Ibrutinib Plus Rituximab Shows PFS Benefit Over Chemoimmunotherapy in Untreated MCL

First-line ibrutinib (Imbruvica) plus rituximab demonstrated superior progression-free survival (PFS) outcomes vs standard chemoimmunotherapy in patients 60 years of age or older with mantle cell lymphoma (MCL), according to primary results from the phase 2/3 ENRICH trial (EudraCT 2015–000832–13).

At a median follow-up of 47.9 months (IQR, 27.1-63.3), the primary analysis of PFS showed the superiority of ibrutinib plus rituximab (n = 199) over immunochemotherapy (n = 198), with an adjusted HR of 0.69 (95% CI, 0.52-0.90; P = .0034).

Among patients pre-assigned to the R-CHOP (rituximab [Rituxan], cyclophosphamide, doxorubicin, vincristine, and prednisolone) group (n = 107), the HR for PFS favored ibrutinib–rituximab (HR, 0.37; 95% CI, 0.22-0.62). The 5-year PFS probability was 52% (95% CI 40%-69%) for patients who received ibrutinib plus rituximab vs 19% (95% CI, 11%-35%) in the R-CHOP group.

However, in patients pre-assigned to the rituximab plus bendamustine (n = 290) arm, the HR for ibrutinib plus rituximab vs rituximab plus bendamustine was 0.91 (95% CI, 0.66-1.25), indicating comparable efficacy between regimens in this subgroup. The 5-year PFS probability was 51% (95% CI, 43%-60%) for the ibrutinib plus rituximab group vs 47% (95% CI, 39%-57%) for the rituximab plus bendamustine group.

Of note, the PFS benefit with ibrutinib plus rituximab compared with chemoimmunotherapy was consistent across most predefined subgroups, excepting blastoid disease, where a trend in favor of immunochemotherapy was observed (HR, 2.33; 95% CI, 0.83-6.52).

“Outcomes compared to the rituximab plus bendamustine subgroup were broadly equivalent. Ibrutinib-rituximab should be considered a new standard of care treatment option for older patients unsuitable for intensive approaches,” lead study author David J Lewis, MBChB, PhD, and colleagues explained in their paper.

Lewis is a consultant hematologist at the University Hospitals Plymouth NHS Trust.

How Was the ENRICH Trial Designed?

The ENRICH trial was an international, randomized, open-label, phase 2/3 superiority study evaluating whether ibrutinib plus rituximab would produce superior outcomes compared with standard frontline chemoimmunotherapy in an older population of patients with previously untreated MCL.2

The trial enrolled patients aged 60 years or older with untreated, Ann Arbor stage II–IV MCL and an ECOG performance status of 0 to 2. Conducted across 66 sites in the United Kingdom, Sweden, Norway, Finland, and Denmark, participants were randomly assigned 1:1 to receive investigator’s choice of either R-CHOP or rituximab plus bendamustine vs ibrutinib plus rituximab. Patients were stratified according to the investigator’s pre-randomization choice of immunochemotherapy regimen.

Patients assigned to the experimental arm received oral ibrutinib at a daily dose of 560 mg in combination with intravenous rituximab at 375 mg/m² on day 1 of each treatment cycle. The treatment schedule mirrored that of the chosen chemoimmunotherapy regimen: every 21 days for R-CHOP or every 28 days for rituximab plus bendamustine.

For patients in the control arm, the R-CHOP regimen consisted of 750 mg/m² of cyclophosphamide, 50 mg/m² of doxorubicin, and 1.4 mg/m² of vincristine on day 1 of each 21-day cycle, along with 100 mg of prednisolone on days 1 through 5. The rituximab plus bendamustine regimen comprised 90 mg/m² of bendamustine on days 1 and 2 of each 28-day cycle, combined with 375 mg/m² of rituximab on day 1.

Following induction, patients in both treatment arms who achieved a response were eligible for maintenance rituximab, which was administered every 8 weeks for 2 years. Patients in the experimental arm continued ibrutinib until disease progression or unacceptable toxicity.

The primary end point of the study was investigator-assessed PFS in the intention-to-treat population. Secondary end points included overall survival (OS), overall response rates (ORR), and safety outcomes.

What Were the Baseline Patient Characteristics?

