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Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

ABSTRACT: INTRODUCTION:This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (Cmin) and treatment outcomes. METHODS:Chronic myeloid leukemia (CML) patients using nilotinib were followed for 12 months. Adherence was measured by Medication Event Monitoring System (MEMS), pill count, and Medication Adherence Report Scale (MARS-5). Nilotinib Cmin and patient-reported outcomes (i.e., quality of life, side effects, beliefs, satisfaction) were measured at baseline, 3, 6, and 12 months. RESULTS:Sixty-eight patients (57.5 ± 15.0 years, 49% female) participated. Median adherence to nilotinib (MEMS and pill count) was ? 99% and adherence < 90% was rare. Self-reported nonadherence (MARS-5) increased in the first year of treatment to a third of patients. In line with the strong beliefs in the necessity of taking nilotinib, forgetting to take a dose was more prevalent than intentionally adjusting/skipping doses. Nilotinib Cmin were generally above the therapeutic target in 95% of patients. Patients reported a variety of side effects, of which fatigue was most frequent. The mean Cmin was higher in patients who reported severe itching and fatigue. The overall 1-year MMR rate ranged from 47 to 71%. CONCLUSION:Substantial nonadherence (< 90%) to nilotinib was rare and nilotinib Cmin were generally above the therapeutic target. Lack of response in our group of patients was not related to nonadherence or inadequate Cmin. Nevertheless, a considerable number of patients experienced difficulties in adhering to the twice daily fasted dosing regimen, emphasizing the importance of continuous support of medication adherence in CML. CLINICAL TRIAL REGISTRATION:NTR3992 (Netherlands Trial Register, www.trialregister.nl ).

SUBMITTER: Boons CCLM

PROVIDER: S-EPMC7419465 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

Boons Christel C L M CCLM Timmers Lonneke L Janssen Jeroen J W M JJWM Westerweel Peter E PE Blijlevens Nicole M A NMA Smit Willem M WM Bartelink Imke H IH Wilschut Janneke A JA Swart Eleonora L EL Hendrikse N Harry NH Hugtenburg Jacqueline G JG

European journal of clinical pharmacology 20200602 9

<h4>Introduction</h4>This comprehensive observational study aimed to gain insight into adherence to nilotinib and the effect of (non)adherence on exposure (C<sub>min</sub>) and treatment outcomes.<h4>Methods</h4>Chronic myeloid leukemia (CML) patients using nilotinib were followed for 12 months. Adherence was measured by Medication Event Monitoring System (MEMS), pill count, and Medication Adherence Report Scale (MARS-5). Nilotinib C<sub>min</sub> and patient-reported outcomes (i.e., quality of ...[more]

PMID: 32488333

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Project description:BackgroundHealth care-related harm is an internationally recognized threat to public health. The United Kingdom's national health services demonstrate that upwards of 90% of health care encounters can be delivered in ambulatory settings. Other countries are transitioning to more family practice-based health care systems, and efforts to understand avoidable harm in these settings is needed.MethodsWe developed 100 scenarios reflecting a range of diseases and informed by the World Health Organization definition of 'significant harm'. Scenarios included different types of patient safety incidents occurring by commission and omission, demonstrated variation in timeliness of intervention, and conditions where evidence-based guidelines are available or absent. We conducted a two-round RAND / UCLA Appropriateness Method consensus study with a panel of family practitioners in England to define "avoidable harm" within family practice. Panelists rated their perceptions of avoidability for each scenario. We ran a k-means cluster analysis of avoidability ratings.ResultsPanelists reached consensus for 95 out of 100 scenarios. The panel agreed avoidable harm occurs when a patient safety incident could have been probably, or totally, avoided by the timely intervention of a health care professional in family practice (e.g. investigations, treatment) and / or an administrative process (e.g. referrals, alerts in electronic health records, procedures for following up results) in accordance with accepted evidence-based practice and clinical governance. Fifty-four scenarios were deemed avoidable, whilst 31 scenarios were rated unavoidable and reflected outcomes deemed inevitable regardless of family practice intervention. Scenarios with low avoidability ratings (1 s or 2 s) were not represented by the categories that were used to generate scenarios, whereas scenarios with high avoidability ratings (7 s 8 s or 9 s) were represented by these a priori categories.DiscussionThe findings from this RAND/UCLA Appropriateness Method study define the characteristics and conditions that can be used to standardize measurement of outcomes for primary care patient safety.ConclusionWe have developed a definition of avoidable harm that has potential for researchers and practitioners to apply across primary care settings, and bolster international efforts to design interventions to target avoidable patient safety incidents that cause the most significant harm to patients.

