Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia

Abstract

Ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase, is an effective therapy for patients with chronic lymphocytic leukemia (CLL). To determine whether rituximab provides added benefit to ibrutinib, we conducted a randomized single-center trial of ibrutinib vs ibrutinib plus rituximab. Patients with CLL requiring therapy were randomized to receive 28-day cycles of once-daily ibrutinib 420 mg, either as a single agent (n = 104), or together with rituximab (375 mg/m²; n = 104), given weekly during cycle 1, then once per cycle until cycle 6. The primary end point was progression-free survival (PFS) in the intention-to-treat population. We enrolled 208 patients with CLL, 181 with relapsed CLL and 27 treatment-naive patients with high-risk disease (17p deletion or TP53 mutation). After a median follow-up of 36 months, the Kaplan-Meier estimates of PFS were 86% (95% confidence interval [CI], 76.6-91.9) for patients receiving ibrutinib, and 86.9% (95% CI, 77.3-92.6) for patients receiving ibrutinib plus rituximab. Similarly, response rates were the same in both arms (overall response rate, 92%). However, time to normalization of peripheral blood lymphocyte counts and time to complete remission were shorter, and residual disease levels in the bone marrow were lower, in patients receiving ibrutinib plus rituximab. We conclude that the addition of rituximab to ibrutinib in relapsed and treatment-naive high-risk patients with CLL failed to show improvement in PFS. However, patients treated with ibrutinib plus rituximab reached their remissions faster and achieved significantly lower residual disease levels. Given these results, ibrutinib as single-agent therapy remains current standard-of-care treatment in CLL. This trial was registered at www.clinicaltrials.gov as #NCT02007044.

Graphical abstract

Figure 1.

Best responses to treatment with Ibr or Ibr + R in CLL. (A) Responses in patients with CLL treated with Ibr or Ibr + R. CRs, including CRs with incomplete count recovery (CR/Cri), are depicted in green; PRs, including PR/nPRs, are in blue; and PRLs are in pink. Although the CR rate with the addition of rituximab was higher, it did not reach statistical significance. (B) Responses in treatment-naive (TN) and relapsed/refractory (RR) patients with CLL treated with Ibr or with Ibr + R.

Figure 2.

Kaplan-Meier curves for PFS and OS. The top panels show the probability of PFS (A) and OS (B) and for all 208 patients. The bottom panels depict PFS with respect to del17p status (C) and 11q deletion status (D). Tick marks indicate censored data.

Figure 3.

Time to remission and kinetics of CLL blood indices during treatment with Ibr or Ibr + R. (A) Number of patients in CR at 12 and 24 months. (B) Bone marrow CLL disease levels, quantified by using flow cytometry, at baseline and after 12 and 24 months of treatment. (C) Trended mean ± SD ALC in patients treated with Ibr (blue line) or with Ibr + R (green line). (D) Trended mean ± SD β₂-microglobulin levels in patients treated with Ibr or with Ibr + R. (E) Trended mean ± SD hemoglobin levels in patients treated with Ibr or with Ibr + R. (F) Trended mean ± SD platelet counts in patients treated with Ibr or with Ibr + R. CR/CRI, CRs with incomplete count recovery.