Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

Abstract

Background: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.

Methods: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.

Results: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (IGHV) mutation, ibrutinib-rituximab resulted in better progression-free survival than chemoimmunotherapy (90.7% vs. 62.5% at 3 years; hazard ratio for progression or death, 0.26; 95% CI, 0.14 to 0.50). The 3-year progression-free survival among patients with IGHV mutation was 87.7% in the ibrutinib-rituximab group and 88.0% in the chemoimmunotherapy group (hazard ratio for progression or death, 0.44; 95% CI, 0.14 to 1.36). The incidence of adverse events of grade 3 or higher (regardless of attribution) was similar in the two groups (in 282 of 352 patients [80.1%] who received ibrutinib-rituximab and in 126 of 158 [79.7%] who received chemoimmunotherapy), whereas infectious complications of grade 3 or higher were less common with ibrutinib-rituximab than with chemoimmunotherapy (in 37 patients [10.5%] vs. 32 [20.3%], P<0.001).

Conclusions: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Figure 1.. Enrollment, Randomization, and Follow-up.

All 529 patients who had been enrolled in the trial were included in the intention-to-treat analysis. Of the 529 patients who underwent randomization, 31 (5.9%) were determined to have not met the eligibility criteria and were excluded from the analysis of eligible patients who started assigned therapy (see the Supplementary Appendix). The safety analysis included 510 patients who started the assigned protocol therapy. GFR denotes glomerular filtration rate.

Figure 2.. Primary and Subgroup Analyses of Progression-free Survival.

Panel A shows the Kaplan–Meier estimate of progression-free survival among all the patients who underwent randomization. Panel B shows the Kaplan–Meier estimate of progression-free survival among patients whose chronic lymphocytic leukemia (CLL) did not have the immunoglobulin heavy-chain variable region (IGHV) mutation. Panel C shows a forest plot of hazard ratios for progression or death, according to prognostic sub-groups of patients with CLL. The subgroup analysis was conducted in the intention-to-treat population. Hazard ratios (ibrutinib–rituximab vs. chemoimmunotherapy with fludarabine–cyclophosphamide–rituximab) were estimated with the use of univariable Cox proportional-hazards models stratified according to the four stratification factors. The size of the box is inversely proportional to the variance of the hazard ratio estimates. The dashed line indicates the overall hazard ratio among all patients who had undergone randomization. Eastern Cooperative Oncology Group (ECOG) performance-status scores are assessed on a 5-point scale, with higher scores indicating greater disability. Rai stages of disease range from 0 (low risk) to I or II (intermediate risk) to III or IV (high risk).

Figure 3.

Overall Survival (Intention-to-Treat Population).