Pacia, Michelle

Background: Ibrutinib is the only Bruton tyrosine kinase inhibitor (BTKi) with once-daily oral capsule, tablet, and oral suspension formulations approved in the United States across indications of chronic lymphocytic leukemia/small lymphocytic lymphoma, Waldenström macroglobulinemia, and previously treated chronic graft-versus-host disease, and for mantle cell lymphoma in Europe. Patients with difficulty swallowing capsules or tablets may require alternative formulations or administration options to optimize treatment. Objectives: To evaluate the relative bioavailability of ibrutinib oral suspension relative to capsule or tablet formulations and to examine compatibility for optimal administration methods. Methods: Relative bioavailability of ibrutinib oral suspension was evaluated in healthy volunteers or patients in comparison to capsule or tablet formulations. Dose recovery and delivery, presence of impurities, particle size, and hold time were evaluated after in vitro mock oral suspension administration via syringe and nasogastric and percutaneous endoscopic gastrostomy (PEG) tubes. Results: Clinical bioavailability was comparable for ibrutinib oral suspension and capsules (420 mg/day) under the fasted state in healthy volunteers. Dose-normalized pharmacokinetic values were similar across ibrutinib formulations in patient studies. All evaluated enteral tubes achieved 90%–110% ibrutinib dose recovery regardless of tube type or syringe after 2 × 3 mL water rinses. Oral suspension preservative may be adsorbed into enteral tubes after a 60-minute hold time. Conclusion: Ibrutinib oral suspension bioavailability was comparable with ibrutinib tablet and capsule formulations. When dosed via standard enteral tube administration methods, ibrutinib oral suspension is stable and compatible with polyurethane, silicone, or polyvinyl nasogastric or PEG tubes. To ensure full dose recovery and prevent drug preservative adsorption into tubes, ibrutinib oral suspension should be administered immediately and followed by two rinses of 3 mL of water each. Ibrutinib oral suspension is a viable BTKi treatment option for patients requiring or preferring alternatives to oral capsules and tablets.

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.

Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.

Background: In patients with Waldenström macroglobulinemia (WM), continuous once-daily ibrutinib-based therapy has been associated with long-term progression-free survival. In addition, patients who continued ibrutinib-based treatment had better survival outcomes than those who discontinued treatment within the first few years. Evidence based on a single-center retrospective study suggests that dose reduction (DR) can be used to effectively manage ibrutinib-related adverse events (AEs) and avoid early treatment discontinuation. However, real-world data on outcomes in patients with WM after ibrutinib DR are limited. In this real-world study, we analyzed short-term (1-year follow-up) dosing patterns and time to treatment discontinuation (TTD) in patients with WM, with and without DR, who were receiving first-line (1L) ibrutinib. Methods: Medicare Fee-for-Service closed-claim medical or pharmacy records were used to identify patients diagnosed with WM who initiated 1L single-agent ibrutinib (420 mg/day) from January 2014 to December 2020. Observed patients were enrolled in Medicare ≥12 months before and after ibrutinib initiation and had post-initiation AEs (both prevalent and incident AEs with DR recommendation from the US Prescribing Information), as identified via ICD-9 or ICD-10 codes. Ibrutinib DR was defined as a reduction of the starting dose following the first AE within the 1-year follow-up period. Patients without a DR were defined as those who had received ibrutinib 420 mg per day during the 1-year follow-up period. Patients with a DR in the absence of AEs and patients with a DR prior to any AE were excluded from the analysis. Demographics, clinical characteristics, time to first AE, and TTD were analyzed among cohorts with and without DR. TTD was defined and evaluated as the time from first observed AE after ibrutinib initiation to the earliest occurrence of (1) a gap of >120 days between the end of 1L therapy and the follow-up period, (2) initiation of a next line of therapy, or (3) death. TTD was analyzed using Kaplan-Meier methodology, log rank test, and a Cox proportional hazards model adjusted for baseline and time-varying covariates. Results: We identified 404 patients (DR, n = 58 [14%]; no DR, 346 [86%]). Overall, 249 patients (62%) were men, 267 patients (66%) had hypertension, 55 patients (14%) had atrial fibrillation, and 114 patients (28%) had other cardiovascular conditions at baseline. The mean ± SD age at baseline was 77 ± 8 years. In both cohorts, the median Charlson Comorbidity Index was 4.0. Among the 404 patients, mean ± SD time from ibrutinib initiation to first AE was 28 ± 44 days. Mean ± SD time between first AE and DR was 137 ± 102 days. Mean TTD was 8.3 months (DR) and 6.2 (no DR) ( P = 0.018; Figure). At 6 and 12 months of follow-up, fewer patients with DR discontinued treatment compared with patients without DR (6 months: 24% vs 46%, P = 0.002; 12 months: 36% vs 50%, P = 0.064). After controlling for baseline and time-varying demographic and clinical characteristics, patients with DR were not significantly more likely to discontinue treatment compared with patients without DR (hazard ratio [95% CI], DR vs no DR: 1.24 [0.86-1.78]). Conclusion: These short-term (1-year follow-up) findings suggest TTD was not impacted by DR of ibrutinib following AEs. Thus, ibrutinib DR can be an effective strategy to manage AEs while maintaining clinical efficacy. Of note, causal association between AE and subsequent DR cannot be inferred from the claims database due to the cross-sectional nature of this study.