Ibrutinib Dose Adherence and Therapeutic Efficacy in Non-Hodgkin Lymphoma: A Single-Center Experience

Abstract

Background: As oral targeted agents, such as ibrutinib, become more widely used understanding the impact of suboptimal dosing on overall and progression-free survival outside of clinical trials is imperative. Methods: Data on ibrutinib discontinuation, dose reductions and treatment interruptions were collected on 170 non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL n=115, 64%) patients treated with ibrutinib at a single institution. Ibrutinib dose adherence was calculated as the proportion of days in which ibrutinib was administered out of the total number of days ibrutinib was prescribed in the first 8 weeks. Kaplan-Meier curves and log-rank tests were used to compare conditional survival outcomes beyond 8 weeks in patients ≥80% dose adherence and patients <80% dose adherence. Results: Median overall survival among those that discontinued for progression was poor (n=51, 1.7 months, 95%CI 0.3–3.7). Lower dose adherence (<80%) was associated with significantly worse progression-free (p=0.002) and overall survival (p=0.024). However, among CLL patients, lower dose adherence was only associated with worse progression-free survival (p=0.043). Patients with early dose reductions had significant worse PFS (p=0.004) and OS (p=0.014). Patients with dose interruptions lasting > 1 week had worse PFS (p=0.047) but not OS (p=0.577). Conclusion: In this observational study, NHL and CLL patients demonstrated poor outcomes after discontinuing ibrutinib for disease progression. The inferior survival related to suboptimal dose adherence of ibrutinib was predominantly due to early dose reduction. These data confirm poor survival in CLL and lymphoma patients alike after ibrutinib discontinuation and support recommendations for full dose at treatment initiation.

Ibrutinib dose modifications in the management of CLL

“…1). Five papers were included in the final analysis which included one clinical trial and four realworld studies [9][10][11][12][13]. Out of the fifty-four studies excluded, thirty-nine were not relevant to ibrutinib dosage, four studies had been previously identified, two were pharmacokinetic studies, seven were phase I clinical trials, and two were not relevant to CLL (Fig.…”

“…William et al analyzed the reasons for ibrutinib discontinuation in patients with non-Hodgkin lymphoma (NHL) and CLL [12]. We did not include this study in Table 2 given the more diverse patient population with reported data combining both CLL and NHL patients.…”

“…al. attempted to evaluate the impact of ibrutinib dose reductions and interruptions on outcomes in patients with CLL (51% high risk) and NHL [12]. In the CLL cohort, 29% of patients had a reduction in dose, and 57.6% had at least one transient dose interruption (of any length) over the study period.…”

Impact and Intricacies of Bone Marrow Microenvironment in B-cell Lymphomas: From Biology to Therapy

“…One emerging hypothesis is that ibrutinib disrupts the molecular signaling cascades in the BM-tumor microenvironment and also reduces T-cell pseudo-exhaustion [126]. This could provide an explanation for why drugs like ibrutinib result in favorable OS in several lymphomas as compared to other single-agent drugs [127,128]. However, developing agents that can specifically target therapeutic agents into the BM and disrupt BM communication with high efficacy without producing non-specific systemic toxicity has been a challenge and is an area that needs more investigation.…”

Pharmacists’ Role in Managing Patients with Chronic Lymphocytic Leukemia

“…When a pharmacist is involved in follow-up and adherence management for oral TKIs in CML, adherence improves from 66% to 88% [24]. Similarly, a single-center retrospective analysis of CLL and non-Hodgkin's lymphoma patients on ibrutinib demonstrated that poor medication adherence (<80%) was associated with worse progression-free survival (PFS) in the subset of CLL patients [25]. In fact, missing just eight consecutive doses of ibrutinib is an important predictor of PFS and further highlights the need for close follow-up and continuity of care [26].…”