ZR2 Plus R-DHAP and Zanubrutinib Maintenance With/Without ASCT Displays Promising Efficacy in Newly Diagnosed MCL

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Treatment with the ZR2 regimen (zanubrutinib [Brukinsa], rituximab [Rituxan], and lenalidomide [Revlimid]) followed by R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin), with or without autologous stem cell transplantation (ASCT), was active in patients with treatment-naive mantle cell lymphoma (MCL), according to data from a phase 2 study (NCT05992597) presented during the 2025 European Hematology Association Congress.1

At the February 20, 2025, data cutoff, the overall response rate (ORR) among patients who completed 3 cycles of ZR2 (n = 14) was 93.3%, including a complete response (CR) rate of 73.3%. The ORR and CR rate among patients who completed induction therapy (n = 14) was 93.3% and 86.7%, respectively.

At a median follow-up of 12 months (95% CI, 8.8-13.9) the median progression-free survival (PFS) and overall survival (OS) were both not reached. The 1-year PFS and OS rates were both 93.3%.

“This regimen significantly reduced the cycles of chemotherapy and associated toxicity,” the study authors wrote in a poster presentation of the data. “These results highlight the potential of this therapeutic approach in improving outcomes for [patients with] MCL.”

Unpacking the Study Design and Baseline Characteristics

The investigator-initiated, single-arm study enrolled patients with treatment-naive MCL who were 18 to 75 years old. Other key inclusion criteria included the presence of measurable lesions and adequate organ function. Those with central nervous system lymphoma, active infections, and/or coagulopathy were excluded from the trial.

Patients received three 21-day cycles of ZR2 followed by 3 cycles of R-DHAP. Patients who achieved a response and who were eligible for ASCT received consolidation therapy and all others continued with zanubrutinib as maintenance therapy for up to 2 years. Mandatory prophylaxis consisted of anticoagulation and antipneumocystis measures.

The primary end point was ORR at the end of induction therapy. Secondary end points included progression-free survival, overall survival, and safety.2

At baseline, the median age in the overall population (n = 15) was 59 years (range, 45-75).1 Most patients were male (86.7%), had an ECOG performance status of 0 or 1 (93.3%), had disease with bone marrow involvement (93.3%), had Ann Arbor stage III or IV disease (93.3%), and did not have TP53-mutated disease (86.7%).

Patients had Mantle Cell Lymphoma International Prognostic Index low- (66.7%), intermediate- (20%), or high-risk (13.3%) disease. Eight patients had confirmed gastrointestinal lymphoma involvement.

Examining the Safety Data and Additional Efficacy Findings

Seven patients received consolidation ASCT. One patient with high-risk disease died after induction failure; all other patients remained free of disease progression.

In terms of safety, adverse effects (AEs) were mostly grade 1 or 2 during ZR2 therapy. The most common any-grade AE was rash (33.3%); grade 3 rash and penumonia were reported in 20% and 6.7% of patients, respectively. Patients who received zanubrutinib maintenance (n = 11) experienced grade 3 pneumonia at a rate of 36.4%. Three cases of grade 3 pneumonia occurred in patients who also received ASCT.

Two patients discontinued treatment, 1 due to recurrent cytopenia following ASCT and another due to intolerable gastrointestinal toxicity. All other patients continued with therapy without any dose-limiting toxicities.

“The AEs associated with zanubrutinib maintenance therapy should not be underestimated, particularly in patients who have undergone ASCT,” the study authors wrote in their conclusion.

References

1. Chen X, Li C, Lei T, et al. Rituximab, lenalidomide and zanubrutinib chemo-free regimen followed by immunochemotherapy for patients with newly diagnosed mantle cell lymphoma: an investigator initiated, single arm, phase 2 trial. Presented at: 2025 European Hematology Association Congress; June 12-15, 2025; Milan, Italy. Abstract PS1893.
2. ZR2 sequential immunochemotherapy for newly treated MCL. ClinicalTrials.gov. Updated September 21, 2023. https://clinicaltrials.gov/study/NCT05992597