This study is the first to demonstrate that ibrutinib plus rituximab significantly improves progression-free survival compared to immunochemotherapy in elderly patients with mantle cell lymphoma, establishing a new standard first-line treatment option for this population.
Literature Overview
This article, 'Ibrutinib Plus Rituximab Versus Immunochemotherapy in Previously Untreated Elderly Patients with Mantle Cell Lymphoma,' published in The Lancet, reviews the findings of the ENRICH trial. The study conducted a randomized, open-label, phase 2/3 superiority trial involving 397 patients to compare the efficacy and safety of ibrutinib plus rituximab against standard immunochemotherapy (R-CHOP or bendamustine-rituximab) in elderly MCL patients. It revealed that the ibrutinib-rituximab combination significantly prolonged progression-free survival (PFS), particularly in specific subgroups, though no significant difference was observed in overall survival (OS). The results provide new first-line treatment options for elderly MCL patients while emphasizing the importance of managing treatment-related toxicities. The text is coherent and logically structured, ending with Chinese periods.
Background Knowledge
Mantle cell lymphoma (MCL) is a rare B-cell lymphoma characterized by chromosomal translocation t(11;14)(q13;q32). It typically presents as an aggressive malignancy, particularly common in elderly patients. Treatment options for MCL remain limited, especially in older individuals ineligible for stem-cell transplantation, where standard immunochemotherapy regimens like R-CHOP or bendamustine-rituximab have demonstrated limited efficacy in extending PFS and OS. Recent advances with Bruton tyrosine kinase (BTK) inhibitors such as ibrutinib have shown promise in relapsed/refractory MCL, but evidence for first-line applications has been lacking. The ENRICH trial directly compared ibrutinib-rituximab against standard immunochemotherapy in first-line treatment, offering critical evidence for future therapeutic strategies. Furthermore, subgroup analyses (e.g., TP53 mutation, Ki67 expression) provided data-driven support for personalized treatment approaches. The paragraph ends with a Chinese period.
Research Methods and Experiments
The ENRICH trial was an international, multicenter, randomized, open-label phase 2/3 superiority study conducted across 66 centers in the UK, Sweden, Norway, Finland, and Denmark. It enrolled MCL patients aged ≥60 years with Ann-Arbor stages II–IV and ECOG performance scores 0–2, who were randomized 1:1 to receive either ibrutinib-rituximab or standard immunochemotherapy (R-CHOP or bendamustine-rituximab). The primary endpoint was investigator-assessed PFS, with secondary endpoints including overall survival (OS), objective response rate, safety, and quality of life. All responding patients received 2 years of rituximab maintenance post-induction, while ibrutinib was continued until disease progression or unacceptable toxicity. Statistical analyses employed Cox proportional hazards models with predefined subgroup analyses (e.g., age, Ki67 expression, TP53 mutation). The trial aimed to enroll 400 patients to detect PFS superiority, assuming a median PFS of 30 months in the immunochemotherapy arm with a hazard ratio (HR) of 0.67 and 90% power. Data were censored as of June 30, 2024, with a median follow-up of 47.9 months.
Key Conclusions and Perspectives
Research Significance and Prospects
The ENRICH trial establishes ibrutinib-rituximab as a new first-line standard for elderly MCL patients, particularly demonstrating sustained PFS benefits during maintenance therapy. It provides critical evidence for optimizing treatment strategies in high-risk subgroups (e.g., TP53 mutations) and supports future investigations into long-term survival benefits and comparisons with next-generation BTK inhibitors or combined targeted therapies. The study also underscores the need to refine toxicity management, especially for infections and cardiovascular events in ibrutinib-treated patients, while highlighting the potential for personalized treatment approaches based on Ki67 expression levels. This research represents a pivotal shift toward chemo-free regimens in MCL treatment, offering improved efficacy-toxicity balances for elderly populations.
Conclusion
The ENRICH trial is a landmark randomized controlled study demonstrating that ibrutinib plus rituximab significantly prolongs PFS in elderly MCL patients compared to standard immunochemotherapy, particularly showing enhanced efficacy in the R-CHOP subgroup. While no significant OS difference was observed, this chemo-free combination provides a novel therapeutic option for patients ineligible for stem-cell transplantation. Safety profiles showed comparable grade ≥3 adverse event rates (67% vs 70%), though ibrutinib-rituximab was associated with higher risks of atrial fibrillation, infections, and bleeding, while immunochemotherapy showed greater hematologic toxicity. The regimen demonstrated superior efficacy in patients with low Ki67 expression (<30%), suggesting suitability for low-proliferation MCL. TP53-mutated patients also showed PFS improvement, albeit non-significant. These findings support ibrutinib-rituximab as a new first-line standard and emphasize the importance of personalized treatment strategies to optimize outcomes in high-risk populations. The study catalyzes the transition from traditional immunochemotherapy to chemo-free combinations in MCL management, offering safer and more effective options for elderly patients with significant clinical and research implications.
