# Early Ibrutinib Dose Modifications in CLL: A Post Hoc Analysis of the Real-World EVIdeNCE Study

## TL;DR

The study finds that early dose reductions of ibrutinib in CLL patients are influenced by comorbidities, but maintaining high dose intensity improves outcomes.

## Contribution

The study provides real-world evidence on how early dose modifications of ibrutinib affect treatment outcomes in CLL patients.

## Key findings

- Higher comorbidity burden and poor performance status are linked to initial dose reductions of ibrutinib.
- Most patients maintained a high RDI rate (≥80%) during the first three months of therapy.
- 100% RDI at 90 days was initially associated with better PFS but lost significance after adjusting for patient factors.

## Abstract

This analysis evaluated treatment relative dose intensity (RDI) among patients with chronic lymphocytic leukemia receiving ibrutinib, administered either as first-line or subsequent lines of therapy, in a real-world setting. The findings indicate that a higher burden of comorbidities and poorer performance status are associated with initial dose reductions. Nonetheless, most patients maintained a high RDI rate (≥80%) during the first three months of therapy. While a 100% RDI rate at 90 days was initially associated with improved progression-free survival (PFS) in patient subsets with adverse features, this association was attenuated after adjusting for patient-specific factors such as age, comorbidities, and cardiovascular history. These results highlight the importance of individualized management of ibrutinib therapy, taking into account disease biology and comorbid conditions, to optimize clinical outcomes.

Background/Objectives: Ibrutinib has significantly improved outcomes in chronic lymphocytic leukemia (CLL), but evidence from real-world settings on the impact of early dose modifications and consequent relative dose intensity (RDI) maintenance on survival outcomes is limited. This study evaluated the impact of dose reductions and RDI maintenance during the first 90 days of treatment on clinical outcomes in patients with CLL receiving ibrutinib in routine clinical practice. Methods: A post hoc analysis of the prospective observational EVIdeNCE study (NCT03720561) was conducted, including 275 patients with CLL treated with ibrutinib. Baseline clinical and biological factors associated with early dose modifications and RDI maintenance over the first 90 days were analyzed. Cox proportional hazards models, adjusted for disease- and patient-related covariates, were applied to assess associations with overall survival (OS) and progression-free survival (PFS), using a landmark approach to control for immortal time bias. Results: Patients with higher comorbidity burden—indicated by higher Cumulative Illness Rating Scale scores and poorer ECOG performance status—were more likely to undergo early dose reductions. RDI declined slightly over 90 days, but most patients maintained ≥80% of their RDI. The impact of disease-risk factors appeared more clearly when assessing the relationship between 100% RDI at 90 days and PFS, with ibrutinib at 100% RDI associated with improved PFS (hazard ratio, HR 2.26, 95% confidence interval, CI: 1.23–4.15). However, after adjusting for patient characteristics (e.g., comorbidity burden and cardiovascular history), the 100% RDI rate no longer showed a statistically significant effect on PFS (HR 1.84, 95% CI: 0.93–3.63). Conclusions: Baseline comorbidities and functional status drive early dose modifications, but these adjustments and RDI variability do not independently impact survival outcomes, confirming the overall tolerability of ibrutinib in real-world CLL management.