For decades mantle‑cell lymphoma (MCL) has posed a particular clinical puzzle: an uncommon B‑cell cancer with varied biological behavior, usually incurable, and especially unforgiving in older patients who cannot tolerate intensive chemotherapy and transplant. The ENRICH trial, published in The Lancet in October 2025, delivers the first large randomized test of a chemotherapy‑free front‑line strategy for this population. It compares the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib combined with the anti‑CD20 antibody rituximab against standard immunochemotherapy; either R‑CHOP or rituximab‑bendamustin, with maintenance rituximab in both arms

The headline finding is clear and clinically consequential: among patients aged 60 and older with previously untreated MCL, ibrutinib‑rituximab significantly prolonged progression‑free survival (PFS) relative to investigator‑chosen immunochemotherapy, with a median PFS of 65.3 months versus 42.4 months and an adjusted hazard ratio of 0.69. The benefit was concentrated in the subgroup whose clinicians would otherwise have used R‑CHOP; in that cohort the hazard ratio was 0.37, indicating a large reduction in risk of progression or death with the chemotherapy‑free doublet. By contrast, outcomes were broadly similar between ibrutinib‑rituximab and rituximab‑bendamustine.

This trial reframes choices for older patients with MCL. It shows that a chemotherapy‑free regimen can be not only active but, in key contexts, superior to conventional cytotoxic combinations. The result will prompt oncologists to reexamine whether front‑line cytotoxic exposure is necessary for many older people with MCL, and it raises immediate questions about personalization, safety, and next steps in clinical research.

ENRICH was a multicenter, randomised, open‑label phase 2/3 trial run across 66 sites in the UK and Nordic countries. Eligibility included age 60 or older, untreated MCL, Ann‑Arbor stage II–IV, ECOG 0–2, and measurable disease by CT. Before randomization investigators selected which immunochemotherapy they would use if the patient were allocated to the control arm: R‑CHOP given every 21 days or rituximab‑bendamustine every 28 days. Patients were then randomized 1:1 to receive either that immunochemotherapy plus rituximab maintenance or the chemotherapy‑sparing strategy: daily oral ibrutinib 560 mg together with the same rituximab induction schedule and the same maintenance rituximab, with ibrutinib continued until progression or intolerable toxicity.

Between 2016 and 2021 the trial randomized 397 patients: median age 74, three‑quarters male, roughly three quarters pre‑assigned to rituximab‑bendamustine and one quarter to R‑CHOP. The trial used progression‑free survival assessed by investigators as the primary endpoint, with overall survival, response rates, safety, quality of life, and time to next treatment among key secondary endpoints. Follow‑up for the primary analysis was a median 47.9 months.

The efficacy picture: PFS, subgroups and overall survival

Ibrutinib‑rituximab improved the trial’s primary endpoint. Median PFS was 65.3 months for the doublet versus 42.4 months for immunochemotherapy (HR 0.69). The overall survival signal was neutral at the time of reporting: 5‑year overall survival was similar between arms (58% vs 55%; HR 0.87) but subgroup differences suggested greater benefit in those whose investigators had chosen R‑CHOP.

The treatment effect was not uniform. The superiority of ibrutinib‑rituximab was driven largely by improved outcomes compared to R‑CHOP: in the R‑CHOP‑choice subgroup the hazard ratio was 0.37 and 5‑year PFS probability rose from 19% to 52% with the BTK doublet. By contrast, among patients whose pre‑randomisation choice was rituximab‑bendamustine, PFS was similar between arms (HR 0.91, 5‑year PFS around 47–51%).

Predefined subgroup analyses hint at where the doublet is most active. Patients whose tumours had Ki67 under 30%—a lower proliferation index—derived greater PFS benefit from ibrutinib‑rituximab (HR 0.58) than those with Ki67 ≥30% (HR 0.86). The trial also examined TP53 mutations: among tested tumours, 26% harboured pathogenic TP53 mutations, and numerically PFS was longer with the doublet in this high‑risk subgroup, though confidence intervals are wide and numbers small (median PFS 18.5 months vs 8.9 months).

Response rates were similar between arms: overall response rate and complete responses were essentially the same across the trial groups, indicating that the PFS advantage comes from durability and perhaps reduced cumulative toxicity rather than larger initial response proportions.

