In a phase II/III study (ENRICH) reported in The Lancet, Lewis et al found that the chemotherapy-free combination of ibrutinib plus rituximab prolonged progression-free survival vs standard immunochemotherapy in patients aged 60 years or older with previously untreated mantle cell lymphoma.
Study Details
In the open-label trial, 397 patients from sites in the United Kingdom, Sweden, Norway, Finland, and Denmark were randomly assigned between February 2016 and June 2021 to receive ibrutinib plus rituximab (n = 199) or a prerandomization immunochemotherapy choice (n = 198) of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone; n = 53) or bendamustine plus rituximab (n = 145).
Ibrutinib plus rituximab treatment consisted of ibrutinib at 560 mg daily combined with six to eight cycles of rituximab at 375 mg/m² on day 1 of each cycle. R-CHOP consisted of cyclophosphamide at 750 mg/m², doxorubicin at 50 mg/m², rituximab at 375 mg/m², vincristine at 1.4 mg/m² on day 1 of each 21-day cycle, and prednisolone at 100 mg on days 1 to 5 of each cycle. Rituximab plus bendamustine consisted of bendamustine at 90 mg/m² on days 1 to 2 of each cycle and rituximab at 375 mg/m² on day 1 of each cycle. All responding patients at the end of induction in both groups received maintenance rituximab every 8 weeks for 2 years, with patients given ibrutinib plus rituximab continuing ibrutinib until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival.
Key Findings
At a median follow-up of 47.9 months (interquartile range = 27.1–63.3 months), median progression-free survival was 65.3 months (95% confidence interval [CI] = 52.7 months to not evaluable) with ibrutinib plus rituximab vs 42.4 months (95% CI = 32.7–55.3 months) with immunochemotherapy (adjusted hazard ratio [HR] = 0.69, 95% CI = 0.52–0.90, P = .0034). Hazard ratios favoring ibrutinib plus rituximab were observed vs R-CHOP (0.37, 95% CI = 0.22–0.62) and vs bendamustine plus rituximab (0.91, 95% CI = 0.66–1.25).
During induction and maintenance therapies, grade ≥ 3 adverse events occurred in 67% of the group given ibrutinib plus rituximab vs 70% of the group given immunotherapy. Grade ≥ 3 hematologic adverse events were reported in 17% of those treated with ibrutinib plus rituximab, 50% of R-CHOP recipients, and 34% of those treated with rituximab plus bendamustine, and grade ≥ 3 nonhematologic adverse events occurred in 61%, 52%, and 52%, respectively.
The investigators concluded: “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.”
David J. Lewis, MBChB, PhD, of the Department of Haematology, University Hospitals Plymouth NHS Trust, Plymouth, UK, is the corresponding author of The Lancet article.
Disclosure: The study was funded by Cancer Research UK and Johnson & Johnson Pharmaceuticals. For full disclosures of all study authors, visit thelancet.com.
