 55% <0.001     By 24 mo 100% 96% 48% <0.001 92% 95% 65% <0.001 EFS at 24 moc 96% 93% 83% 0.004 88% 92% 85% 0.331 OS at 24 moc 100% 99% 88% 0.004 97% 99% 95% 0.090 Bcr-Abl/Abl ratio on IS at Month 6 BOS (n = 193) IM (n = 226) ≤1% (n = 157) ≤10%a (n = 181) >10% (n = 12) P valueb ≤1% (n = 112) ≤10%a (n = 186) >10% (n = 40) P valueb MMR     By 12 mo 67% 59% 0% <0.001 60% 39% 0% <0.001     By 24 mo 82% 76% 8% <0.001 84% 61% 8% <0.001 CCyR     By 12 mo 98% 97% 33% <0.001 98% 90% 30% <0.001     By 24 mo 99% 98% 33% <0.001 98% 93% 48% <0.001 EFS at 24 moc 94% 94% 64% 0.003 97% 94% 67% <0.001 OS at 24 moc 99% 99% 92% 0.096 99% 98% 90% 0.014 Bcr-Abl/Abl ratio on IS at Month 9 BOS (n = 185) IM (n = 216) ≤1% (n = 160) ≤10%a (n = 179) >10% (n = 6) P valueb ≤1% (n = 134) ≤10%a (n = 195) >10% (n = 21) P valueb MMR     By 12 mo 65% 59% 0% 0.004 50% 35% 0% <0.001     By 24 mo 84% 77% 0% <0.001 78% 59% 5% <0.001 CCyR     By 12 mo 98% 97% 17% <0.001 98% 89% 29% <0.001     By 24 mo 100% 99% 17% <0.001 99% 94% 43% <0.001 EFS at 24 moc 95% 95% 0% <0.001 96% 95% 49% <0.001 OS at 24 moc 100% 99% 83% 0.001 99% 99% 85% <0.001 a Includes pts with Bcr-Abl/Abl ratio ≤1%. b Comparison of pts with Bcr-Abl/Abl ratio ≤10% vs >10% on the IS. c Based on Kaplan-Meier estimates.

Disclosures:
Brümmendorf: 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.