Female and Elderly Chronic Myeloid Leukemia Patients Often Do Not Receive an Adequate TKI Treatment
Authors: Lauseker Michael , Gerlach Roman , Tauscher Martin , Hasford Joerg 
Published: October 2019

Abstract
Introduction
For one and a half decade, tyrosine kinase inhibitors (TKI) have been the standard treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML). Recent studies have shown that elderly patients above 65 years benefit from a TKI treatment too. Since there were sporadic reports that elderly CML-patients receive less often TKI the aim of our study was to determine if the prescribing of TKI for CML in Germany follows the current recommendations, especially in the elderly. This was done by analyzing population-based claims data from the Bavarian Association of Statutory Health Insurance Physicians (Kassenärztliche Vereinigung Bayerns).
Methods
Data on ICD-10 codes as well as prescribed medication were available for about 10.5 million patients in the statutory health insurance system in Bavaria for the years 2008 to 2013. To avoid misclassification, only patients with at least two recorded diagnoses of CML over time were counted.
All analyses on daily doses of TKI in this work are based on the daily doses recommended by the EMA, i.e. 400 mg/d for imatinib, 100 mg/d for dasatinib, 300 mg twice/d for nilotinib, 500 mg/d for bosutinib and 45 mg/d for ponatinib.
Analyses were performed with R 3.1.0 and SPSS 22.
Results
1880 different CML patients were identified between 2008 and 2013.
During the six years analysed, 1,431,882 daily doses of TKI were administered. The majority of TKI doses were imatinib with 1,204,025 daily doses (84%), followed by nilotinib with 145,291 daily doses (10%) and dasatinib with 81,818 daily doses (6%). The percentage of CML patients receiving TKI increased from 55% in the first quarter year of 2008 to 72% in the last quarter year of 2013.
1534 patients were observed for at least four quarter years between 2008 and 2013. At median, they received 64 doses of TKI per quarter year. 1209 patients (78.8%) were treated with TKI. Only 711 patients (46.3%) received more than 67.5 daily doses, thereof 71 (4.6%) with more than 100 daily doses per quarter year. The latter are supposed to be patients with a high-dose imatinib treatment.
Out of the 325 patients that did not receive any TKI, 293 (90.2%) were treated with Hydroxyurea, only 14 patients (4.3%) received Interferon.
When stratifying for age group and sex, we found that for the males, the median number of daily doses in patients that actually received TKI sank from 88 doses per quarter year for patients younger than 20 years to a median of 72 daily doses for patients of 80 years and older. For women the median number of daily TKI doses was generally lower than for men. Here the highest median number of daily doses per quarter year was reached between 50 and 69 years with 80 doses and decreased to 58 in the oldest patients. However, the percentage of patients that did not receive any TKI increased steadily with age. While all patients below 20 years received TKI, 46% of the males and 43% of the women in the oldest age group of 80 years and above did not get any TKI treatment.
In total, 429 (28.0%) of the patients received any second-generation TKI. The use of second-generation TKI did not depend on age or sex.
Discussion
Our analyses have shown, that even in the most prosperous part of a highly developed country with an extensive statutory health insurance system, still a considerable number of CML patients did not receive the adequate treatment. We found that especially elderly patients were often treated with Hydroxyurea only. There might be various reasons, as especially elderly patients might suffer from other malignancies, but also an underestimation of the patient's remaining life expectancy by the physician, resulting in withholding the expensive treatment to the elderly. Besides, it was noteworthy that women received a lower median dose than men.
As it has been repeatedly shown that too low doses of treatment with TKI are accompanied with less therapeutic success, patients and physicians need to be motivated to take more care for administering the required doses over time. It has been shown that this may even be cost effective as poor adherence with TKI treatment results in higher health care costs.

Disclosures
No relevant conflicts of interest to declare.