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Real World Treatment Practices for Chronic Lymphocytic Leukemia in Japan: an Observational Database Research Study (CLIMBER-DBR)

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Real World Treatment Practices for Chronic Lymphocytic Leukemia in Japan: an Observational Database Research Study (CLIMBER-DBR) lin Journal of clinical and experimental hematopathology JC Vol. 61 No.X, XXX-XXX, 2021 EH xp ematopathol Original Article Real World Treatment Practices for Chronic Lymphocytic Leukemia in Japan: An Observational Database Research Study (CLIMBER-DBR) Jun Takizawa,1) Koji Izutsu,2) Hirokazu Nagai,3) Kenjiro Fukase,4) Maki Nakamura,4) Masahisa Jinushi,4) Junji Suzumiya5) There are limited real-world data on the treatment practices and healthcare resource utilization associated with chronic lympho- cytic leukemia (CLL) in Japan. In this study (CLIMBER-DBR), we performed retrospective analyses of the Japanese Medical Data Vision database, and extracted data for 2562 patients with newly diagnosed CLL (CLL-1 cohort) and 930 patients receiv- ing CLL treatment (CLL-2 cohort) registered between March 1, 2013 and February 28, 2018. The median follow-up in the CLL-1 cohort was 721 (quartile 1–3: 363–1267) days and the median time to initial (first-line) treatment was 1331 (quartile 1–3: 189–not reached) days. In the CLL-2 cohort, the most frequently used regimens were fludarabine alone (17.7%), cyclo- phosphamide alone (13.7%), and bendamustine/rituximab (8.2%). The median (quartile 1–3) times to second-line and third- line treatments were 1066 (273–not reached) and 1795 (631–not reached) days, respectively. The CLIMBER-DBR was the first database research study to assess current treatment practices for CLL in Japan, where the treatment patterns were driven by the approval/reimbursement status of drugs in the study period. Our study provides an important benchmark for future studies of CLL in Japan. Keywords: Chronic lymphocytic leukemia, Japan, real world, treatment patterns, resource utilization Lymphocytic Leukemia guidelines.8 The JSH guidelines INTRODUCTION recommend a “watch and wait” approach initially for patients Chronic lymphocytic leukemia (CLL) is a relatively rare without active disease. For patients who do require treat- disease, with an annual age-adjusted incidence of approxi- ment, the recommended regimens include ibrutinib, fludara- mately 0.2 cases per 100,000 people in Japan1 and an esti- bine + cyclophosphamide rituximab (FCR) and bendamus- mated 2000 patients nationwide.2 It is estimated that CLL tine + rituximab (BR). accounts for ~3% of all cases of malignant lymphomas in In recent years, there have been marked changes to the Japan,1,3 a much lower rate than that of ~25% in Western treatment landscape in Japan, with the approval of rituximab countries.4 for CLL in 2019 (previously approved for B-cell non-Hodg- CLL has a long clinical course, and avoiding treatment- kin lymphoma in 2003), bendamustine in 2016, ibrutinib for related deaths or adverse events (AEs) is an important aspect relapsed/refractory CLL in 2016 and as first-line treatment in of its management. Therefore, it is important to start treat- 2018, and venetoclax for relapsed/refractory CLL in 2019.5 ment by identifying the disease stage and activity. A recent Overseas, other new treatments have been incorporated into review proposed an evolution of initial CLL therapy in the 2020 National Comprehensive Cancer Network Clinical Japan,5 extending the previous 2018 guidelines issued by the Practice Guidelines,9 which recommend ibrutinib, acalabruti- Japanese Society of Hematology (JSH),6,7 which are now nib ± obinutuzumab, or venetoclax + obinutuzumab as first- mostly in line with the International Workshop on Chronic line treatment, of which only ibrutinib is approved in this set- Received: September 11, 2020. Revised: February 18, 2021. Accepted: April 4, 2021. J-STAGE Advance Published: June 5, 2021 DOI: 10.3960/jslrt.20044 1)Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan, 2)Department of Hematology, National Cancer Center Hospital, Tokyo, Japan, 3)Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan, 4)AstraZeneca K.K., Osaka, Japan, 5)Innovative Cancer Center, Shimane University Hospital, Izumo, Japan Present affiliation: JS, Department of Hematology, Koga Community Hospital, Yaizu, Japan Corresponding author: Jun Takizawa, MD, PhD, Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, 1-757 Asahimachi-dori, Chuo-ku, Niigata, 951-8510, Japan. E-mail: [email protected] Copyright © 2021 The Japanese Society for Lymphoreticular Tissue Research This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. 