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

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 (MR(4) (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 MR(4) 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.

Figure 1

Analysis populations. ^aThe original target enrollment of N=806 (determined using an approximation of a normal distribution to achieve a precision of 3.3% for the 95% CI of the primary end point, assuming an MR⁴ rate of 25% at 18 months, a discontinuation rate of 15% and a Philadelphia chromosome-negative and/or atypical BCR-ABL1 transcript prevalence of 5%) was increased to allow a more robust analysis of the study's exploratory results. ITT, intent to treat.

Figure 2

Cumulative molecular response rates. Raw cumulative incidence (95% CI) of (a) MMR (BCR-ABL1^IS⩽0.1%), MR⁴ (BCR-ABL1^IS⩽0.01%) and MR^4.5 (BCR-ABL1^IS⩽0.0032%) in the molecular analysis population (n=1052) and (b) MR⁴ according to European Treatment and Outcome Study (EUTOS) and Sokal risk scores at diagnosis.

Figure 3

Cumulative molecular response rates according to 3-month BCR-ABL1^IS. (a) Raw cumulative rates (95% CI) of MMR (BCR-ABL1^IS⩽0.1%), (b) MR⁴ (BCR-ABL1^IS⩽0.01%) and (c) MR^4.5 (BCR-ABL1^IS⩽0.0032%) among patients in the landmark analysis population (n=783) with BCR-ABL1^IS⩽1%, >1–⩽10% and >10% at 3 months. Patients who had already achieved MMR, MR⁴ or MR^4.5, respectively, at 3 months were excluded from the landmark analyses of MMR, MR⁴ and MR^4.5 rates over time.