Randomized Phase III Trial of Ibrutinib and Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone in Non-Germinal Center B-Cell Diffuse Large B-Cell Lymphoma

Abstract

Purpose: Ibrutinib has shown activity in non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL). This double-blind phase III study evaluated ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in untreated non-germinal center B-cell DLBCL.

Patients and methods: Patients were randomly assigned at a one-to-one ratio to ibrutinib (560 mg per day orally) plus R-CHOP or placebo plus R-CHOP. The primary end point was event-free survival (EFS) in the intent-to-treat (ITT) population and the activated B-cell (ABC) DLBCL subgroup. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety.

Results: A total of 838 patients were randomly assigned to ibrutinib plus R-CHOP (n = 419) or placebo plus R-CHOP (n = 419). Median age was 62.0 years; 75.9% of evaluable patients had ABC subtype disease, and baseline characteristics were balanced. Ibrutinib plus R-CHOP did not improve EFS in the ITT (hazard ratio [HR], 0.934) or ABC (HR, 0.949) population. A preplanned analysis showed a significant interaction between treatment and age. In patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS (HR, 0.579), PFS (HR, 0.556), and OS (HR, 0.330) and slightly increased serious adverse events (35.7% v 28.6%), but the proportion of patients receiving at least six cycles of R-CHOP was similar between treatment arms (92.9% v 93.0%). In patients age 60 years or older, ibrutinib plus R-CHOP worsened EFS, PFS, and OS, increased serious adverse events (63.4% v 38.2%), and decreased the proportion of patients receiving at least six cycles of R-CHOP (73.7% v 88.8%).

Conclusion: The study did not meet its primary end point in the ITT or ABC population. However, in patients age younger than 60 years, ibrutinib plus R-CHOP improved EFS, PFS, and OS with manageable safety. In patients age 60 years or older, ibrutinib plus R-CHOP was associated with increased toxicity, leading to compromised R-CHOP administration and worse outcomes. Further investigation is warranted.

Trial registration: ClinicalTrials.gov NCT01855750.

FIG 1.

Patient disposition. Random assignment was stratified by revised International Prognostic Index (1 to 2 v 3 to 5), region (United States/Western Europe v rest of world), and prespecified rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) cycle number (six v eight). COO, cell of origin; DLBCL, diffuse large B-cell lymphoma; GCB, germinal B cell–like.

FIG 2.

Kaplan-Meier survival curves for event-free survival (EFS) and overall survival (OS). (A) Investigator-assessed EFS, intent-to-treat (ITT) population. (B) Investigator-assessed EFS, activated B cell–like population. (C) OS, ITT population. HR, hazard ratio; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

FIG 3.

Hazard ratios (HRs) of overall survival (OS) by different discrete age groups. Bars indicate 95% CIs.

FIG 4.

Kaplan-Meier survival curves for event-free survival (EFS) and overall survival (OS) by cutoff of age 60 years in the intent-to-treat population. (A) EFS, age younger than 60 years (n = 342). (B) OS, age younger than 60 years (n = 342). (C) EFS, age 60 years or older (n = 496). (D) OS, age 60 years or older (n = 496). HR, hazard ratio; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

FIG A1.

Subgroup analysis of event-free survival (EFS) in the intent-to-treat (ITT) population. ABC, activated B cell–like; ECOG, Eastern Cooperative Oncology Group; GEP, gene expression profiling; LDH, lactate dehydrogenase; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-IPI, Revised International Prognostic Index.

FIG A2.

Subgroup analysis of event-free survival (EFS) in patients age younger than 60 years. ABC, activated B cell–like; ECOG, Eastern Cooperative Oncology Group; GCB, germinal center B cell–like; GEP, gene expression profiling; LDH, lactate dehydrogenase; R-CHOP, rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; R-IPI, Revised International Prognostic Index. (*) No patient had an R-IPI score of 5 because all patients were age younger than 60 years. (†) More than one extranodal lesion showed a hazard ratio of >1, but the CI was wide because of small event size.

FIG A3.

Adverse event (AE) rate by age cutoffs. (A) Ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm. (B) Placebo plus R-CHOP arm. TEAEs, treatment-emergent AEs.

FIG A4.

Steady-state ibrutinib concentrations by age. Solid line represents median; dashed lines represent fifth and 95th percentiles. In previous studies, ibrutinib was administered at the following doses: chronic lymphocytic leukemia: ibrutinib 420 mg per day, CLL3001, PCYC 1112, PCYC 1115, PCYC 1117, and PCYC 1102; mantle cell lymphoma: ibrutinib 560 mg per day, PCYC 1104, MCL2001, and MCL3001; miscellaneous doses, PCYC 04753.