Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression-Free Survival Compared with Bendamustine plus Rituximab in Untreated Older Patients with CLL

Despite widespread use, the efficacy of ibrutinib versus standard chemoimmunotherapy has not been previously investigated. The ALLIANCE study seeks to evaluate the clinical benefit of adding rituximab to ibrutinib in the frontline setting. The study compares bendamustine plus rituximab (BR; Arm 1) with ibrutinib (I; Arm 2) and the combination of ibrutinib plus rituximab (IR; Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy in terms of progression-free survival (PFS). Another goal of ALLIANCE is to determine whether adding rituximab to ibrutinib prolongs PFS over ibrutinib alone.

Eligible patients were aged ≥65 years with previously untreated, symptomatic chronic lymphocytic leukemia (CLL). A total of 547 patients were randomized 1:1:1 to the 3 study arms. At time of progression, patients in Arm 1 could cross over to ibrutinib monotherapy (Arm 2).

In terms of patient characteristics, the median age was 71 years, 67% of patients were men, and 97% had Eastern Cooperative Oncology Group performance status of 0 or 1. High-risk characteristics included unmethylated Zap-70 in 53%, complex karyotype in 29%, and del(17p) or del(11q) by local fluorescence in situ hybridization in 25% of patients. At 24 months, PFS estimates were 74% in the BR arm, compared with 87% and 88% in the I and IR arms, respectively. In the intent-to-treat population, PFS in the del(17p) subgroup strongly favored I and IR over BR; interestingly, the PFS curves are relatively similar for patients with and without complex karyotype, and I and IR both showed an advantage over BR. Thus far, median overall survival (OS) has not been reached for any arm, and 2-year OS estimates were 95%, 90%, and 94% in arms 1, 2, and 3, respectively.

Grade ≥3 hematologic adverse events were seen in 61%, 41%, and 38% of patients, and grade ≥3 nonhematologic adverse events were seen in 63%, 74%, and 74% of patients in arms 1, 2, and 3, respectively. There were 28 deaths during the active treatment period +30 days: 2 in Arm 1, 13 in Arm 2, and 13 in Arm 3.

In conclusion, the trial demonstrated that ibrutinib produces superior PFS to standard chemoimmunotherapy in older patients with CLL. However, the addition of rituximab does not prolong PFS with ibrutinib.

Woyach JA, et al. ASH 2018. Abstract 6.