Ibrutinib Established as Standard for Older CLL Patients

Jason M. Broderick @jasoncology
Published: Saturday, Dec 01, 2018

Jennifer A. Woyach, MD

Jennifer A. Woyach, MD

Ibrutinib (Imbruvica) as monotherapy and combined with rituximab (Rituxan) significantly improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) as frontline therapy for older patients with chronic lymphocytic leukemia (CLL), according to findings presented at the 2018 ASH Annual Meeting.

The results also showed that the addition of rituximab to ibrutinib added no additional PFS benefit. At 24 months’ follow-up, the PFS rates were 87% (95% CI, 81-92) with single-agent ibrutinib, 88% (95% CI, 81-92) with ibrutinib/rituximab, and 74% (95% CI, 66-80) with BR.

“Our results establish that ibrutinib should be a standard of care for older patients with CLL—it is more effective than the best available chemoimmunotherapy regimen,” said lead study author Jennifer A. Woyach, MD, of The Ohio State University Comprehensive Cancer Center. “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.”

Frontline ibrutinib monotherapy was approved by the FDA in 2016 for patients with CLL and is widely used in clinical practice; however, the pivotal data the FDA reviewed compared ibrutinib to chlorambucil. Woyach noted that standard frontline chemoimmunotherapy regimens for older CLL patients, including BR and chlorambucil plus obinutuzumab (Gazyva), have not previously been compared with single-agent ibrutinib.

The Alliance North American Intergroup Study A041202 randomized 547 patients with CLL aged ≥65 years in a 1:1:1 ratio to ibrutinib alone (n = 182), ibrutinib/rituximab (n = 182), or BR (n = 183). Patients in the BR group were treated with bendamustine at 90 mg/m2 on days 1 and 2 of each 28-day cycle plus rituximab at 375 mg/m2 on day 0 cycle 1, then 500 mg/m2 on day 1 of cycles 2 to 6. Ibrutinib was administered at 420 mg daily. In the ibrutinib combination arm, patients received rituximab at 375 mg/m2 weekly for 4 weeks starting at cycle 2 day 1, then day 1 of cycle 3 to 6. Patients in the BR group were allowed to cross over to ibrutinib monotherapy at disease progression.

Overall, patient characteristics were well balanced between the 3 arms. Across the overall population, the median age was 71 years (range, 65-89), 67% of patients were male, and 97% had an ECOG performance status of 0-1. Six percent had del(17p), 19% had del(11q), 10% had a TP53 mutation, Zap-70 unmethylated disease was observed in 53% of patients, and 61% were IGVH unmutated.

The only patient characteristic with variance of note at baseline was complex karyotype, in which there was a slightly higher rate in the ibrutinib/rituximab arm. The rates of patients with a complex karyotype were 36% in the ibrutinib/rituximab group, 27% in the BR group, and 24% in the single-agent ibrutinib group.

The PFS benefit with ibrutinib monotherapy versus BR was observed across almost all patient subgroups, including those defined by disease stage (Rai), presence or absence of del(17p) or del(11q), and Zap-70 unmethylated disease.

“Ibrutinib [was] superior to bendamustine plus rituximab throughout, except for the subgroup of patients with methylated Zap-70 disease—which equates to mutated IGVH—where the trend is toward improved PFS with ibrutinib, but has not yet reached statistical significance,” said Woyach.

At the time of the analysis, there was not an overall survival difference between the study arms.  Woyach explained this may be a result of the short follow-up, as well as the crossover study design.

Given the extensive previous reporting of the safety profile of ibrutinib, Woyach focused on grade ≥3 adverse events (AEs) of special interest with ibrutinib or that varied among the arms. The AEs she reported were regardless of attribution and included all events, both during active treatment and follow-up (excluding any crossover patients).

Grade 3/5 hematologic AEs occurred at higher rates with BR at 61%, compared with 41% and 38%, respectively, for ibrutinib and ibrutinib/rituximab. These included higher rates of anemia (13% vs 12% vs 6%), neutropenia (40% vs 15% vs 21%), and thrombocytopenia (15% vs 7% vs 5%). 

Nonhematologic AEs were for the most part more common in the ibrutinib arms at 74% in each arm versus 63% in the BR arm. These included bleeding (2% with ibrutinib; 4% with ibrutinib/rituximab; 0% with BR), infections (20% vs 19% vs 15%, respectively), atrial fibrillation (9% vs 6% vs 3%), hypertension (29% vs 34% vs 15%), and unexplained/unwitnessed death (4% vs 2% vs 1%). The rate of febrile neutropenia, however, was higher with BR at 7% versus 2% with ibrutinib and 1% with ibrutinib/rituximab. 

“BTK inhibition with ibrutinib is not without significant toxicity in older patients, so close monitoring is still warranted. Strategies to limit toxicity through either the use of more selective BTK inhibitors or potentially limiting the duration of therapy are of great interest,” said Woyach.

In her summary remarks, Woyach noted that 2 of the next key cooperative group studies in this patient population are A041702 (NCT03737981) and EA9161 (NCT03701282), which are comparing ibrutinib plus obinutuzumab with or without venetoclax (Venclexta) in patients with CLL.
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. Presented at: ASH Annual Meeting and Exposition; December 4-8, 2018; San Diego, California. Abstract 6.
 
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