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The introduction of protein kinase inhibitors (PKIs) for chronic myeloid leukaemia (CML) has considerably improved prognosis of the disease but has also demonstrated a great potential for drug-drug interactions. Using the French health insurance databases, we aim to investigate the frequency, identify the associated factors and describe the potential consequences of potential drug-drug interactions (pPKI-DIs) between PKIs and concurrent medications in CML. A retrospective cohort study has been performed among patients with CML identified in the French healthcare database from 2011 to 2014. A pPKI-DI is defined as the presence of drugs listed as 'interacting' on the same day as PKI dispensing (co-dispensing) or in its coverage period (co-medication) during the first year of follow-up. The list of interacting drugs is based on the summary of products characteristics (SPCs) and Thesaurus of interactions. We performed specific nested case-control comparisons to investigate the association between PKI-DI and each of the three potential outcomes (death, hospitalisation for adverse drug reactions and switch to another PKI). We included 3480 patients; 1429 (41%) had a co-dispensing pPKI-DI, and 2153 (62%) had a co-medication pPKI-DI; 50% of the pPKI-DIs were 'to be taken into account', and 17% were 'not recommended'. The PKI with the most interactions was imatinib, and additional common drug classes included statins, benzodiazepines and proton pump inhibitors. Multivariate analysis demonstrated that the use of a higher number of additional drugs, comorbidities at baseline, high number of prescribers and higher ages were potential risk factors. Nilotinib and dasatinib showed a tendency towards a higher risk of pPKI-DI compared to imatinib. Despite the fact that some PKI-DIs were potentially clinically relevant, we did not find any significant association with death, hospitalisation for adverse drug reactions and switching. These findings should increase awareness to help reduce the prevalence of PKI-drug interactions and thereby ensure better management of CML patients., (© 2023 The Authors. Fundamental & Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of Société Française de Pharmacologie et de Thérapeutique.)

Aims: Pharmacovigilance signals of heart failure (HF) following exposure to protein kinase inhibitors (PKIs) have been detected in recent years. Our aim was to identify the PKIs most frequently associated with the development of HF., Methods: Using the French National Healthcare Database, all patients newly exposed to a PKI between January 2011 and June 2014 were followed up for 18 months. Specific hospitalization diagnosis and long-term HF-related disease codes were used to identify HF patients. HF incidence rate ratios (IRRs) were measured and adjusted hazard ratios (aHRs) were estimated using a Cox model. Sensitivity analyses were performed to limit the potential indication and competitive risk bias., Results: Thirteen PKIs were studied. Among the 49 714 new PKI users registered during the study period, the mean IRR of HF was 3.38 per 100 person-years, with a median time to onset of 155 days. We found a significant increase in the incidence of HF for six medicinal products: pazopanib (aHR = 2.42, 95% confidence interval [CI] 1.67-3.52), dasatinib (aHR = 2.22, 95% CI 1.42-3.44), ruxolitinib (aHR = 2.11, 95% CI 1.69-2.64), crizotinib (aHR = 1.71, 95% CI 1.07-2.72), everolimus (aHR = 1.45, 95% CI 1.26-1.67) and vemurafenib (aHR = 1.37, 95% CI 1.01-1.86). Sensitivity analyses were consistent with our primary analysis., Conclusions: The current study provides knowledge on HF following exposure to a PKI. Additional studies could confirm these results for dasatinib, everolimus, pazopanib and ruxolitinib, and particularly for the two medicinal products with results slightly above the significance threshold, namely, crizotinib and vemurafenib, in our sensitivity analyses., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: The advent of chronic myeloid leukaemia (CML) tyrosine-kinase inhibitors (TKI) has led to new paradigms including occupational rehabilitation., Objectives: This study aimed to characterize the impact of CML treatment on sick leaves within the 2 years following diagnosis in working-age patients., Methods: A cohort of all 18-60-year-old newly diagnosed CML patients initiating a TKI between January 1 st 2011 and December 31 st 2014 in France was identified in the French National Healthcare database (Système National des Données de Santé [SNDS]). Patients with a sick leave identified in the 24 months after TKI initiation were compared with sex and initiation date matched controls in a nested case-control design. Factors associated with sick leaves were identified through a conditional logistic regression model, providing adjusted odds-ratio (OR) with their 95% confidence interval (CI)., Results: Among 646 18-60-year-old patients, 268 were prescribed at least one sick leave in the study period, with 176 (27.2%) having their first sick leave prescribed after TKI initiation. The median number of sick days over the 2-years period was 115 per patient (interquartile range 25.5-384.5). In the nested case-control study (176 cases and 176 matched controls), sick leaves were more likely observed with second generation TKI (OR 4.11 [1.80-9.38]), whereas they were less likely observed in case if social deprivation (OR 0.07 [0.02-0.28]., Conclusion: More than 25% of working-age CML patients had at least one sick leave within 2 years of TKI initiation, with a higher impact of second generation TKI, and with a median duration of 115 days., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We analyzed demographic characteristics, comorbidities and patterns of treatment with tyrosine kinase inhibitors (TKIs) in a cohort of 3,633 incident cases of chronic myeloid leukemia (CML) identified across France from 1 January 2011 to 31 December 2014. Patients were identified through a specific algorithm in the French Healthcare Data System and were followed up 12 months after inclusion in the cohort. The estimated incidence rate of CML for this period in France was 1.37 per 100,000 person-years (95% Confidence Interval 1.36-1.38) and was higher in men, with a peak at age 75-79 years. At baseline, the median age of the cohort was 60 years (Inter Quartile Range 47-71), the Male/Female ratio was 1.2, and 25% presented with another comorbidity. Imatinib was the first-line TKI for 77.6% of the patients, followed by nilotinib (18.3%) and dasatinib (4.1%). Twelve months after initiation, 86% of the patients remained on the same TKI, 13% switched to another TKI and 1% received subsequently three different TKIs. During the follow-up, 23% discontinued and 52% suspended the TKI. Patients received a mean of 16.7 (Standard Deviation (SD) 9.6) medications over the first year of follow-up, and a mean of 2.7 (SD 2.3) concomitant medications on the day of first TKI prescription: 24.4% of the patients received allopurinol, 6.4% proton pump inhibitors (PPI) and 6.5% antihypertensive agents. When treatment with TKI was initiated, incident CML patients presented with comorbidities and polypharmacy, which merits attention because of the persistent use of these concomitant drugs and the potential increased risk of drug-drug interactions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pajiep, Conte, Huguet, Gauthier, Despas and Lapeyre-Mestre.)