Incident users of tyrosine kinase inhibitors in patients with chronic myeloid leukemia: Analysis of anticancer treatment trajectories—A French population‐based study using the French national health data system

To the Editor: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm mainly characterized by the excessive production of white blood cells. In 2018, the CML incidence in France was approximately 1.0–1.5/100000 persons with a median age of 60–62 years, 55% of whom were men. The first tyrosine kinase inhibitor (TKI) was imatinib, approved in 2001, which have improved the prognosis of this disease with patients reaching the life expectancy of the general population. Due to resistance or adverse drug reactions, other drugs have been developed for this indication: dasatinib and nilotinib, both recommended for first-line treatment (LT) by the European LeukemiaNet (ELN), bosutinib, and ponatinib. Few data are available regarding the real-life use of TKIs for CML, especially on the entire population of a country, but these data can provide a description of care pathways, which are sometimes complex in real-life conditions. The objective of this study was to describe TKI treatment courses in patients with CML who initiated treatment between 2014 and 2017 and who were followed for 3 years, using data from the French Health Data System (SNDS). This study was based on the SNDS, which covers 99% of the French population (i.e., approximately 67 million inhabitants) and compiles several data from two sources: the French health insurance claims database and the French hospital and discharge database (online supplementary method). We included all adult patients (≥18 years old) newly treated with TKI for CML: imatinib, dasatinib, nilotinib, bosutinib, and ponatinib, between 01 January 2014 and 31 December 2017 in France. Patients with CML were identified using an algorithm already used within the SNDS (Table S1). Incident TKI users were defined as having at least one reimbursement for a TKI of interest between 01 January 2014 and 31 December 2017 and no TKI reimbursement during the 2 years prior to the first reimbursement. The index date is the date of the first reimbursement of TKI. Each patient was followed 3 years after the index date, that is, until 2020 for patients included in 2017, or until disease progression, defined as the blast phase (BP), or death, whichever came first. The five TKIs were identified in the database using the ATC code (Table S1). The first TKI was defined as the TKI dispensed at the index date. If the patient received ≥2 different TKIs, the 2-LT was defined as the second TKI prescribed chronologically and so on for the subsequent LT (third, fourth, fifth). Individuals who switched were defined as patients with at least two different TKIs during follow-up. The time frame was defined as the period between the index date and the date of the switch. A treatment interruption was defined as a gap of 90 days or more between two TKI dispensations. Medical comorbidities were identified at the index date, for the five previous years, using LTD and hospital diagnostic codes according to ICD-10 (Table S1). A Sankey diagram was designed to visualize the different LT for each patient using SankeyMatic. Characteristics of TKI utilization and time frames were described in relation to the first-line TKI. Cumulative incidence functions of the first switch according to the first TKI prescription and Gray's test (competitive risk, in our case death and BP, were taken into account) were used to estimate whether occurrence of the first switch was different. To determine whether the utilization pattern differed over time, we also described first-line and second-line prescription according to the year of prescription. Analyses were carried out using the SAS EG 7.15 software. Of the 8701 individuals with a first TKI reimbursement between 2014 and 2017, we identified 4162 CML adults newly treated with a TKI (Figure S1). The median age was 62 years and 56.3% of the patients were male (Table S1). More than 16.5% had cardiovascular comorbidities, 15.7% diabetes and 42.2% had antihypertensive drugs.1-L imatinib patients were older than 1-L nilotinib or dasatinib patients (median age, years): 65 versus 49 and 52 respectively, and had more comorbidities (cardiovascular comorbidities: 19.5% vs. 4.4% and 10.2%). During the 3-year follow-up, death occurred in 10.8% and progression to BP in 1.6% (median time of 526 and 454 days, respectively) of the patients. CML patients with death or disease progression presented more comorbidities (Table S1). Approximately 70% of the overall population had only one TKI during the 3-year follow-up and among individuals alive and in the chronic phase at the end of follow-up, 88% were still under TKI treatment (Table S1). Individuals had approximately one dispensation per month with a median of 34 dispensations [IQR: 24–37] over the 36months with a median time of 30 days [27–35] between dispensations. Treatment was interrupted for approximately 20% of the patients. The main 1-LT were imatinib (78.4%) and nilotinib (18.2%). Dasatinib was the main 2-LT prescribed (approximately 70%) and nilotinib the main 3-LT (33%). Bosutinib and ponatinib were mainly prescribed in 2-LT or a subsequent line, unlike imatinib (Figure 1). Received: 14 February 2022 Revised: 13 May 2022 Accepted: 14 May 2022