Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial

Abstract

In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP.

Figure 1

CONSORT diagram for ENESTnd 5-year analysis (data cutoff 30 September 2013). Efficacy analyses, including molecular and cytogenetic response rates, were based on all randomized patients (intent-to-treat population). Safety analyses were based on patients who received ⩾1 dose of study treatment. ^aReasons for discontinuation: AEs/abnormal laboratory values (n=34), suboptimal response/treatment failure (n=34), withdrawal of consent (n=17), death (n=6), disease progression (n=2), other (n=17). On discontinuation, 24 patients entered the extension study. ^bReasons for discontinuation: AEs/abnormal laboratory values (n=56), withdrawal of consent (n=16), suboptimal response/treatment failure (n=13), disease progression (n=4), death (n=1), other (n=15). On discontinuation, three patients entered the extension study. ^cReasons for discontinuation: suboptimal response/treatment failure (n=59), AEs/abnormal laboratory values (n=38), withdrawal of consent (n=17), disease progression (n=12), death (n=1), other (n=12). On discontinuation, 43 patients entered the extension study. ^dDiscontinued before receiving intervention owing to protocol deviation (n=1), withdrawal of consent (n=2). ^eDiscontinued before receiving intervention owing to protocol deviation (n=1), withdrawal of consent (n=2), QTc>450 ms at baseline (n=1). ^fOne patient allocated to nilotinib 400 mg twice daily received imatinib 400 mg once daily for 6 days before discontinuing intervention and was excluded from safety analysis for nilotinib 400 mg twice daily. ^gDiscontinued before receiving intervention owing to protocol deviation (n=2), withdrawal of consent (n=1), QTc>450 ms at baseline (n=1). ^hOne patient allocated to nilotinib 400 mg twice daily received imatinib 400 mg once daily for 6 days before discontinuing intervention and was included in safety analysis for imatinib 400 mg once daily. ⁱOwing to atypical transcripts at baseline (n=5), discontinuation prior to the month 3 assessment (n=15), or missing month 3 assessment (n=4). ^jOwing to atypical transcripts at baseline (n=1), discontinuation prior to the month 3 assessment (n=17), or missing month 3 assessment (n=3). ^kOwing to atypical transcripts at baseline (n=2), discontinuation prior to the month 3 assessment (n=12), or missing month 3 assessment (n=5).

Figure 2

Cumulative molecular response rates. Cumulative proportion of patients with (a) major molecular response (MMR; BCR-ABL^IS⩽0.1%), (b) molecular response 4 (MR⁴; BCR-ABL^IS⩽0.01%) and (c) molecular response 4.5 (MR^4.5; BCR-ABL^IS⩽0.0032%). P values vs imatinib are nominal. IS, International Scale.

Figure 3

Summary of deaths on study by treatment arm. ^aThe presence/absence of cardiovascular events (CVEs) was collected during treatment (core or extension) only. ^bDeath due to advanced chronic myeloid leukemia (CML) was defined as any death for which the principal cause was reported by the investigator as ‘study indication' or, if subsequent to documented progression to accelerated phase/blast crisis (AP/BC), any death for which the cause was reported as ‘unknown' or was not reported. ^cOne patient randomized to imatinib who died prior to receiving treatment is not shown. CABG, coronary artery bypass grafting.

Figure 4

Kaplan–Meier estimated (a) progression-free survival on study and (b) overall survival on study.

Figure 5

Kaplan–Meier estimated time to first cardiovascular event (CVE) on study. The shaded portion of the graph shows censored data and events that occurred after 60 months of treatment and up to the data cutoff date. Because patients had variable follow-up durations beyond the 60-month time point at the data cutoff for this exploratory analysis, the shaded portion of the graph does not fully reflect outcomes after 60 months of treatment exposure.