A Phase I Study of the Combination of Rituximab and Ipilimumab in Patients with Relapsed/Refractory B-Cell Lymphoma

Clin Cancer Res. 2019 Dec 1;25(23):7004-7013. doi: 10.1158/1078-0432.CCR-19-0438. Epub 2019 Sep 3.


Purpose: Based on the potential for ipilimumab (I) to augment T-cell activation, we hypothesize that ipilimumab would augment the efficacy of rituximab (R) in patients with relapsed/refractory (R/R) CD20+non-Hodgkin's lymphoma (NHL). This phase I study aimed to identify a recommended phase 2 dose, document toxicities, and preliminarily assess efficacy and potential predictive biomarkers.

Patients and methods: Thirty-three patients with R/R CD20+B-cell lymphoma received R at 375 mg/m2weekly for 4 weeks and I at 3 mg/kg on day 1 and every 3 weeks for four doses. Responding patients went on to maintenance with each agent given every 12 weeks. To facilitate correlative analysis, the expansion phase randomized patients to simultaneous R+I versus R with I delayed 2 weeks.

Results: Toxicity was manageable; no dose-limiting toxicity was observed at the doses studied. When considering the entire cohort, efficacy was modest, with an objective response rate (ORR) of 24% and median progression-free survival (PFS) of 2.6 months. However, in follicular lymphoma patients, the ORR was 58% with a median PFS of 5.6 months. The randomized comparison of R with R+I demonstrated that R+I resulted in more effective B-cell depletion (BCD). Both B-cell depletion and the ratio of CD45RA-regulatory T cell (Treg) to Treg were associated with response at all time points.

Conclusions: The combination of R+I has manageable toxicity and encouraging efficacy in R/R follicular lymphoma. The ratio of CD45RA-Tregs to total Tregs, and peripheral BCD should be studied further as potential predictors of response.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Follow-Up Studies
  • Humans
  • Ipilimumab / administration & dosage
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / pathology
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Rituximab / administration & dosage
  • Salvage Therapy*
  • Survival Rate


  • Ipilimumab
  • Rituximab