Real-world toxicity and discontinuation risk in ibrutinib therapy: a retrospective cohort study

Background Ibrutinib is widely used in B-cell malignancies, yet real-world safety data remain heterogeneous, particularly in underrepresented regional populations. Objective To characterize the adverse-event profile and severity and explore factors associated with Grade 3–5 toxicity and permanent treatment discontinuation among patients receiving ibrutinib in routine clinical practice. Methods A retrospective cohort study was conducted at King Abdullah Medical City, Makkah, Saudi Arabia, with follow-up through December 2025. Adult patients with B-cell malignancies who received ibrutinib and had sufficient clinical documentation for safety-outcome ascertainment were included. The primary endpoint was the occurrence of at least one Grade 3–5 adverse event according to CTCAE v5.0. Secondary outcomes included dose modifications, permanent treatment discontinuation, factors associated with toxicity, and temporal adverse-event patterns. Results Among 57 patients, all 57 (100%) experienced at least one adverse event and 41 (71.9%) experienced at least one Grade 3–5 adverse event. Neutropenia and hypertension were the most frequent severe toxicities. Dose modification occurred in 47 patients (82.5%), and permanent discontinuation occurred in 17 (29.8%). In reduced Firth penalized-likelihood models adjusted for starting-dose category, pre-existing ischemic heart disease was associated with permanent discontinuation (aOR 6.25, 95% profile-likelihood CI 1.29–39.19; p = 0.023), while creatinine clearance <60 mL/min was associated with Grade 3–5 toxicity (aOR 5.53, 95% profile-likelihood CI 1.26–38.46; p = 0.022). A patient-level omnibus permutation test indicated a difference in adverse-event cluster distributions between the early (≤90 days) and late (>90 days) periods ( p = 0.004), although an equal-window sensitivity analysis comparing days 0–90 with days 91–180 was not significant ( p = 0.240). Conclusion Ibrutinib was associated with substantial toxicity and frequent treatment modification in routine clinical practice. Pre-existing ischemic heart disease and impaired renal function emerged as exploratory markers of treatment vulnerability. The temporal findings support continued surveillance throughout therapy but do not establish a phase-specific monitoring strategy.