Toxicity and tolerability: a changed trade‑off rather than fewer harms

The safety profiles reflect known drug classes rather than surprises. Ibrutinib‑rituximab produced less haematological toxicity; fewer high‑grade neutropenias and cytopenias than immunochemotherapy, which is unsurprising given the myelotoxicity of cytotoxic agents. However, non‑haematological grade ≥3 adverse events were more frequent with the ibrutinib doublet, driven by hypertension, atrial fibrillation, bleeding, and infections. Atrial fibrillation of grade 3 or above occurred in about 7% of patients on ibrutinib versus 1% across the immunochemotherapy groups; grade ≥3 hypertension and bleeding events were also more common on the BTK inhibitor arm.

Importantly, infections and cardiac events contributed markedly to non‑relapse mortality in both arms. ENRICH recruited and followed up patients through the COVID‑19 pandemic; COVID‑19 deaths were numerous and affected non‑relapse mortality substantially. Overall infectious deaths were higher than in older trials run before the pandemic, and COVID‑19‑related deaths accounted for a large fraction of infectious fatalities in the trial, particularly among patients on continuous ibrutinib exposure. Sensitivity analyses censoring COVID‑19 deaths did not change the primary PFS conclusions.

Another notable observation is that more patients completed induction and entered maintenance in the ibrutinib‑rituximab arm than in the chemotherapy arms, but more patients discontinued ibrutinib during maintenance for cardiac and infectious reasons. Median time on ibrutinib was 33.8 months and half the ibrutinib cohort had stopped therapy by the data cutoff, usually for progression, cardiac toxicity, infection, or a second malignancy.

Why R‑CHOP patients benefited most

Interpreting ENRICH requires attention to the trial’s design choice that investigators pre‑specify which chemotherapy they would have used. That choice produced two distinct control subgroups with different natural histories. Rituximab‑bendamustine performed better than R‑CHOP in this trial, echoing older trials where bendamustine‑based regimens have shown superior PFS and tolerability relative to CHOP‑like combinations in the elderly MCL population. The chemotherapy‑sparing ibrutinib‑rituximab regimen matched rituximab‑bendamustine in PFS but substantially outperformed R‑CHOP, a result that suggests that ibrutinib‑rituximab may be especially attractive when the alternative would be R‑CHOP rather than bendamustine‑based therapy.

Mechanistic explanations are plausible. R‑CHOP is less durable in MCL than bendamustine‑rituximab in several datasets, and maintenance rituximab after R‑CHOP does not fully offset early relapses in some populations. A continuous targeted therapy such as ibrutinib may suppress disease biology more effectively over time than a time‑limited anthracycline‑based approach in older patients, particularly where tumour biology is less aggressive. Conversely, rituximab‑bendamustine already provides long PFS for many patients, narrowing the margin for added benefit from BTK inhibition.

Clinical implications for practice

ENRICH supports ibrutinib‑rituximab as a front‑line option for older patients with MCL, particularly when the alternative is R‑CHOP or when patients prefer to avoid cytotoxic chemotherapy. The regimen is attractive because it is chemotherapy‑free, largely outpatient, and associated with rapid improvement in quality of life at mid‑induction compared with immunochemotherapy. For frail patients or those prioritising preservation of marrow reserve, the lower haematological toxicity is a meaningful advantage.

However, clinicians must weigh the trade‑offs carefully. Continuous ibrutinib exposure carries cardiovascular and bleeding risks and may increase infection susceptibility, an issue amplified during periods of community viral threats. Shared decision‑making should include discussion of atrial fibrillation risk, baseline cardiac evaluation, vigilant blood‑pressure control, and infection prophylaxis where indicated. For patients with high‑proliferation disease (Ki67 ≥30%) or blastoid histology, the data suggest chemotherapy remains an important option, and in those rare but difficult high‑risk settings clinicians will need to individualize therapy or consider clinical trials investigating multi‑agent targeted combinations or intensive regimens for those who can tolerate them.

ENRICH also affects sequencing: many patients in the immunochemotherapy arm who later relapsed received BTK inhibitors as second‑line therapy, which likely influenced overall survival parity between groups. For health services, wider adoption of front‑line BTK therapy could reshape drug budgets, outpatient clinic workflows, and monitoring needs, shifting costs from inpatient chemotherapy administration to long‑term oral targeted‑therapy management.

No single trial is definitive for all patients, and ENRICH has limitations that should temper universal adoption.

