A new analytical tool to assess the adverse event burden in older patients with CLL treated with bendamustine plus rituximab or ibrutinib regimens: based on the Alliance A041202 trial

Chronic lymphocytic leukemia (CLL) is a disease that is common in older patients and has a median age of diagnosis of 72 years. Comorbidities are often present in this patient population, which increases the risk of adverse events (AEs) with treatment and leads to disruption or discontinuation of therapy, resulting in a worse clinical outcome compared with younger patients. Myelosuppression is frequently associated with chemotherapy and chemo-immunotherapy—such as chlorambucil or bendamustine plus rituximab (BR)—in older patient populations and, in addition to CLL-associated immune dysfunction, makes these patients at increased risk for infection.

Ibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, has been shown to have superior progression-free survival (PFS) compared with BR in older patients with CLL. However, there are differences in treatment duration, as ibrutinib is typically administered continuously until disease progression, unlike chemotherapy and chemo-immunotherapy regimens that are administered for a fixed duration, and this has complicated comparisons of AEs between these regimens. Ruppert, et al. published a new AE burden score (AE_sc) in Leukemia that more accurately compares AEs across treatment groups. This new scoring system provides an additional safety analysis for patients treated on the Alliance for Clinical Trials in Oncology (Alliance; NCT01886872) A041202 study.

Methods

A041202 study design, study population, and treatments

The A041202 study was a phase III trial in patients aged ≥65 years with no prior CLL treatment. Overall, 537 patients were randomized to receive one of three treatments in a 1:1:1 ratio:

• Arm A: six 28-day cycles of BR followed by observation until disease progression (n = 176).
• Arm B: 420 mg of ibrutinib administered daily until disease progression (n = 180).
• Arm C: rituximab for the first six cycles plus 420 mg of daily ibrutinib until disease progression (n = 181).

Schedule and assessment of AEs

All AEs were graded using the Common Terminology Criteria for Adverse Events version 4.0. Mild, moderate, severe, and life-threatening AEs were allocated Grades 1–4, respectively, and Grade 5 represented death. Every AE was also assigned an attribution ranging from definitely unrelated to definitely related to treatment. All AEs were assessed every 28 days during Cycles 1–6 of treatment and then every three cycles (every 84 days) until disease progression.

The AE burden score was calculated for each patient by summating the reporting period length and grade recorded for each all-cause Grade 1–4 AE and then dividing by the length of time over which AEs were assessed.

Results

Regarding adherence to treatment and assessment schedule

Across the 537 patients, 95.7% of the expected AE assessments were performed. The proportion of patients with completed AE assessments was higher in the ibrutinib-containing arms (IBR) compared with the BR group (99% vs 87.9%, respectively; p < 0.0001). Adherence to treatment was high regardless of therapy group during the first six cycles (IBR 100% vs BR 99.6%), and remained high (98.6%) for patients in the IBR arm after the first six cycles, but declined for patients in observation following six cycles of BR (81.1%).

Regarding AE scores by treatment groups

Patients who received BR had a significantly higher AE burden in the initial six cycles of treatment vs patients who received IBR. Following six cycles of therapy, the AE burden in the IBR arm significantly decreased.  

• The median AE_sc was 2.3 (interquartile range [IQR], 1.3–5.1) in the BR arm and 4.3 (IQR, 2.7–6.6) in the IBR arm (p < 0.0001).
• In the initial six cycles of treatment, the median AE_sc was significantly greater in the BR arm (7.2; IQR, 4.2–10.2) vs the IBR arm (4.9; IQR, 3.2–8.7; p < 0.0001).
• Amongst the 325 patients who completed six cycles of IBR therapy, the median AE_sc reduced significantly from 4.7 (IQR, 2.9–7.0) in the first six cycles to 3.7 (IQR, 2.2–5.9) after six cycles (p < 0.0001).

In the observation period after BR treatment, the median AE_sc was 0.4 (IQR, 0–1.1); no AEs were reported for 72% of AE assessments. There was no significant difference in AE_sc between treatment groups (p = 0.46) when restricting AE_sc to Grade 3 or 4 AEs; however, AE_sc was still significantly greater in the first six cycles of treatment with BR vs IBR. Overall, among patients who received IBR, the AE_sc decreased after six cycles.

Regarding cumulative incidences by treatment groups

The estimated 3-year cumulative incidence of Grade 3 or higher atrial fibrillation, hypertension, and infection in patients who were treated with IBR (n = 361) was 7.7%, 25.4%, and 20.5%, respectively. By contrast, patients who were treated with IBR (n = 176) had a cumulative incidence of Grade 3 or higher atrial fibrillation of 1.1%, 1.8%, 2.4%, and 3.5% at 6, 12, 24, and 36 months, respectively.

Cumulative incidence for all grades of atrial fibrillation was higher in the IBR group compared with the BR group:

• 5.6%, 8.6%, 12.6%, and 15.4% for the IBR group at 6, 12, 24, and 36 months.
• 1.8%, 2.4%, 3.1%, and 4.2% for the BR group at 6, 12, 24, and 36 months.

The cumulative incidence of all grades of hypertension for patients who were treated with IBR was 35%, 40.3%, 47%, and 51.7% vs patients receiving BR who had cumulative incidence of 24%, 25.3%, 25.9%, and 26.8% at 6, 12, 24, and 36 months, respectively. For patients who were treated with IBR, the cumulative incidence of Grade 3 or higher infection was 8.3%, 12.8%, 18.5%, and 20.5% at 6, 12, 24, and 36 months, respectively. In the BR arm, the cumulative incidence of Grade 3 or higher infection was 8.7% at 6 months, 12.6% at 12 and 24 months, and 14.2% at 36 months. The cumulative incidence of Grade 3 or higher atrial fibrillation, hypertension, and infection increased slowly following the initial 6–12 months of IBR treatment.

Regarding discontinuation of therapy for AE

Only 30 patients began treatment with ibrutinib following disease progression with BR therapy, but the rates of Grade 3 or higher atrial fibrillation, hypertension, and infection remained consistent.

After ibrutinib discontinuation for AEs, the median PFS was 9.1 months (95% confidence interval, 3.3–23.0 months) for patients who received treatment for less than a year, and the median PFS was not reached by patients who had received treatment for more than a year.

Conclusion

Analysis of individual AE types by grade is vital to understanding safety profiles, and analytical tools such as the AE_sc and the cumulative incidence of AEs are imperative to the determination of clinical outcomes. This analysis showed that older patients with CLL that received BR on the A041202 study had an AE burden that was significantly higher compared with those that received IBR during the first six cycles of treatment. Patients who completed six cycles of IBR therapy saw a decrease of AE burden with continued treatment. The results also demonstrated that Grade 3 or higher atrial fibrillation, hypertension, and infection were highest in the first year of IBR treatment and slowly decreased thereafter. Additionally, the difference in treatment discontinuation due to AEs was not significant between the BR and IBR arms as 10% of patients discontinued BR due to AE and 14% discontinued IBR for AE; these patients were receiving a fixed six cycles of BR or IBR at a median time of 32 months. These results indicate that the AE_sc may provide a standardized framework to assess global AE burden.