Among the 397 patients enrolled, 27% of patients were pre-allocated to R-CHOP (n = 107) and 73% to rituximab plus bendamustine (n = 290).1 The median age in both treatment arms was 74 years (IQR, 70-77) in the intervention group and 74 years (IQR, 70-78) in the control group.1 The study population was predominantly male (75%; n = 296), with 101 female participants (25%). Of note, ethnicity data were not collected, as recording ethnicity is prohibited under Swedish law.

Among evaluable patients (n = 393), 56% had a high Mantle Cell Lymphoma International Prognostic Index (MIPI) score; data were missing for 4 patients. Blastoid morphology was identified in 7% of patients with available histopathologic data (n = 370).

Patients who withdrew or were lost to follow-up were censored at the time of last recorded contact. The data cutoff for the primary analysis was June 30, 2024.

What Additional Efficacy Outcomes Were Observed?

Among the 199 patients who underwent random allocation for ibrutinib plus rituximab, the ORR was 86%, including a complete response (CR) rate of 54%. The ORR was 85% in the 198 patients who were allocated for chemoimmunotherapy, with a CR rate of 53%.

The 5-year OS probability was 58% (95% CI, 51%-66%) for patients treated with ibrutinib plus rituximab, compared with 55% (95% CI, 47%-63%) in the control group (HR, 0.87; 95% CI 0.64-1.18). For patients with a pre-randomization choice of R-CHOP, the 5-year OS probability for ibrutinib plus rituximab was 59% (95% CI, 47%-75%) vs 46% (95% CI, 34%-64%) with R-CHOP (HR, 0.64; 95% CI, 0.36-1.13). For those in the rituximab plus bendamustine arm pre-randomization, the 5-year OS probability was 57% (95% CI, 49%-67%) with ibrutinib plus rituximab vs 58% (95% CI, 50%-68%) in the rituximab plus bendamustine group (HR, 1.00; 95% CI, 0.70-1.44).

What Safety Outcomes Were Observed With Ibrutinib Plus Rituximab During the Induction and Maintenance Phases?

Regarding safety, grade 3 or higher adverse effects (AEs) during the induction phase occurred in 51% of patients receiving bendamustine plus rituximab, 67% of those receiving R-CHOP, and 42% of those treated with ibrutinib plus rituximab. During the maintenance phase, these respective rates were 31%, 21%, and 49%.

The incidence of cardiac AEs during induction was 5% with bendamustine plus rituximab, 10% with R-CHOP, and 11% with ibrutinib plus rituximab; atrial fibrillation occurred in 1%, 0%, and 3% of patients treated with these respective regimens, respectively. During maintenance, cardiac AEs were reported in 1%, 6%, and 15% of patients, respectively, with atrial fibrillation observed in 0%, 0%, and 5%.

Bleeding-related AEs were infrequent across all arms, occurring in 1% of patients treated with bendamustine–rituximab, 6% with R-CHOP, and 3% with ibrutinib–rituximab during induction, and in 1%, 0%, and 3%, respectively, during maintenance.

Hematologic AEs were among the most common events during induction, affecting 20% of patients treated with bendamustine–rituximab, 31% with R-CHOP, and 10% with ibrutinib–rituximab. Neutropenia was reported in 13%, 17%, and 4% of patients, respectively, while febrile neutropenia occurred in 4%, 10%, and 2%. During maintenance, hematologic AEs were seen in 8%, 6%, and 9% of patients, respectively, with neutropenia reported in 7%, 6%, and 7%.

Infection-related AEs of grade 3 or higher occurred in 11% of patients treated with bendamustine–rituximab, 23% with R-CHOP, and 12% with ibrutinib–rituximab during induction. Rates during maintenance were 15%, 6%, and 18%, respectively. Pneumonia occurred in 2%, 2%, and 2% of patients during induction and 3%, 2%, and 4% during maintenance. COVID-19 infection was reported in 7%, 2%, and 7% of patients, respectively.

Gastrointestinal AEs were generally low across all treatment groups. Diarrhea was reported in 3% of patients treated with bendamustine–rituximab and 1% with ibrutinib–rituximab during induction, and in 1% and 3%, respectively, during maintenance.

References

1. Lewis DJ, Jerkeman M, Sorrell L, et al. Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial. The Lancet. Published online October 2025. doi: 10.1016/s0140-6736(25)01432-1
2. ‌Ibrutinib and rituximab in treating patients with relapsed or refractory mantle cell lymphoma or older patients with newly diagnosed mantle cell lymphoma. Clinicaltrials.gov. Updated October 3, 2025. Accessed October 7, 2025. https://www.clinicaltrials.gov/study/NCT01880567