A Retrospective Analysis of Treatment Patterns in Elderly Patients with Chronic Myeloid Leukemia Receiving Dasatinib or Nilotinib As Second-Line Therapy after Imatinib
Authors: Smith B. Douglas , Liu Jun , Latremouille-Viau Dominick , Zhou Zhou , Guerin Annie , Fernandez Daniel , Yi Dingdong , Wang Xufei , Wu Eric Q , Mhatre Shivani K , Keir Christopher H , Chen Lei 
Published: October 2019

Abstract
Introduction: Dasatinib and nilotinib are second-generation tyrosine kinase inhibitors (TKIs) originally approved as second-line treatment for patients with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase resistant or intolerant to imatinib. Despite the fact that one half of patients with CML are ≥65 years of age, elderly patients are often under-recruited in clinical trials and there are few studies that focus on these often medically complex patients. This study aimed to compare treatment patterns of elderly CML patients initiating dasatinib vs nilotinib as second-line TKI therapy after imatinib therapy in a real-world setting.
Methods: Elderly Medicare beneficiaries (≥65 years old) with ≥2 CML diagnoses who initiated dasatinib or nilotinib following prior treatment with imatinib were identified in the Medicare Research Identifiable Files (RIF) from 2006 to 2012. Selected patients were continuously covered by Part A (i.e., institutional claims), Part B (i.e., non-institutional claims), and Part D (i.e., drug events) for ≥6 months before and ≥1 month after the second-line TKI therapy initiation date (i.e., index date). Patients were excluded from the study if they were enrolled in a clinical trial, had a stem-cell transplant, or received chemotherapy (except hydroxyurea) within the 6 months before the index date (i.e., baseline period). Patients were classified as dasatinib users or nilotinib users based on the second-line TKI therapy. Dose decreases and increases, defined as a dose change of ≥20mg for dasatinib and ≥100mg for nilotinib compared to the initial dose, were measured from the index date up to the end of follow-up or treatment discontinuation. Treatment adherence was measured using the proportion of days covered (PDC) during the 6- and 12-month periods following the index date and among patients with continuous insurance coverage during these periods. Treatment persistence, measured between the index date and the end of follow-up, included time to treatment discontinuation (i.e., a treatment gap of ≥30 consecutive days) or switch to another TKI. Multivariate regression analyses were used to test for statistical significance while adjusting for potential confounding factors.
Results: Of the 659 patients that met the sample selection criteria, 379 were dasatinib users and 280 were nilotinib users. The average age was 76 years (inter-quartile range 70 – 81) and 62% were female. After the index date, 88% of selected patients were observed for ≥6 months and 73% for ≥12 months. The average patient follow-up was 24 months (median=22 months). Dasatinib users were more likely to start on the recommended dose compared to nilotinib users (74% vs 53%; p<.001); only 15% of dasatinib users started on a dose ≤70mg/day and 10% started on 140mg/day; also 18% of nilotinib users started on ≤400mg/day and 24% started on 600mg/day. Dose reductions were almost twice as common in dasatinib users (21% vs 11%; adjusted hazard ratio [HR]=1.94; p=.002) and dose increases were also more common in dasatinib users (9% vs 7%; adjusted HR=1.81; p=.048) compared with nilotinib users. During the 6- and 12-month periods following the index date, dasatinib and nilotinib users had similar adherence level (6-month period: average PDC=78% for dasatinib vs 76% for nilotinib, adjusted mean difference=1.19 percentage points, p=.520; 12-month period: average PDC=69% for dasatinib vs 70% for nilotinib, adjusted mean difference=-1.37 percentage points, p=.570). Nilotinib users were more persistent compared to dasatinib users as fewer patients discontinued (59% vs 67%; adjusted HR=0.79; p=.024) or switched to another TKI treatment (21% vs 29%; adjusted HR=0.72; p=.049).
Conclusion: There are little data available on treatment patterns of elderly CML patients. This study suggests that it is hard to determine the right starting dose of drug in elderly patients receiving a second generation TKI following treatment with imatinib. Interestingly, those receiving nilotinib had fewer dose adjustments (decreases or increases) and were more persistent (fewer discontinuation and switching) compared to those receiving dasatinib despite having similar levels of adherence over the first 6- and 12-month periods following the treatment initiation. Studies which focus on patients with elderly CML may help to provide better treatment guidelines for this important population.

Disclosures
Liu: Jun Liu is an employee of Harvard University which has received research funding from Analysis Group, Inc.: Employment. Latremouille-Viau:Dominick Latremouille-Viau is an employee of Analysis Group, Inc. which has received consulting fees from Novartis Pharmaceuticals Corporation: Employment. Zhou:Zhou Zhou is an employee of Analysis Group, Inc. which has received consulting fees from Novartis Pharmaceuticals Corporation: Employment. Guerin:Annie Guerin is an employee of Analysis Group, Inc. which has received consulting fees from Novartis Pharmaceuticals Corporation: Employment. Fernandez:Daniel Fernandez is an employee of Harvard University which has received research funding from Analysis Group, Inc.: Employment. Yi:Dingdong Yi is an employee of Harvard University which has received research funding from Analysis Group, Inc.: Employment. Wang:Xufei Wang is an employee of Harvard University which has received research funding from Analysis Group, Inc.: Employment. Wu:Eric Q. Wu is an employee of Analysis Group, Inc. which has received consulting fees from Novartis Pharmaceuticals Corporation: Employment. Mhatre:Novartis Pharmaceuticals Corporation: Employment. Keir:Novartis: Employment, Equity Ownership. Chen:Novartis Pharmaceuticals Corporation: Employment; Novartis: stock options Other.