Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial

Abstract

Background: Ibrutinib, a Bruton tyrosine kinase inhibitor, prolongs progression-free survival when added to immunochemotherapy as first line treatment. The ENRICH trial compared the chemotherapy-free combination of ibrutinib and the anti-CD20 antibody rituximab (ibrutinib-rituximab) with standard immunochemotherapy (R-CHOP [rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone] or bendamustine-rituximab) in patients 60 years and older with untreated mantle-cell lymphoma.

Methods: This randomised, open-label, phase 2/3 superiority trial was performed at 66 sites in the UK, Sweden, Norway, Finland, and Denmark. Patients 60 years and older with untreated mantle-cell lymphoma (Ann-Arbor stage II-IV disease, an Eastern Cooperative Oncology Group performance-status score of 0-2) were randomly assigned to receive either rituximab plus immunochemotherapy or ibrutinib-rituximab in a 1:1 ratio, stratified by investigator choice of immunochemotherapy. Patients randomly allocated to the ibrutinib-rituximab (intervention) group received 560 mg oral ibrutinib daily in combination with six to eight cycles of 375 mg/m² intravenous rituximab on day 1 of each cycle in the matched schedule of the pre-randomisation choice of immunochemotherapy (every 21 days for R-CHOP or every 28 days for rituximab-bendamustine). R-CHOP comprised 750 mg/m² of cyclophosphamide, 50 mg/m² of doxorubicin, and 1·4 mg/m² vincristine on day 1 of each 21-day cycle, with 100 mg prednisolone on days 1-5 of each cycle. Rituximab-bendamustine comprised 90 mg/m² of bendamustine on days 1 and 2 of each cycle, in combination with 375 mg/m² rituximab on day 1 of each cycle. All responding patients in both groups at the end of induction received maintenance rituximab administered every 8 weeks for 2 years, and patients allocated to the intervention group continued ibrutinib until disease progression or unacceptable toxicity. The primary outcome was investigator-assessed progression-free survival, stratified by immunochemotherapy choice and analysed in the intention-to-treat population. The trial was registered with EudraCT (2015-000832-13) and is closed for recruitment.

Findings: Between Feb 15, 2016, and June 30, 2021, 397 patients were randomly allocated to immunochemotherapy (control) or ibrutinib-rituximab (intervention). Of the 397, 107 (27%) were pre-allocated to the immunochemotherapy choice of R-CHOP and 290 (73%) were pre-allocated to rituximab-bendamustine. In total, 198 were allocated to the control group (53 to R-CHOP and 145 to bendamustine-rituximab) and 199 were allocated to intervention. The median age was 74 years (IQR 70-77) for the intervention group and 74 years (70-78) in the control group. 296 patients (75%) were male and 101 patients (25%) were female; ethnicity data were not collected. At a median follow-up of 47·9 months, the median progression-free survival of ibrutinib-rituximab was superior to immunochemotherapy, with an adjusted hazard ratio (HR) of 0·69 (95% CI 0·52-0·90); p=0·0034. For those with pre-randomisation choice R-CHOP, the HR was 0·37 (0·22-0·62), and with bendamustine-rituximab, the HR was 0·91 (0·66-1·25). Across induction and maintenance, 67% of patients assigned to ibrutinib-rituximab and 70% of patients receiving immunotherapy reported grade 3 or above adverse events.

Interpretation: To our knowledge, this is the first randomised trial in untreated mantle-cell lymphoma to demonstrate significant improvement in progression-free survival for ibrutinib-rituximab compared to immunochemotherapy. This study suggests that ibrutinib-rituximab should be considered a new standard of care option for first-line treatment of older patients with mantle-cell lymphoma.

Funding: Cancer Research UK (C7627/A17938) and Johnson and Johnson Pharmaceuticals.

Figure 1

ENRICH trial profile The trial profile details the ENRICH treatment pathway for participants. Not all progressions of disease or deaths are listed, as events might occur once a participant has discontinued ENRICH treatment (appendix pp 32, 36). GI=gastrointestinal. MCL=mantle-cell lymphoma. R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone. *One death for each named cause.

Figure 1

ENRICH trial profile The trial profile details the ENRICH treatment pathway for participants. Not all progressions of disease or deaths are listed, as events might occur once a participant has discontinued ENRICH treatment (appendix pp 32, 36). GI=gastrointestinal. MCL=mantle-cell lymphoma. R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone. *One death for each named cause.

Figure 2

Progression-free survival Kaplan–Meier curves for all patients (A), the R-CHOP choice group (B), and the bendamustine–rituximab choice group (C) Progression-free survival Kaplan–Meier curves for the intention-to-treat population. (A) Overall Kaplan–Meier curve for ibrutinib–rituximab versus immunochemotherapy. (B) Pre-randomisation investigator choice of R-CHOP (ibrutinib–rituximab vs R-CHOP). (C) Pre-randomisation investigator choice of bendamustine–rituximab (ibrutinib–rituximab vs bendamustine–rituximab). HR=hazard ratio. R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 3

Subgroup analysis of progression-free survival Subgroup analysis of progression-free survival by treatment allocation, adjusted hazard ratios for ibrutinib–rituximab or immunochemotherapy. (A) Ibrutinib–rituximab versus immunochemotherapy where all comparisons are adjusted for the pre-randomisation investigator choice of immunochemotherapy. (B) Pre-randomisation investigator choice of R-CHOP (ibrutinib–rituximab vs R-CHOP). (C) Pre-randomisation investigator choice of bendamustine–rituximab (ibrutinib–rituximab vs bendamustine-rituximab). Analysis of subgroups MIPI and Ki67 with multiple imputation for missing grouping values are provided in the appendix (p 42). ECOG=Eastern Cooperative Oncology Group. MIPI=Mantle Cell Lymphoma International Prognostic Index. R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 3

Subgroup analysis of progression-free survival Subgroup analysis of progression-free survival by treatment allocation, adjusted hazard ratios for ibrutinib–rituximab or immunochemotherapy. (A) Ibrutinib–rituximab versus immunochemotherapy where all comparisons are adjusted for the pre-randomisation investigator choice of immunochemotherapy. (B) Pre-randomisation investigator choice of R-CHOP (ibrutinib–rituximab vs R-CHOP). (C) Pre-randomisation investigator choice of bendamustine–rituximab (ibrutinib–rituximab vs bendamustine-rituximab). Analysis of subgroups MIPI and Ki67 with multiple imputation for missing grouping values are provided in the appendix (p 42). ECOG=Eastern Cooperative Oncology Group. MIPI=Mantle Cell Lymphoma International Prognostic Index. R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone.

Figure 4

Overall survival Kaplan–Meier curves for all patients (A), the R-CHOP choice group (B) and the bendamustine–rituximab choice group (C) Overall survival Kaplan–Meier curves of the intention-to-treat population. (A) Overall Kaplan–Meier curve for ibrutinib–rituximab versus immunochemotherapy. (B) Pre-randomisation investigator choice of R-CHOP (ibrutinib–rituximab vs R-CHOP). (C) Pre-randomisation investigator choice of rituximab plus bendamustine (ibrutinib–rituximab vs bendamustine–rituximab). R-CHOP=rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisolone.