Adverse event burden in older patients with CLL receiving bendamustine plus rituximab or ibrutinib regimens: Alliance A041202

Abstract

Ibrutinib has superior progression-free survival compared with bendamustine plus rituximab (BR) in older CLL patients, however, differences in treatment duration, six monthly BR cycles versus continuous ibrutinib, complicate adverse event (AE) comparisons. We introduce the AE burden score (AE_sc) to compare AEs, calculated for each patient by summing over products of reporting period length and grade for each all-cause grade 1-4 AE and dividing by the length of time over which AEs are assessed. A total of 176 patients received BR and 361 ibrutinib alone or with six cycles of rituximab. At 38 months median follow-up, 64% remained on ibrutinib. Median AE_sc was higher with BR versus ibrutinib in the first six cycles (7.2 versus 4.9, p < 0.0001). Within ibrutinib arms, median AE_sc decreased significantly to 3.7 after six cycles (p < 0.0001). 10% and 14% of BR and ibrutinib patients discontinued treatment for AEs. In ibrutinib arms, cumulative incidence of grade 3 or higher atrial fibrillation, hypertension, and infection (AEs of clinical interest) at 12 months was 4.5%, 17.5%, and 12.8%, respectively, and increased more slowly thereafter to 7.7%, 25.4%, and 20.5% at 36 months. Analytical tools including the AE_sc and cumulative incidence of AEs can help to better characterize AE burden over time. ClinicalTrials.gov identifier: NCT01886872.

Figure 1:. Sample calculation of the AE score for a typical patient receiving bendamustine plus rituximab (BR).

The AE score (AE_SC) is calculated for an individual patient by summing over the products of reporting period length and grade recorded for each AE and dividing by the length of time over which AEs were assessed. If AEs were assessed during a particular reporting period but the grade for an AE was blank, the grade of the AE was equal to 0. If AEs were not assessed during a particular reporting period, AEs from that reporting period were not used in the calculation of the AE_SC. For the purposes of this study, the AE reporting length is the difference between reporting period start and end dates divided by 28, to represent the number of 28-day cycles. In general, reporting period lengths are approximately 1 for the first 5 AE assessments, 1 or 3 for AE assessment 6 depending on whether the patient received BR or ibrutinib regimens, and 3 for assessments 7 and higher.

Figure 2:. AE score by treatment group, across all assessments/cycles, the first 6 cycles of treatment, and after 6 cycles of treatment.

Box-and-whisker plots show the distribution of AE scores for patients treated with bendamustine plus rituximab (BR) or ibrutinib regimens (IBR). Across all cycles and in the first 6 cycles of treatment, 176 patients in the BR group had AE scores and 361 patients in the IBR group had AE scores. Among those who completed 6 cycles of therapy, after 6 cycles 117 patients in the BR group had AE scores and 325 patients in the IBR group had AE scores. AE scores for six outliers are not shown in the plots (AE score of 59 with BR across all cycles and during the first 6 cycles of treatment, AE score of 34 with IBR during the first 6 cycles of treatment, AE score of 33 with BR across all cycles and during the first 6 cycles of treatment, and AE score of 29.3 with BR during the first 6 cycles of treatment) to better visualize the AE score distributions.

Figure 3:. Limited to grade 3/4 AEs, AE score by treatment group, across all assessments/cycles, the first 6 cycles, and after 6 cycles.

Box-and-whisker plots show the distribution of AE scores for patients treated with bendamustine plus rituximab (BR) and ibrutinib regimens (IBR). Across all cycles and in the first 6 cycles of treatment, 176 patients in the BR group had AE scores and 361 patients in the IBR group had AE scores. Among those who completed 6 cycles of therapy, after 6 cycles 117 patients in the BR group had AE scores and 325 patients in the IBR group had AE scores. AE scores for two outliers are not shown in the plots (AE score of 41 with BR across all cycles and during the first 6 cycles of treatment) to better visualize the AE score distributions.

Figure 4:. Cumulative incidence of atrial fibrillation, hypertension, and infection, by treatment group.

The cumulative incidence of grade 3 or higher atrial fibrillation occurring in 176 patients treated with bendamustine plus rituximab (BR) and 361 patients treated with ibrutinib regimens (IBR) is depicted (a), all grades of atrial fibrillation (b), grade 3 or higher hypertension (c), all grades of hypertension (d), grade 3 or higher infection (e), all grades of infection (f).

Figure 5:. Progression-free survival from date of off-treatment for AE.

Kaplan-Meier curves are shown for 18 patients who discontinued treatment with bendamustine plus rituximab (BR) for AE and 52 patients who discontinued treatment with ibrutinib regimens (IBR) for AE (a), and Kaplan-Meier curves for 24 patients who received less 1 year (yr) of IBR and discontinued treatment for AE versus 28 patients who received more than 1 yr of IBR and discontinued treatment for AE (b). Differences in curves were tested using two-sided log-rank tests.