Nilotinib dose‐optimization in newly diagnosed chronic myeloid leukaemia in chronic phase: final results from ENESTxtnd

Abstract

SummaryThe Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Extending Molecular Responses (ENESTxtnd) study was conducted to evaluate the kinetics of molecular response to nilotinib in patients with newly diagnosed chronic myeloid leukaemia in chronic phase and the impact of novel dose‐optimization strategies on patient outcomes. The ENESTxtnd protocol allowed nilotinib dose escalation (from 300 to 400 mg twice daily) in the case of suboptimal response or treatment failure as well as dose re‐escalation for patients with nilotinib dose reductions due to adverse events. Among 421 patients enrolled in ENESTxtnd, 70·8% (95% confidence interval, 66·2–75·1%) achieved major molecular response (BCR‐ABL1 ≤ 0·1% on the International Scale) by 12 months (primary endpoint). By 24 months, 81·0% of patients achieved major molecular response, including 63·6% (56 of 88) of those with dose escalations for lack of efficacy and 74·3% (55 of 74) of those with dose reductions due to adverse events (including 43 of 54 patients with successful re‐escalation). The safety profile of nilotinib was consistent with prior studies. The most common non‐haematological adverse events were headache, rash, and nausea; cardiovascular events were reported in 4·5% of patients (grade 3/4, 3·1%). The study was registered at clinicaltrials.gov (NCT01254188).

Optimal treatment strategy with nilotinib for patients with newly diagnosed chronic‐phase chronic myeloid leukemia based on early achievement of deep molecular response (MR4.5): The phase 2, multicenter N‐Road study

“…Regarding patient background characteristics in the ENESTxtnd trial, 23 GIMEMA trial, 25 and the present N‐Road study, the median age (range) was comparable. The rates of high Sokal score were no data, 23 21%, 25 and 13%, respectively. A higher MR 4.5 accumulative rate in this study may have been a result of the inclusion of fewer individuals who had a high Sokal score within our sample.…”

“…The N‐Road study aimed to achieve early response; thus, the dose increase criteria for no optimal response at 3, 6, and 12 months recommended by ELN 2013 was applied in this study 26 . The dose increase criteria applied in N‐Road were, therefore, even stricter than those of ENESTxtnd 23 and GIMEMA trials 24,25 . Consequently, the cumulative rate of MR 4.5 by 24 months was high in our study.…”

“…A total of 17.6% of patients decreased doses because of AEs. The cumulative incidence of MMR was 81% by 24 months 23 . Conversely, in the GIMEMA trial, 25 77% of patients continued nilotinib up to the last observation.…”

Short overview on the current treatment of chronic myeloid leukemia in chronic phase

“…1) due to the few clinical trials in these settings. However, the efficacy of bosutinib, which shares its dual SRC/ABL-inhibitory activity with dasatinib, is markedly reduced (CCyR 17% vs. 54% and MCyR 43% vs. 78%) after imatinib and dasatinib failure compared with its use in dasatinib-naïve patients, e. g., those having failed imatinib and nilotinib [25, 26].

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Successful determination of nilotinib dosage by therapeutic drug monitoring in a patient with chronic myeloid leukemia developing hepatic dysfunction: A case report

“…Typical adverse events of nilotinib include hepatic dysfunction, elevated bilirubin, prolongation of QTc interval, hyperlipidemia, and hyperglycemia. Hepatotoxicity caused by other tyrosine kinase inhibitors is known, but it is reported that the frequency of nilotinib hepatotoxicity is rare . When hepatic dysfunction occurs, drug withdrawal or dose reduction is required, but there are currently no indicators for dose adjustment.…”