Response and adherence to Nilotinib in daily practice (RAND-study): An in-depth observational study of patients with chronic myeloid leukemia treated with Nilotinib

Abstract

Background: In chronic myeloid leukemia (CML), oral treatment needs to be taken indefinitely in the majority of patients and specifically for nilotinib, the necessity of a twice daily, fasted schedule is an extra burden. Non-adherence to CML treatment may influence plasma levels and has been recognized as a determinant of treatment failure in CML. Objectives: To gain insight into adherence with the use of nilotinib in daily clinical practice and its influence on exposures and treatment outcome. Methods: A multicentre prospective observational study conducted between August 2013-April 2017. CML patients treated with nilotinib were followed for twelve months. Achievement of a major molecular response (MMR) within the first twelve months of nilotinib treatment was assessed. Adherence was measured by three methods: medication event monitoring system (MEMS) (proportion of days covered [PDC]), pill count (adherence rate [AR]), and self-reported Medication Adherence Report Scale (MARS-5). Nilotinib trough plasma concentrations were measured at baseline, three, six, and twelve months. Results: Sixty-eight patients (57.0 ± 15.0 years;48% female) participated. At baseline, 29 patients were newly starting nilotinib (subpopulation- A) and 39 were already on treatment with nilotinib (subpopulation-B) with a median treatment duration of 39 months (range 3-92). The overall 1-year MMR rate ranged from 44-75%. Median PDC and AR were 99.6 and 100.2 in subpopulation-A and 97.6 and 98.1 in subpopulation-B, respectively. Three and five patients, respectively, had PDC and AR <90%. The percentage of patients reporting any non-adherence behaviour (MARS-5) increased in subpopulation-A from 8% at three months to 26% at twelve months, and remained steady in subpopulation-B at 23-30%. Average trough plasma concentration was 1084 ± 556 ug/L (range 196-2540). Six patients (9.8%) had a plasma concentration below the therapeutic target level (<490 ug/L) at any time. There was no association between nilotinib trough level or nilotinib adherence and MMR at twelve months. Conclusions: Substantial non-adherence (<90%) to nilotinib was rare and nilotinib blood levels were above the therapeutic target in 90% of patients. Achievement of MMR on nilotinib was not related to nilotinib non-adherence or inadequate blood levels. However, incidental non-adherence increases over time to a quarter of patients, emphasizing the importance of continuous support of medication adherence in CML care.