MRD-Guided Therapy Shows Promise as a Time-Limited Frontline Strategy for MCL

A new phase 2 clinical trial suggests that a chemotherapy-free, minimal residual disease (MRD)–driven treatment strategy may offer durable remissions and the possibility of time-limited therapy for patients with previously untreated mantle cell lymphoma (MCL).¹

The investigators describe their findings as a “proof of concept” for response-adapted, limited-duration frontline therapy in MCL. The study, published in Blood Advances, assessed acalabrutinib (Calquence; AstraZeneca) and lenalidomide paired with either rituximab (Rituxan; Genentech) (ALR) or obinutuzumab (Gazyva; Genentech) (ALO) guided by MRD monitoring, finding that both regimens produced high molecular response rates, favorable survival outcomes, and manageable toxicity profiles.

Although novel targeted therapies have improved outcomes in relapsed MCL, traditional frontline treatment still relies heavily on cytotoxic chemotherapy. The new study explores a different paradigm—one that replaces chemotherapy with targeted agents while using MRD monitoring to individualize treatment duration and reduce long-term toxicity.

The trial enrolled 34 patients with untreated, measurable MCL. Twenty-four received ALR, while 10 were treated in a subsequent feasibility cohort with ALO, which substitutes obinutuzumab for rituximab. All patients had advanced-stage disease, and many had high-risk features such as elevated lactate dehydrogenase, bone marrow involvement, or TP53 mutations.

Molecular monitoring played a central role in the study's design, explained the researchers. Serial MRD assessments allowed investigators to track treatment response with high sensitivity, observe the kinetics of molecular clearance, and identify patients eligible for treatment de-escalation. Nearly all evaluable patients in both cohorts eventually achieved undetectable MRD, and many were able to stop oral therapy at 2 years while remaining in remission. Among those who discontinued therapy, only a small number relapsed, typically after prolonged treatment-free intervals.

In addition to MRD tracking through clonoSEQ, the investigators performed extensive profiling of circulating tumor DNA (ctDNA), enabling longitudinal monitoring of tumor mutations and clonal evolution. In the ALR cohort, targeted sequencing revealed a dramatic reduction in ctDNA variant allele frequency after 12 cycles and provided early insight into molecular changes associated with relapse. These findings support the feasibility of integrating ctDNA analysis into early-line MCL management, complementing cell-based MRD tools.

One persistent challenge emerged among patients with TP53 mutations, a high-risk genetic subgroup with historically poor outcomes.² While most achieved molecular remission, they were more likely to relapse earlier.

“Our observation that TP53 mutations continue to challenge effective treatment strategies and are associated with inferior prognosis is consistent with other non-chemo-based regimens (AIM, BOVEN and ENRICH), suggesting that simply replacing chemotherapy with targeted drugs will be insufficient therapy to fully overcome resistance for many of these patients with high risk MCL,” noted the researchers.¹

In the ALR cohort, overall response rate (ORR) reached 100%, with 83% achieving complete remission after 12 cycles. Molecular remission followed a similar pattern: 67% of patients achieved undetectable MRD at the 12-cycle mark, and the rate rose to 83% with continued therapy. After a median of 53 months of follow-up, 4-year progression-free survival (PFS) was 76%, and overall survival (OS) was 91%.

Results from the ALO cohort were comparable, and in some respects even stronger, with a 90% ORR and 90% CR rate following induction, along with 90% molecular remission after 12 cycles. At 2 years, both PFS and OS were 100%.

“Although not designed as a randomized study, the immediate juxtaposition of the ALO cohort following ALR revealed a more rapid uMRD6 clearance for ALO (90%) compared to ALR (67%) after 12 cycles of induction, which warrants further investigation in randomized fashion comparing obinutuzumab with rituximab as the anti-CD20 antibody combination,” explained the researchers.

The safety profile of both regimens was favorable. Grade 3 to 4 hematologic toxicities included neutropenia, thrombocytopenia, and anemia, with no cases of febrile neutropenia. Nonhematologic toxicities such as rash, fatigue, and mild gastrointestinal symptoms were generally low-grade. The ALO cohort had a higher incidence of transient liver enzyme elevations during induction, while COVID-related infections were noted across both groups during the pandemic period. Importantly, no atrial fibrillation events were reported, a notable distinction from some earlier BTK inhibitors. Secondary skin cancers occurred in a minority of patients, a known risk associated with lenalidomide exposure.

References

1. Ruan J, Bond DA, Shah BD, et al. MRD-driven initial therapy of acalabrutinib and lenalidomide plus rituximab (ALR) or obinutuzumab (ALO) for mantle cell lymphoma. Blood Adv. Published online November 25, 2025. doi:10.1182/bloodadvances.2025017760

2. Zhang N, Xu J, Luo C, et al. Treatment outcomes for patients with TP53-mutated mantle cell lymphoma: a systematic review and meta-analysis. Blood. 2024;144(S1):3041. doi:10.1182/blood-2024-209480