Achievement and Maintenance Of Deeper Molecular Response By Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Residual Disease On Long-Term Imatinib: ENESTcmr 36-Month Follow-Up

The 12- and 24-mo results of the Evaluating Nilotinib Efficacy and Safety in clinical Trials–complete molecular response (ENESTcmr) trial showed that pts with CML-CP with minimal residual disease after ≥ 2 y on imatinib achieved deeper molecular responses with switch to nilotinib. Results from ENESTcmr with 36-mo follow-up will be presented.

Pts with Philadelphia chromosome–positive (Ph+) CML-CP who had achieved complete cytogenetic response (CCyR) but had detectable BCR-ABL after ≥ 2 y on imatinib were included. Pts (N = 207) were randomized 1:1 to continue the same dose of imatinib (400 or 600 mg once daily [QD]; n = 103) or switch to nilotinib 400 mg twice daily (BID; n = 104). Rates of major molecular response (MMR; BCR-ABL ≤ 0.1% according to the International Scale [IS]) and MR^4.5 (BCR-ABL^IS ≤ 0.0032%) were evaluated by real-time quantitative polymerase chain reaction (RQ-PCR). Confirmed undetectable BCR-ABL was measured by RQ-PCR with a sensitivity of ≥ 4.5 logs, confirmed with a sensitivity of at least 4 logs in the next sample. Predictors of response were evaluated by multivariate logistic regression. Pts receiving imatinib were allowed to cross over to nilotinib if they had not achieved confirmed undetectable BCR-ABL by 24 mo or if they experienced treatment failure or confirmed loss of undetectable BCR-ABL at any time.

By 24 mo, 77% of pts in the nilotinib arm and 91% in the imatinib arm remained on study treatment. Discontinuation rates were comparable between arms during year 2; 7% and 5% of pts discontinued study treatment in the nilotinib and imatinib arms, respectively, between years 1 and 2. Three pts crossed over to nilotinib before 24 mo; the no. of pts who crossed over at or after 24 mo will be presented. By 24 mo, more pts in the nilotinib arm achieved confirmed undetectable BCR-ABL compared with imatinib (22.1% vs 8.7%; P = .0087; Table). Regardless of molecular response at study start, more pts in the nilotinib arm than the imatinib arm achieved MR^4.5 by 24 mo. None of the pts in the imatinib arm who lacked MMR at study start achieved confirmed MR^4.5 or confirmed undetectable BCR-ABL by 24 mo (vs 20.8% and 16.7% in the nilotinib arm, respectively). Twice as many pts achieved and maintained MR^4.5 in 3 consecutive assessments in the nilotinib vs imatinib arm (n = 12 vs 6). Age, sex, BCR-ABL level at study start, duration of prior imatinib (≤ 36 mo vs > 36 mo), and prior interferon were analyzed as predictors of response in univariate and multivariate analyses. None of these was clearly predictive of achieving MR^4.5 or undetectable BCR-ABL in multivariate logistic regression. No cases of progression to accelerated phase/blast phase were observed with 24 mo follow-up. Three pts in the imatinib arm had confirmed loss of CCyR vs 0 in the nilotinib arm.

Switching to nilotinib continues to induce deeper molecular responses in pts with minimal residual disease on long-term imatinib therapy. More pts achieved confirmed undetectable BCR-ABL in the nilotinib arm vs the imatinib arm, with the difference between arms increasing between 12 and 24 mo and notably marked in pts lacking MMR at study start. Maintenance of deeper molecular responses achieved with nilotinib therapy may enable more pts to benefit from treatment-free remission trials.

Leber:novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cervantes:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees. Spector:Novartis: Honoraria, Research Funding. Lipton:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ariad: Equity Ownership, 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. Etienne:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Guerci-Bresler:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis : Honoraria, Membership on an entity’s Board of Directors or advisory committees; AMGEN: Honoraria. Forrest:Bristol Myers Squibb: Consultancy. Schwarer:Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Collins:Novartis: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Hughes:Araid: Consultancy, Honoraria; Bristol Myers Squib: Consultancy, Honoraria, Research Funding; Novarits: Consultancy, Honoraria, Research Funding; CSL: Research Funding.