The Incidence of BCR-ABL Mutations and Their Impact on Outcome in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Nilotinib or Imatinib in ENESTnd: 36-Month Follow-up
Authors: Hughes Timothy P. , Kim Dong-Wook , Etienne Gabriel , Souza Carmino De , Kurokawa Mineo , Kalaycio Matt , Saglio Giuseppe , Larson Richard A. , Kantarjian Hagop M. , Hoenekopp Albert , Shou Yaping , Yu Richard , Blakesley Rick E. , Rosti Gianantonio , Hochhaus Andreas 
Published: October 2019

Abstract
Abstract 2755

Background:
In ENESTnd, nilotinib demonstrated superior efficacy vs imatinib in newly diagnosed patients (pts) with CML-CP, including a significantly reduced rate of progression to AP/BC on treatment. Here, we examined the occurrence of emergent mutations on treatment and their impact on response. Data on the incidence of mutations and impact on efficacy with a minimum follow-up of 36-months (mo) for all pts will be presented. Methods: Pts with CML-CP were randomized to receive nilotinib 300 mg BID (n = 282), nilotinib 400 mg BID (n = 281), or imatinib 400 mg QD (n = 283). Mutation testing was performed by direct sequencing of the kinase domain (amino acids 230 to 490; sensitivity, 10%-20%) in a central lab at: baseline, 5-fold increase in BCR-ABL levels, lack of MMR at 12 mo, loss of MMR, or treatment discontinuation. Results: With a minimum follow-up of 24 mo, twice as many pts had emergent mutations on imatinib (n = 20) vs nilotinib (n = 10, nilotinib 300 mg BID; n = 8, nilotinib 400 mg BID), with the majority of mutations emerging in pts with high and intermediate Sokal scores (Table). Of pts with mutations emerging on imatinib, the majority (65%) had nilotinib-sensitive, imatinib-resistant mutations; whereas nilotinib was effective in preventing the emergence of clones with nilotinib-sensitive mutations. The incidence of T315I mutations was similar for the nilotinib (n = 3, nilotinib 300 mg BID; n = 2, nilotinib 400 mg BID) and imatinib (n = 3) arms and most of these T315I mutations (6/8) were detected within the first 12 mo of therapy. All but 1 pt with the T315I mutation had a high Sokal risk; the other pt had an intermediate Sokal risk. Overall, across the 3 treatment arms, the incidence of any mutation was 14% in pts who had BCR-ABLIS > 10% at 6 mo vs 4% in pts with BCR-ABLIS ≤ 10% at 6 mo. The majority of pts with emerging mutations had suboptimal response (SoR) or treatment failure (TF) on treatment; all pts with the T315I mutation had SoR or TF. Of the pts with mutations, 1/10 pts on nilotinib 300 mg BID, 2/8 pts on nilotinib 400 mg BID, and 7/20 pts on imatinib, progressed to AP/BC on treatment. BCR-ABL mutations did not account for all cases of progression to AP/BC, loss of CCyR, and loss of MMR on treatment (Table). Of the pts who achieved an MMR on treatment, 0/203 (0%), 2/192 (1%) and 3/131 (2%) had a mutation and lost MMR with nilotinib 300 mg BID, nilotinib 400 mg BID or imatinib, respectively. Conclusions: Nilotinib may be more effective in preventing the development of emerging mutations vs imatinib. More pts with new mutations progressed to AP/BC on imatinib than on nilotinib. These data suggest that deeper molecular responses with nilotinib protect from the development of emerging mutations and progression to AP/BC vs imatinib.

Disclosures:
Hughes: Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kim:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurokawa:Novartis Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kalaycio:Novartis Pharmaceutical: Honoraria, Research Funding, Speakers Bureau. Saglio:Bristol Myers Squipp: Consultancy, Speakers Bureau; Novartis Pharmaceutical: Consultancy, Speakers Bureau; Pfizer: Consultancy. Larson:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian:Pfizer: Research Funding; Novartis: Research Funding; Novartis: Consultancy; BMS: Research Funding. Hoenekopp:Novartis Pharmaceutical: Employment, Equity Ownership. Shou:Novartis: Employment. Yu:Novartis: Employment, Equity Ownership. Blakesley:Novartis Pharmaceutical: Employment. Rosti:Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria; Roche: Honoraria. Hochhaus:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis Pharmaceutical: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding.