Results from a randomized phase III study indicate that the Bruton tyrosine kinase (BTK) inhibitor ibrutinib with or without rituximab was superior to standard-of-care, upfront chemoimmunotherapy for older patients with chronic lymphocytic leukemia (CLL). Lead author Jennifer A. Woyach, MD, from the Ohio State University Comprehensive Cancer Center, presented the findings of the Alliance North American Intergroup Study A041202 as a plenary abstract at the 2018 ASH Annual Meeting, and published simultaneously in the New England Journal of Medicine.
The study is the first head-to-head comparison of ibrutinib with bendamustine plus rituximab (BR), Dr. Woyach said, “which is probably our most aggressive and most effective therapy in older [patients with] CLL.” Previously, ibrutinib was compared with chlorambucil, an earlier standard of care that is no longer routinely used in practice.
“This really changes the conversation we have with patients,” Dr. Woyach told ASH Clinical News. “Before, we could say, ‘ibrutinib is showing very impressive results, but we really don’t know how it compares with our standard chemoimmunotherapy.’ The results of this study allow us to say, ‘[ibrutinib] is better.’”
The study evaluated ibrutinib (with or without rituximab) and BR in 547 patients with treatment-naïve, intermediate- or high-risk CLL. Participants’ median age was 71 years (range = 65-89 years), and most (54%) had high-risk disease (defined as Ri stage III/IV). Twenty-five percent of patients had high-risk cytogenetics (del17p or del11q).
Participants were stratified according to disease stage (high or intermediate) and cytogenetics, then randomized to one of three treatment arms:
- arm A: BR administered in six 28-day cycles (n=183)
- arm B: ibrutinib administered orally (n=182)
- arm C: ibrutinib plus rituximab on days 1, 8, 15, and 22 of course 2 and on day 1 of courses 3-6 (n=182)
Patients were treated until disease progression or unacceptable toxicity; at the point of disease progression in arm A, patients could cross over to arm B.
Of the 547 patients who underwent randomization, 524 patients (96%) could be assessed for the primary progression free-survival (PFS) analysis (arm A = 176; arm B = 178; arm C = 170).
After a median follow-up of 38 months (range not provided), the median PFS was 41 months in arm A but was not reached in either ibrutinib-containing arm. Rates of two-year PFS also were higher in the ibrutinib-containing arms: 74 percent in arm A, 87 percent in arm B, and 88 percent in arm C. This translated to a lower risk of disease progression or death in both ibrutinib-containing arms (hazard ratio = 0.39 for arm A vs. arm B and 0.38 for arm A vs. arm C; p<0.001 for both).
Dr. Woyach noted that, at the time of presentation, there were no significant differences in overall survival (OS) among the treatment arms (p=0.87) and that median OS was not reached for any arm, “likely due to the relatively short follow-up and crossover design” of the study, she noted.
When the authors compared outcomes in patients enrolled in arms B and C, they found that the addition of rituximab did not significantly improve response or survival rates, compared with ibrutinib alone. When asked if there was a patient population that might benefit from ibrutinib plus rituximab, Dr. Woyach commented, “all the data suggest that there probably are not patients – especially in the older population – who would benefit from the combination.” However, she added anecdotally that those with autoimmune hemolytic anemia or with a higher white blood cell count might be candidates for this approach.
Grade ≥3 hematologic adverse events (AEs), including anemia, neutropenia, and thrombocytopenia, were more common in the BR group (61%) compared with the ibrutinib-alone or ibrutinib-rituximab group (41% and 38%, respectively; p<0.001). However, grade ≥3 non-hematologic AEs were more prevalent in the ibrutinib-containing arms (74% for both), compared with the BR group (63%)
The researchers observed grade 5 AEs in five (2.8%), 14 (7.8%), and 14 (7.7%) patients, respectively, in each arm; two (1.1%), seven (3.9%), and four (2.2%) patients died in each arm, respectively.
The safety profile might limit the use of ibrutinib in the entire population of older patients, the authors cautioned. “BTK inhibition is not without toxicity in this age group, including significant toxicity, so close monitoring is important,” Dr. Woyach said. “Strategies to limit toxicity through the use of more selective BTK inhibitors or potentially limiting the duration of therapy are also important areas to explore.”
The authors report financial relationships with Pharmacyclics, Janssen, Genentech, and Teva Pharmaceuticals.
Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202. Abstract #6. Presented at the 2018 ASH Annual Meeting, December 2, 2018; San Diego, CA.