1 Takizawa J, et al. ting in Japan. International Classification of Diseases 10th Edition (ICD- Currently, there is limited evidence on how physicians in 10) codes and treatments are recorded using Anatomical Japan treat CLL patients in real-world settings. In particular, Therapeutic Chemical Classification (ATC) codes. it is unclear how long physicians wait until they prescribe Patients and definition of study cohorts first-line treatment for patients with newly diagnosed CLL. In addition, it remains largely obscure which treatment regi- We searched the MDV database for patients with an ICD- mens are used or preferred by physicians in real-world prac- 10 diagnosis code of C83 for non-follicular lymphoma or tice, especially considering the recent changes to the treat- C91 for lymphocytic leukemia, filtered with the Japanese ment landscape in Japan.5 Information is also needed on the claim code ‘8847359’, with a study period of March 1, 2013 impact of CLL on healthcare resource utilization and to February 28, 2018. As a “watch and wait” approach is expenditure. often appropriate for patients without symptoms, we estab- Some insight into the real-world management of CLL lished two cohorts, CLL-1 and CLL-2, which were defined as came from a US study using a commercial healthcare insur- follows: The CLL-1 cohort comprised patients with a diagno- ance claims database of patients diagnosed between July sis of CLL recorded during the study period who were aged 2012 and June 2015.10 In that study, BR was the most com- ≥18 years at diagnosis. The objectives of this cohort were to mon first-line treatment regimen (28.1%), with a median time assess the characteristics of patients with newly diagnosed to initial (first-line) treatment (TIT) of 3.3 months (versus CLL and to determine the TIT from diagnosis. The CLL-2 16.4 and 7.7 months for ibrutinib and rituximab, respec- cohort comprised patients with a diagnosis of CLL who tively).10 The authors also revealed a high cost of treating received treatment for CLL during the study period at ≥18 CLL, with mean monthly all-cause and CLL-related costs of years of age. The objectives of this cohort were to assess the $7943 and $5185, respectively, among patients prescribed characteristics of patients who received antineoplastic agents systemic treatment. as first-line or second-/third-line treatments, and to evaluate Similar data are therefore needed in Japan in order to bet- the characteristics of patients under treatment, and the times ter understand the current clinical practices for CLL and its from the first prescription of antineoplastic treatment to first healthcare resource utilization. Accordingly, the CLIMBER- subsequent (second-line) treatment (TFST) and second sub- DBR study was performed with the objectives of determining sequent (third-line) treatment (TSST). Both cohorts were the characteristics, treatment patterns, and healthcare also used to evaluate healthcare resource utilization and fre- resource utilization of CLL in a real-world clinical setting in quency of Richter’s transformation. The index date was Japan using a secondary data source. defined as the date of the first diagnosis of CLL in the CLL-1 cohort and as the date of first treatment in the CLL-2 cohort. Some overlap of the CLL-1 and CLL-2 cohorts was expected MATERIALS AND METHODS because of the possibility that some patients were first diag- nosed and received antineoplastic treatment in the study Ethics period; patients who were first diagnosed but did not receive The MDV database (Medical Data Vision Co., Ltd., antineoplastic treatment in the study period were included in Tokyo, Japan), the database used in this study, comprises data the CLL-1 cohort. Patients who were diagnosed before the collected under contract from the participating institutions. study period but who received treatment during the study All data regarding personal information were anonymized by period were included in the CLL-2 cohort. We excluded each institution and the database does not include the loca- patients aged <18 years at the index date, patients with an tion of institution. Therefore, patient information cannot be index date outside the study period, and patients who under- retrieved from the database. This complies with the Act on went stem cell transplantation before the index date. the Protection of Personal Information in Japan. The con- Measures and outcomes tracts between MDV and the institutions permit this MDV database to be used for research purposes. The study was All data and clinical records, including diagnostic proce- also approved by the Institutional Review Board of the dures, were retrospectively collected from the MDV data- Clinical Research Promotion Network-Japan (Osaka, Japan; base. Follow-up data were recorded for all patients until approval number: 7625-NIS-8326-00; date: June 20, 2019). February 28, 2019, or until their last recorded visit or death. Baseline data included age, sex, body weight, and modified MDV database
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