PracticeUpdate Conference Series ASH 2018

Older PatientsWithCLL See Better OutcomesWith IbrutinibThanChemoimmunotherapy But toxicities may pose a problem for some elderly patients. O lder patients with chronic lymphocytic leukemia (CLL) experience better progression-free survival (PFS) rates when given the targeted therapy ibrutinib rather than the combination regimen of bendamustine plus rituximab, according to results of the phase III Alliance A041202 study. yet reach statistical significance,” Dr. Woyach said during a press conference. “Ibrutinib is associated with toxicities, including serious toxicities, so future studies (including the successor to this study) are focus- ing on whether we can limit time on drug by combining targeted therapies,” she told Elsevier’s PracticeUpdate .

Until now, the combination of the chemo- therapy drug bendamustine and the immunotherapeutic rituximab has been considered among the most effective therapies among older patients with CLL. While ibrutinib has been approved for use in the United States as a first-line therapy for CLL since 2016, it had only been previously compared with chloram- bucil in this setting.

She specified that there “are toxicities that are more common with ibrutinib compared to [bendamustine plus rituximab], espe- cially atrial fibrillation and hypertension. So, while ibrutinib is more effective, there may still be patients who are more appro- priate for [bendamustine plus rituximab].” Notably, as many as 17% of patients who received ibrutinib developed atrial fibrillation. Hypertension was also significantly more common among patients receiving ibrutinib: 29% of those receiving ibrutinib and 34% of those receiving ibrutinib plus ritux- imab experienced hypertension, compared with 15% of those receiving bendamustine plus rituximab (P < .001). According to Dr. Woyach, the elevated rates of adverse events seen with ibrutinib in this trial, which included older CLL patients, highlight the fact that older patients are typically under-repre- sented in clinical trials of therapies for CLL.

Dr. Jennifer A. Woyach

The researchers enrolled 547 patients between 2013 and 2016 who had previously untreated, symptomatic CLL and who ranged in age from 65 to 89 years of age. The median age was 71 years old and 67% of patients were men. Participating patients were randomized such that 183 received bendamustine plus rituximab, 182 received ibrutinib alone, and 182 received ibrutinib plus rituximab. Patients were followed from randomization for a median of 38 months. The predefined primary endpoint of the study was 2-year PFS. The best 2-year PFS rates were observed with ibrutinib plus rituximab (88%; 95% CI 81% to 92%) and ibrutinib alone (87%; 95% CI 81% to 92%), followed by bendamustine plus rituximab (74%; 95% CI 66% to 80%). Overall response rates were 94% in patients receiving ibrutinib alone, 93% in patients receiving ibrutinib plus rituximab, and 81% in patients receiving bendamustine plus rituximab. There were no significant differences in overall survival among the three treatment groups at 2 years. This study, which was the first direct comparison of outcomes between ibrutinib and the chemoimmunotherapy combination regimen, also demonstrated that adding rituximab to ibrutinib does not confer additional benefits not seen with ibrutinib alone. “Our results establish that ibrutinib should be a standard of care for older patients with CLL. It is more effective than the best avail- able chemoimmunotherapy regimen,” study presenter Jennifer A. Woyach, MD, of The Ohio State University in Columbus, said during a press conference. “The findings also suggest that when designing trials for CLL in older patients, ibrutinib is the efficacy standard by which other drugs should be measured.” Upon subgroup analysis, there was only one set of patients whose PFS did not meet the significance threshold for favoring ibrutinib over bendamustine plus rituximab: patients who had methylated Zap-70 (HR 0.81; 95% CI 0.45–1.48). “Ibrutinib is superior to bendamustine plus rituximab throughout, except for in that subgroup of patients with methylated Zap-70, which equates to mutated IGBH, where the trend is towards improved progression-free survival with ibrutinib but does not

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© ASH/Todd Buchanan 2018

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