Duration of Therapy in Patients with Waldenström Macroglobulinemia Undergoing Dose Reductions of First-Line Ibrutinib: A Real-World Analysis
Authors: Sarosiek Shayna R , Salkar Monika , Agatep Barnabie , Jones Barton , Pacia Michelle , Saifan Chadi , Bacchus Shaffee , Karve Sudeep , Paludo Jonas 
Published: December 2024

Background: Continuous single-agent ibrutinib (Ibr) treatment has been associated with extended progression-free survival in patients with Waldenström macroglobulinemia (WM). Previous clinical studies have shown that Ibr dose reductions (DRs) improved or resolved adverse events (AEs) in most patients, while hematologic responses were sustained. However, real-world data on long-term outcomes for patients with WM undergoing Ibr DR in first-line (1L) settings remain limited.
Methods: Medicare Fee-for-Service (FFS) medical and pharmacy records were used to identify patients diagnosed with WM who initiated 1L single-agent Ibr (420 mg/day) or 1L Ibr + rituximab from January 1, 2015, to September 30, 2022. Observed patients were enrolled in Medicare FFS ≥12 months before and after 1L treatment initiation and had ≥1 qualifying post-treatment initiation AE of special interest (AESI; both prevalent and incident AEs), as identified via ICD-9-CM or ICD-10-CM diagnosis codes. Ibr DR was defined as a reduction of the starting dose (420 mg/day) following the first AESI during 1L treatment. Patients without an Ibr DR were defined as those who had received Ibr at 420 mg/day during 1L treatment. Patients without an AESI post-Ibr initiation and prior to DR were excluded from the analysis. Demographics, clinical characteristics, time to AESI, duration of therapy (DOT), and time to treatment discontinuation (TTD) were assessed in cohorts with and without DRs. DOT was measured at the date of Ibr treatment initiation through treatment discontinuation (end of 1L treatment). Patients were considered to have discontinued treatment if they received a subsequent systemic therapy after the 1L regimen, had a gap of ≥120 days with no systemic therapy following the last administration, or died while on the 1L regimen. Patients without a discontinuation were censored at the earliest date of end of follow-up or disenrollment. TTD was analyzed using the Kaplan-Meier method. A Cox proportional hazards model adjusted for patient demographics and clinical characteristics was used to identify factors associated with treatment discontinuation.
Results: A total of 407 patients with WM were included in the analysis (DR, n=55 [14%]; no DR, n=352 [86%]). Patients in the DR and no DR cohorts, respectively, had similar a median age (78 years vs 77 years), Charlson Comorbidity Index score (3 vs 4), and prevalence of the most common baseline comorbidities: hypertension (67% vs 68%) and cardiovascular conditions (31% vs 28%). The median time between treatment initiation and the occurrence of the first AESI was 89 days versus 76 days, and total Ibr DOT mean ± SD [median] was 786.1 ± 692.6 [661] days versus 454.8 ± 510.4 [279] days (P=0.001) for DR cohort versus no DR cohort. Following DR, patients remained on Ibr for mean ± SD [median] 336.0 ± 422.8 [179] days until the end of 1L therapy. After adjusting for variations in baseline characteristics, patients with a DR had significantly longer TTD post-treatment initiation than those without a DR (median TTD, DR vs no DR: 22.5 months vs 9.3 months; adjusted HR [95% CI], 0.52 [0.37-0.72]).
Conclusion: This real-world evidence study suggests that implementing DRs to manage AEs can be a valuable strategy in supporting patients with WM to remain on 1L Ibr longer, thus maintaining beneficial clinical outcomes. These findings are consistent with previous studies, demonstrating that Ibr DRs help to improve tolerability while maintaining treatment efficacy.