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.