Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study

Andreas Hochhaus ,M C Müller,W Wiktor-Jedrzejczak,Tamás Masszi ,Mahon Fx ,L N Petrov ,Steegmann Jl ,Philipp Le Coutre ,Gianantonio Rosti ,Daniel Coriu ,Laimonas Griškevičius ,Gert J Ossenkoppele ,Guenther Gastl ,Delphine Réa ,Giuseppe Saglio ,Peter Schuld ,Angela Maria Pellegrino ,P Di Matteo ,Luca Dezzani ,Nicholas C P Cross ,Michele Baccarani ,Kimmo Porkka ,Andrzej Hellmann ,T Brümmendorf ,F Giles

doi:10.1038/leu.2015.270

Abstract

The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4 (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10 000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal.

Highlights

European Treatment and Outcome Study (EUTOS) and Sokal risk scores could not be calculated in 8.7% (n = 95) and 9.8% (n = 107) of patients, respectively, owing to missing baseline data for ⩾ 1 parameter required for the calculation
Dose changes or interruptions occurred in 45.2% of patients (n = 492), including 36.7% (n = 400) with changes or interruptions owing to adverse events (AEs) or laboratory abnormalities
Results from this study confirm the high rates of deep responses achieved with frontline nilotinib; 38.4% of patients in the molecular analysis population achieved the primary end point of molecular response 4 (MR4) at 18 months, and by 24 months, 55.2% achieved MR4 and 38.6% achieved MR4.5

Summary

Introduction

Throughout 6 years of follow-up in the pivotal trial of frontline nilotinib vs imatinib for patients with CML-CP (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd)), nilotinib showed improved efficacy over imatinib, including earlier and deeper molecular responses.[2,3,4,5,6,7] ENESTnd met its primary end point, with statistically significantly higher rates of major molecular response (MMR; BCR-ABL1 ⩽ 0.1% on the International Scale (IS)) at 12 months with nilotinib 300 mg twice daily (44%) and nilotinib 400 mg twice daily (43%) than with imatinib (22%; P o0.001 vs either nilotinib arm).[5] progression to AP or blastic phase (BP) tended to be less common with nilotinib; by the 6-year data cutoff, 11 (nominal P = 0.0661 vs imatinib), 6 (nominal P = 0.0030 vs imatinib) and 21 patients in the nilotinib 300-mg twice-daily, nilotinib 400-mg twice-daily and imatinib arms, respectively, progressed to AP/BP on study.[6] the total number of deaths on study was similar in the nilotinib. In ENESTnd, nausea, diarrhea and muscle spasms were the most common adverse events (AEs) reported with imatinib, whereas rash and headache were most common with nilotinib; not among the most common AEs, cardiovascular events were more frequent with nilotinib.[3,4,5,6,7] In contrast to the trend for fewer deaths with the higher dose of nilotinib vs the lower dose, cardiovascular events were less common with the lower nilotinib dose.[6]

Methods

Results

Conclusion