Page 266 - Haematologica Vol. 109 - July 2024

LETTER TO THE EDITOR C
Figure 1. Incidence of any-grade non-hematologic treatment-emergent adverse events and exposure-adjusted incidence rates of adverse events of special interest. (A) Treatment-emergent adverse events (TEAE) reported in ≥10% or grade ≥3 TEAE in ≥5% of patients treated with zanubrutinib (N=1,550) are shown. TEAE were defined as adverse event (AE) preferred terms with an onset date or worsening in severity from baseline (prior to treatment) at or after the first dose of zanubrutinib and up to the last zanubrutinib dose date + 30 days or initiation of new anticancer therapy, whichever occurred first. Worsening of an event to grade 5 beyond the last zanubrutinib dose date + 30 days and prior to initiation of new anticancer therapy was also considered treat- ment emergent. (B, C) The AE of special interest (AESI) shown are grouped terms. The preferred terms for the TEAE included in each AESI category are as previously published,1 except for “opportunistic infections,” which included preferred terms under the narrow standardized MedDRA query “opportunistic infections.” Exposure-adjusted incidence rates (EAIR) were calculated as the number of patients who experienced a specific AESI divided by the total exposure time (i.e., the first dose date to the first event date or to the treatment-emergent period end date if there was no event) in years for all patients and then multiplied by 100 to express as persons per 100 person-years. Of note, EAIR assumes that the risk of an event occurring is constant over time and serves as an additional means for evaluating safety events. In (B), data are shown for the total pooled zanubrutinib population (N=1,550). In (C), data are shown for the comparative analysis of patients treated with zanubrutinib (N=425) or ibrutinib (N=422) as part of the randomized studies ASPEN (cohort 1) or ALPINE. The Poisson regression model was used to compare EAIR between treatment groups, with the number of patients who experienced events as the dependent variable and log(exposure time) as the offset. The P value based on χ2 test was reported. All statistical tests were two-sided, with P<0.05 considered significant; no adjustments for multiple comparisons were made. COVID-19: coronavirus disease 2019.
Importantly, across all ten trials, no zanubrutinib-treated patients discontinued due to hypertension.
In the comparative analysis, all EAIR of AESI, except for neutropenia, were numerically lower in patients treated with zanubrutinib versus ibrutinib (Figure 1C). Although the neutropenia EAIR was slightly higher with zanubrutinib, the infection EAIR was significantly lower (64.81 vs. 79.63 persons per 100 PY; P=0.0098) with zanubrutinib, even after excluding COVID-19-related infection terms (54.48 vs. 69.96 persons per 100 PY; P=0.0029). The EAIR for afib/flutter was also significantly lower with zanubrutinib versus ibrutinib (P<0.0001). The hypertension EAIR was also reduced in patients receiving zanubrutinib versus ibrutinib (P=0.0610). AESI EAIR analyzed over time were relatively constant or decreased with zanubrutinib (Figure 2; time to first event data, Online Supplementary Figure S1). In the comparative analysis, AESI EAIR over time were numerically lower with zanubrutinib versus ibrutinib, except for neutropenia, which
was higher in the first 12 months of treatment and is con- sidered an on-target effect of BTK inhibition.6 However, this was not accompanied by an elevated infection EAIR nor was neutropenia a substantial cause of discontinuation (7.1% [3/42]). Increases of >10 persons per 100 PY in the EAIR for anemia and hemorrhage were observed with ibrutinib between the >24-month exposure intervals. In contrast, the greatest increase between consecutive intervals with zanubrutinib was 4.1 persons per 100 PY (hemorrhage).
At all treatment intervals evaluated, the EAIR for afib/ flutter was 6.7 to 13.6 persons per 100 PY higher with ibrutinib than with zanubrutinib. In the present analysis, the afib/flutter EAIR was relatively constant in the first 2 years of ibrutinib exposure but steadily increased with each subsequent year of treatment. In contrast, the EAIR in patients who received zanubrutinib was much lower at all intervals, with only slight increases observed after 2 to 3 years of exposure. This relatively stable incidence of
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