A Patient-Centric Registry Dataset Generates Real-World Insights about Cause, Timing, Type, and Impact of Cardiotoxic Adverse Events in Chronic Lymphocytic Leukemia
Authors: Littleford Hana E. , Singh-Bulkan Nivita , Bacchus, MHS, PA-C Melissa , Kim Joseph , Martin Richard L. , Lacoste Alix M.B. , Brimble Elise , O'Brien Conner , Saltzman Larry A. , Greenberger Lee M. , Nottke Amanda 
Published: December 2023

INTRODUCTION
Chronic Lymphocytic Leukemia (CLL) is a hematological malignancy characterized by a progressive accumulation of abnormal monoclonal B lymphocytes. The treatment landscape for CLL has undergone significant changes with the introduction of novel targeted agents, notably BTK inhibitors (BTKis). While BTKis have contributed to advancements in CLL management, the class effect of cardiac-related toxicity has emerged in several clinical trials, particularly associated with the first generation BTKi ibrutinib. Our study utilizes a real-world registry dataset to quantify cardiotoxic adverse events (CT AEs) across treatment classes, and explores resulting changes in the treatment journey and disease course for CT AEs associated with ibrutinib.
METHODS
766 participants with CLL from the Leukemia and Lymphoma Society (LLS) registry had data extracted from collected medical records via the Invitae CiitizenⓇ platform, a patient-centric platform that leverages the HIPAA right-of-access to organize clinical data into a standardized, research-ready format using machine learning and human clinician review. Lines of therapy (LOTs) were generated using a proprietary logic-based algorithm, and defined as “ibrutinib” if they contained ibrutinib, “2nd-generation” if they contained a 2nd-generation BTKi (e.g. acalabrutinib), or “CD20” if they contained a CD20-targeting monoclonal antibody (e.g. rituximab). Categories were not mutually exclusive (e.g. LOT containing ibrutinib and rituximab counted as both “ibrutinib” and “CD20”). If the medical record stated that AEs resulted from only one medication in the LOT, the AE was assigned to that medication; if it was unclear which medication in a LOT caused the AE, that LOT and AE were excluded from analysis. A proprietary logic-based algorithm was used to calculate endpoints. Statistical significance was assessed using chi-square, with Bonferroni correction applied for multiple comparisons.
RESULTS
Out of 766 patients in the cohort, 411 received a total of 703 LOTs, of which 228 contained ibrutinib, 91 contained 2nd-generation BTKis, 358 contained CD20s, and 71 contained neither BTKis nor CD20s (“Other”). Ibrutinib-containing LOTs had a statistically significantly higher rate of at least one CT AE (21.5%; 49/228) as compared to LOTs containing 2nd-generation BTKis (5.5%; 5/91; p=0.002), CD20s (2.8%; 10/358; p&lt;0.00001), or Other (8.5%; 6/71; p=0.005). The 49 individuals with an ibrutinib-associated cardiac AE experienced a total of 57 events, which were then characterized for timing, pre-existing cardiac comorbidities, treatment setting, and treatment impact ( Table 1).
Ibrutinib CT AEs were not significantly concentrated in any numerical LOT, with a 22.5% (34/151) frequency in 1L, 28.6% (16/56) in 2L, and 22.6% (7/31) in 3+L settings. Individuals with a pre-existing cardiac comorbidity were neither more likely to experience an ibrutinib-associated CT AE, nor more likely to have a treatment impact if they did have a CT AE. Atrial fibrillation was more likely to result in a dose reduction, treatment hold, or discontinuation than hypertension (60% (12/20) vs. 18.2% (4/22), p=0.008); other differences were not statistically significant.
We next explored outcomes and subsequent treatments for ibrutinib-containing LOTs that did or did not have any associated CT AE ( Table 2). Outcomes for LOTs associated with a CT AE were not statistically significantly different for ToT, TtNT, CRR, or ORR (see table 2). While the overall distribution of subsequent classes of therapy was similar for those who did or did not experience a CT AE, we note that for those who had treatment discontinued as a result of the CT AE, only 2/11 switched to a 2nd gen BTKi (the remainder switched to a BCL2i-containing regimen), suggesting a potential trend towards out-of-class switching.
CONCLUSION
Our data support the established higher rate of CT AEs associated with ibrutinib compared to 2nd-generation BTKis or non-BTKi LOTs. However, in this dataset the presence of an ibrutinib-associated CT AE did not significantly alter either the patient's treatment journey or disease course overall. Future analyses will characterize the real-world incidence and impact of other types of AEs at the level of individual medications, LOTs, and medication classes.