• Open‑label design and investigator‑assessed endpoints introduce potential bias, particularly in secondary analyses and quality‑of‑life reporting. Central blinded radiologic review could have strengthened the PFS assessment.
• The pre‑randomisation selection of chemotherapy is pragmatic and reflects real‑world decision making, but it produces two heterogeneous control subgroups. Because investigators chose the comparator, confounding by indication is possible despite baseline characteristics appearing similar; the R‑CHOP group was small (n≈53), which reduces precision of subgroup comparisons and increases risk that chance imbalances influenced outcomes.
• The trial occurred across the COVID‑19 pandemic. COVID‑19 deaths were substantial and disproportionately affected non‑relapse mortality, especially in the ibrutinib arm. Although sensitivity analyses censoring COVID‑19 deaths preserved the primary PFS conclusion, the pandemic complicates interpretation of safety and non‑cancer mortality and may limit generalizability to non‑pandemic contexts.
• Biological assays had incomplete coverage. Ki67 and TP53 data were missing for many participants, limiting power for biomarker‑driven subgroup conclusions. Ki67 assessment was local rather than centrally standardized, and interoperator variability reduces confidence in thresholds.
• The trial tested ibrutinib rather than newer, possibly better‑tolerated BTK inhibitors such as acalabrutinib or zanubrutinib in a randomized front‑line setting. Whether alternate covalent or non‑covalent BTK inhibitors would reproduce the efficacy with lower cardiac or bleeding risks remains unanswered.
• Median follow‑up of nearly four years captures many but not all long‑term events for a disease with variable trajectories. Overall survival analyses may evolve with longer follow‑up.

ENRICH creates a scaffold for several practical research directions.

1. Head‑to‑head comparison of modern BTK inhibitors in front‑line doublets: randomized trials should compare ibrutinib‑rituximab to regimens using second‑generation BTK inhibitors with potentially superior cardiac safety or to zanubrutinib/obinutuzumab doublets. These trials could preserve the chemotherapy‑free concept while optimizing tolerability.
2. Biomarker‑directed strategies: prospective trials should integrate robust central assessment of Ki67, TP53 mutation status, and other genomic and transcriptomic signatures to personalize first‑line choice. A stratified trial design could test whether patients with low‑risk biology can safely receive time‑limited doublets, while high‑risk patients are steered to combinations including venetoclax, cytarabine‑containing chemotherapy, or cellular therapies.
3. Time‑limited targeted combinations: ENRICH used continuous ibrutinib maintenance until progression. Trials should test whether fixed‑duration BTK‑based doublets or triplets (for example, BTK inhibitor plus venetoclax plus anti‑CD20 for a defined interval) can deliver durable remissions without lifelong exposure, reducing cumulative toxicities and infection risk.
4. Comparative effectiveness with bendamustine‑based regimens: given the parity between ibrutinib‑rituximab and rituximab‑bendamustine in ENRICH, prospective trials powered to compare these two options directly with attention to long‑term toxicity, second‑line efficacy, and impact on later cellular or T‑cell engaging therapies are necessary.
5. Integration into evolving treatment sequences: as chimeric antigen receptor (CAR) T‑cell therapy and bispecific T‑cell engagers advance into earlier lines, research must evaluate whether front‑line exposure to bendamustine (with its potential long‑term immune effects) or prolonged BTK inhibition affects the efficacy, toxicity, or feasibility of later immunotherapies. Trials and prospective registries should collect data on subsequent therapies and outcomes.
6. Real‑world studies and health‑economics: implementation studies and economic modelling will be needed to guide policy and reimbursement decisions, assessing total cost of care, impact on hospital resources, and patient preference for oral continuous therapy versus periodic chemotherapy infusions.
7. Infection mitigation and cardiac risk management: dedicated trials or pragmatic studies should explore prophylactic strategies, vaccination timing, antiviral prophylaxis, and cardiovascular risk reduction in patients receiving continuous BTK inhibition, especially in the elderly.

ENRICH demonstrates that a chemotherapy‑free, targeted approach; ibrutinib combined with rituximab, provides a meaningful progression‑free survival advantage over investigator‑chosen immunochemotherapy in older patients with MCL, with the largest benefit observed when the comparator is R‑CHOP. The doublet matches rituximab‑bendamustine for PFS, offers faster quality‑of‑life improvement, and reduces marrow toxicity at the cost of greater cardiovascular and infection‑related risks that require active management. Clinicians should incorporate these data into shared decisions with patients, balancing disease biology, comorbidities, personal priorities, and local access to drugs and supportive care.

ENRICH reframes front‑line care for a disease long dominated by cytotoxic paradigms. It opens a door toward personalized, less cytotoxic treatment pathways for many older patients while reminding the field that targeted therapies carry distinct, sometimes underappreciated harms. The most useful next steps are trials that refine which patients should receive time‑limited versus continuous targeted treatments, which targeted agents offer the safest long‑term profiles, and how best to sequence targeted and cellular therapies to maximize durable remissions and preserve options for later lines of care.