By Sarah LaCorte
A study presented at the ASCO 2020 Annual Meeting used a simple global adverse event score to compare toxicity burden of ibrutinib (IB) versus the combination of bendamustine with rituximab (BR) in older patients with chronic lymphocytic leukemia (CLL) (Abstract e20004).
Ibrutinib, a Bruton's tyrosine kinase inhibitor, was FDA-approved for the treatment of patients with untreated chronic lymphocytic leukemia (CLL) in 2016. Since then, it has shown superior progression-free survival compared with bendamustine and rituximab in CLL patients 65 years or older in a randomized phase III trial (N Engl J Med 2018; DOI: 10.1056/NEJMoa1812836).
In the phase III trial, patients receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR patients had higher rates of hematologic toxicity. The study showed that differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons.
Amy S. Ruppert, MAS, PhD, from The Ohio State University Comprehensive Cancer Center, and her research team wanted to investigate these adverse event comparisons further. To do so, they used an exploratory approach to compare toxicity burden between arms and provide assessment of atrial fibrillation, hypertension and infections (INF) in a clinical trial funded by the NIH (NCT01886872).
The researchers studied 537 patients as they began therapy, with 176 taking BR and 361 on IB. The 68 percent of patients on BR completed all 6 cycles. Adverse events (AE) were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. Ruppert and her team then calculated a simple global AE score for each patient by summing grades of all grade 1-4 AEs and dividing by the number of cycles over which AEs were submitted.
At a median follow-up of 38 months, 64 percent of patients remained on IB. Treatment discontinuation for AE occurred in 10 percent and 14 percent of BR and IB patients. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01).
In the IB arm, researchers found the median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Grade 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. A total of 100 patients (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 grade 5 INF (3 BR, 4 IB), however none confirmed fungal.
The researchers concluded from the results that there was no difference in treatment discontinuation rates for AE. The overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for patients receiving BR. Ruppert and authors stated that the risk of severe AFIB, HTN, and INF is highest in the first year of IB. Overall, the main takeaway from the study was that a simple AE score provides valuable information, especially when evaluating regimens of varying length.
Sarah LaCorte is associate editor.