Project description:Introduction: Capecitabine is a widely prescribed oral anticancer agent. We studied medication adherence and explored its use in daily practice from a patients' perspective. Patients and Methods: Patients (n = 92) starting capecitabine were followed up to five 3-week cycles. Adherence was assessed using a pill count, pharmacy data and dosing information from the patients' medical file. Self-reported adherence was measured using the Medication Adherence Report Scale (MARS). At baseline and during week 2 of cycles 1, 3, and 5, patients filled out questionnaires about quality of life, symptoms, attitude toward medicines and disease and use in daily practice. Simultaneously, blood samples were taken to determine the area under the curve (AUC) of 5'-deoxy-5-fluorouridine (5'-DFUR), 5-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL) by a population pharmacokinetic model. Associations between AUCs and patient-reported symptoms were tested for cycles 3 and 5. Results: Most patients (84/92; 91%) had an adherence rate of ≥95 and ≤ 105%. The percentage of patients reporting any non-adherence behavior measured with MARS increased from 16% at cycle 1 to 29% at cycle 5. Symptoms were reported frequently and the dosing regimen was adjusted by the physician at least once in 62% of patients. In multivariate analysis the probability of an adjustment increased with the number of co-medication (OR 1.19, 95% CI: 1.03-1.39) and a stronger emotional response to the disease (OR 1.32, 95% CI: 1.10-1.59). The AUC of 5'-DFUR was associated with weight loss (OR 1.10, 95% CI: 1.01-1.19), AUC of FBAL with hand-foot syndrome (OR 0.90, 95% CI: 0.83-0.99), rhinorrhea (OR 1.21, 95% CI: 1.03-1.42 weight loss (OR 1.09, 95% CI: 1.00-1.20) and depression (OR 0.90, 95% CI: 0.82-0.99). Side effects were reported by one third of patients as the reason to discontinue treatment. Conclusion: Adherence to capecitabine was generally high. Nevertheless, adherence measured with MARS decreased over time Adherence management to support implementation of correct capecitabine use is specifically relevant in longer term treatment. In addition, it appears that adverse event management is important to support persistence. With the extending armamentarium of oral targeted anticancer agents and prolonged treatment duration, we expect the issue of medication adherence of increasing importance in oncology.

Project description:Tyrosine kinase inhibitors (TKIs) have radically changed the outcome of chronic myeloid leukemia (CML) patients in the last 20 years. Moreover, the advent of second generation TKIs, namely nilotinib and dasatinib, have largely increased the number of CML patients achieving deep and sustained molecular responses. However, the possible mechanisms capable of influencing the maintenance of the long-term molecular response are not yet fully known and understood. In this light, polymorphisms in MDR-ABC transporters may influence the efficacy and safety of TKIs. In this study, we examined seven single nucleotide polymorphisms (SNPs) in four ABC transporter genes: ABCC1 rs212090 (5463T>A), ABCC2 rs3740066 (3972C>T), ABCC2 rs4148386 G>A, ABCC2 rs1885301 (1549G>A), ABCG2 rs2231137 (34G>A), ABCG2 rs2231142 G>C, ABCB1 rs1045642 (3435C>T), to determine their effect on the achievement and/or loss of molecular response in 90 CML patients treated with nilotinib. We found that ABCC2 rs3740066 CC and CT as well as the ABCB1 rs1045642 TT genotypes correlated with a higher probability to achieve MR3 in a shorter time (p=0.02, p=0.004, and p=0.01), whereas ABCG2 rs2231137 GG was associated with lower probability of MR3 achievement (p=0.005). Moreover, ABCC2 rs3740066 CC genotype, the ABCB1 rs1045642 CC and TT genotypes were positively correlated with MR4 achievement (p=0.02, p=0.007, and p=0.003). We then generated a predictive model incorporating the information of four genotypes, to evaluate the combined effect of the SNPs. The combination of SNPs present in the model affected the probability and the time to molecular response. This model had a high prognostic significance for both MR3 and MR4 (p=0.005 and p=0.008, respectively). Finally, we found ABCG2 rs2231142 GG genotype to be associated with a decrease risk of MR3 loss. In conclusion, MDR-transporters SNPs may significantly affect the achievement and loss of molecular response in CML patients treated with nilotinib.

Dataset Information

Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

Publications

Response and Adherence to Nilotinib in Daily practice (RAND study): an in-depth observational study of chronic myeloid leukemia patients treated with nilotinib.

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