Experimental Triplet Regimen Shows Early Promise in High-Risk MCL

Early results from a multicenter phase 2 trial detailed in Blood suggest that a novel triple combination may offer an effective frontline strategy for patients with high-risk mantle cell lymphoma (MCL), a group that traditionally faces limited options and poor outcomes.

The interim analysis of glofitamab (Columvi; Genentech), lenalidomide (Revlimid; Celgene), and venetoclax (Venclexta; Genentech and AbbVie)—together known as the GLOVe regimen—represents the completion of the study’s first stage of enrollment, reporting rapid and deep responses across a heavily high-risk population, with manageable toxicity and encouraging early progression-free survival (PFS).

MCL remains one of the most challenging B-cell malignancies to treat, particularly for patients with aggressive biological features such as TP53 mutations, complex cytogenetics, blastoid morphology, or high proliferative index. Although BTK inhibitors have become increasingly integrated into frontline care—supported by recent trials such as TRIANGLE and ECHO—patients with multiple high-risk factors continue to demonstrate suboptimal long-term outcomes.

The GLOVe trial was designed to test whether the CD20/CD3 bispecific antibody glofitamab could be incorporated into a multi-agent frontline regimen alongside venetoclax, a BCL2 inhibitor, and lenalidomide, an immunomodulatory therapy.² Investigators hypothesized that these agents could complement one another by both debulking disease and modulating immune engagement, potentially lowering the risk of severe cytokine release syndrome while delivering deeper remissions.¹

The study enrolled 25 treatment-naïve patients, all meeting high-risk criteria and significant disease burden: nearly all had stage III/IV disease and bone marrow involvement, almost half carried TP53 mutations, more than one-third had del17p, and 83% had complex cytogenetics. Blastoid histology and high Ki-67 proliferative index were also well represented.

Among the 20 patients evaluable for treatment response, all achieved complete response, and 95% reached undetectable minimal residual disease at a threshold of 10⁻⁶. The median time to best response was 53 days, underscoring the rapid activity of the regimen. Notably, no patients had experienced disease progression at the time of analysis, with six-month PFS estimated at 90% and duration of response at 95%.

With a median follow-up of just over 7 months, the results remain preliminary, and longer observation is essential to determine durability of response and long-term tolerability. However, the consistency and depth of early responses provide a compelling rationale for continued enrollment and future randomized studies.

Patients underwent a structured, multi-agent induction sequence beginning with venetoclax ramp-up, followed by obinutuzumab debulking, step-up dosing of glofitamab, and finally lenalidomide beginning in cycle 3. The design aimed to maximize disease control while reducing the risk of immune-mediated toxicities, noted the trial researchers.

Toxicity data reflected a profile consistent with glofitamab and its class, although the investigators noted more modest rates of cytokine release syndrome (CRS) than typically observed with bispecific antibodies in relapsed disease settings. CRS occurred in 55% of patients, mostly grade 1 or 2; only 1 case reached grade 3 severity.

“Data thus far after the completion of the 1st stage of the study indicates that CRS associated with glofit can be mitigated using targeted therapies as a debulking strategy,” wrote the researchers.

A single case of grade 2 immune effector cell-associated neurotoxicity syndrome was reported and resolved. Hematologic side effects, including neutropenia and thrombocytopenia, were common but manageable, and dose reductions were primarily limited to lenalidomide.

Two deaths occurred during treatment, 1 from treatment-related sepsis and 1 from unrelated multi-organ failure during venetoclax escalation. Both events highlight the vulnerability of this biologically frail patient population, though the overall safety profile remained acceptable for a high-risk frontline trial, highlighted the researchers.

References
1. Phillips T, Chen L, Barnhizerr T, et al. Interim analysis of the phase II study of glofitamab, lenaliomide and venetoclax (GLOVe) in untreated patients w/ high-risk mantle cell lymphoma. response and safety outcomes after the completion of stage 1 of 2 enrollment. Blood. 2025;146(S1):883. doi:10.1182/blood-2025-883
2. Glofitamab with obinutuzumab, venetoclax, and lenalidomide for the treatment of newly diagnosed high risk mantle cell lymphoma. ClinicalTrials.gov. Updated August 29, 2025. Accessed December 14, 2025. https://clinicaltrials.gov/study/NCT05861050