Rituximab Maintenance After Frontline BR Linked to Longer MCL Survival

Bendamustine-rituximab (BR) is a widely used frontline backbone for mantle cell lymphoma (MCL), yet whether to follow it with rituximab maintenance has remained unsettled. Pooled data from 2698 patients now link maintenance after BR to longer progression-free survival (PFS) and overall survival (OS), according to a systematic review and meta-analysis published in Haematologica.¹

Conflicting Evidence on Maintenance After Bendamustine-Rituximab

Rituximab maintenance became established after a different induction regimen. In the phase 3 European MCL Elderly trial (NCT00209209), which enrolled patients 60 years or older who were not eligible for high-dose therapy, rituximab maintenance reduced the risk of progression or death vs interferon alfa (HR, 0.55; 95% CI, 0.36-0.87; P = .01). Among patients who responded to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), maintenance also raised 4-year OS from 63% to 87%.²

The picture after BR has been murkier. The only randomized test, the phase 2 MAINTAIN trial conducted within the German and Austrian StiL NHL7-2008 study, enrolled 122 patients and found a median PFS of 72.3 months with maintenance vs 54.7 months with observation, a difference that was not statistically significant (HR, 0.71; 95% CI, 0.41-1.23). Several observational studies reported better outcomes with maintenance, leaving prospective and real-world evidence at odds and the use of maintenance after BR inconsistent across clinical practice and trials.¹

Analysis Pooled 1 Trial and 6 Real-World Cohorts

The researchers searched PubMed/MEDLINE, Embase, and abstracts from the American Society of Hematology, American Society of Clinical Oncology, and European Hematology Association meetings from inception through April 2026, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines. Eligible studies included adults with newly diagnosed MCL who received frontline BR and compared rituximab maintenance with observation, reporting HRs for PFS, OS, or both. In observational studies, event-free survival or time to next treatment or death served as proxies for PFS.

Of 242 publications identified, 7 studies comprising 2698 patients met the criteria: MAINTAIN and 6 observational cohorts drawn from a US multicenter retrospective study; a British Columbia cohort; the US Flatiron Health database; the Surveillance, Epidemiology, and End Results (SEER)-Medicare database; a North American multicenter study; and the Danish National Lymphoma Registry. In total, 1370 patients (50.8%) received maintenance, and follow-up ranged from 3.1 to 6.1 years. Results were pooled with a random-effects model; pooled age, sex, or prognostic index data were not reported.

Maintenance Linked to Longer PFS and OS in MCL

Across the 7 studies, rituximab maintenance was associated with significantly longer PFS (HR, 0.56; 95% CI, 0.49-0.63; P < .001), with no detectable heterogeneity between studies (I² = 0%). Maintenance was also associated with longer OS (HR, 0.64; 95% CI, 0.52-0.77; P < .001), with low to moderate heterogeneity (I² = 27%).

Because the British Columbia cohort allowed autologous stem cell transplant after BR in 71 patients, the researchers repeated the analysis without it, and the results held for PFS (HR, 0.56; 95% CI, 0.49-0.63) and OS (HR, 0.63; 95% CI, 0.51-0.78). Leave-one-out analyses were consistent, and funnel plots showed no significant publication bias, although the small number of studies limited that assessment.

“Our findings suggest that contemporary clinical trials using BR as the control arm should ideally incorporate rituximab maintenance to reflect current evidence-based practice,” the researchers wrote.

Among recent trials that used BR as a control arm, ENRICH and ECHO incorporated maintenance, whereas MANGROVE did not include maintenance after BR. The authors said that difference should be considered when comparing efficacy across trials.

Observational Data and Missing Safety Analysis Limit Conclusions

Most of the pooled evidence came from observational studies, which carry risks of selection bias and confounding by indication, and the researchers acknowledged that residual confounding cannot be excluded and that a formal risk-of-bias assessment was not comprehensively performed. Without patient-level data, they could not adjust for key prognostic variables, and features such as Ki-67, TP53 alterations, and blastoid or pleomorphic morphology could not be assessed. Maintenance schedules, treatment durations, subsequent therapies, and end point definitions also varied across studies, and the analysis did not address adverse events from maintenance treatment.

The authors also cautioned that the findings should not be extrapolated to intensified regimens that add cytarabine or venetoclax to BR. Within those bounds, they supported maintenance for patients who respond to frontline BR and are suitable for ongoing therapy, with decisions individualized by comorbidities, infection risk, and patient preference.

References

1. Wang J, Yi D, Gao Y, et al. Rituximab maintenance following frontline bendamustine-rituximab in mantle cell lymphoma: a systematic review and meta-analysis. Haematologica. Published online September 24, 2026. doi:10.3324/haematol.2026.301413
2. Kluin-Nelemans HC, Hoster E, Hermine O, et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012;367(6):520-531. doi:10.1056/NEJMoa1200920