Inflammatory/Immune Adverse Events in Chronic Myeloid Leukemia Patients during Treatment with Bosutinib
Authors: Agostani Elena , Tassistro Elena , Antolini Laura , Gambacorti-Passerini Carlo 
Published: December 2024

Introduction
Bosutinib, a third-generation tyrosine kinase inhibitor (TKI), is effective in treating Chronic Myeloid Leukemia (CML) patients who are resistant or intolerant to previous TKIs. Unlike other TKIs, bosutinib lacks inhibition of c-KIT and PDGFR, potentially contributing to its unique tolerability profile. It targets Bcr/Abl and SRC kinases, particularly Lyn, which plays a crucial role in immune response, particularly in myeloid cells and B lymphocytes, where it is involved in signaling cascades essential for self-tolerance and anergy. The susceptibility of Lyn -/- mice to lupus-like autoimmune disorders and the deregulation of Lyn- dependent pathways in patient with lupus were previously shown. The study aims to assess the time-adjusted rate (TAR) of inflammatory/immune-related adverse events (irAEs) in bosutinib-treated patients.
Methods
This retro-prospective observational cohort study was conducted involving 60 CML patients treated with bosutinib at San Gerardo Hospital from 2006 to 2020, with a minimum follow-up of three months, as part of bosutinib registration trials. The study also included 10 imatinib-treated patients enrolled as a control group in the same clinical studies. Data on adverse events (AEs) were collected and classified according to CTCAE terminology (v5.0). Patient characteristics were described using median and interquartile ranges for continuous variables and frequencies and percentages for categorical variables. The distribution of irAEs was displayed using a bar plot. The TAR of first and repeated AEs was calculated along with 95% confidence intervals (CI) using an exponential model. The cumulative incidence probability of the first AE was estimated using the Kaplan-Meier method. Analyses were performed with Stata 15 software.
Results
Of the 60 bosutinib-treated patients, 34 (56.6%) were male and almost all the patients were caucasian (98.3%) with a median age of 62.8 years. The median follow-up duration was 47.9 months (IQR 38.4-121.8 months). Median bosutinib dose was 489.2 mg/day (IQR 437.1- 509.6 mg/day). IrAEs occurred in 55% of the subjects (n=33) with many experiencing multiple or recurrent events. A total of 94 irAEs were reported (2.3% of total AEs, n=4060), including giant cell arteritis, psoriasis, erythema nodosum, articular pain, pleural effusion and three cases of recurrent sterile pneumonia. Most irAEs occurred in the respiratory system (52.1%, n=49), followed by those in the musculoskeletal system and connective tissue (30%, n=28), skin/ subcutaneous tissue (8.5%, n=8), and in heart and vascular system (6.4%, n=6).Non-infectious fever occurred on 3 occasions (3.19%). The median time to the first irAE was 14.8 months (IQR: 7.1-42). The TAR for the first irAE was 14.7 events per 100 person-years, while the TAR for repeated irAEs was 28.4 events per 100 person-years. Using the Aalen-Nelson method, we calculated that the expected number of irAEs in 100 patients was 59 in the first year, increased by 21 additional AEs in the second year, and reached a total of 134 by the seventh year, remaining stable until the 12th year, which was the maximum follow-up duration. In a comparative analysis, 10 patients randomized to imatinib were used as controls. In the imatinib group the TAR for the first irAE was 8.4 events per 100 person-years. The relative risk (RR) of developing an irAE with bosutinib compared to imatinib was 1.75. For repeated irAEs, the TAR in the imatinib group was 12.01 events per 100 person-years, with an RR of 2.26 (95% CI: 0.99 - 6.32, p=0.04), indicating a significantly higher risk in the bosutinib group.
Conclusions
This is the first study to estimate the incidence of inflammatory and potentially autoimmune AEs in patients treated with bosutinib, suggesting a link to autoimmune side effects. Bosutinib's inhibition of Lyn, a critical kinase in immune response regulation, may explain the higher rate of irAEs. The findings demonstrate a significant incidence of irAEs in bosutinib-treated patients, higher than in imatinib-treated patients, despite the small sample size. These findings highlight the need for careful monitoring and management of irAEs to ensure patient safety and improve quality of life during long-term therapy. Further studies are required to confirm these initial results and explore the mechanisms underlying these adverse events.