Fixed‑Duration Venetoclax After RBAC Improves 2‑Year PFS in High‑Risk Older Mantle Cell Lymphoma: Final Results of the FIL_V‑RBAC Phase 2 Study

Highlights

– FIL_V‑RBAC is the first prospective trial to use risk stratification at diagnosis to guide initial treatment intensity in mantle cell lymphoma (MCL).

– In older, fit patients with high‑risk disease features (blastoid morphology, Ki‑67 ≥30%, TP53 mutation, or 17p deletion), four cycles of RBAC followed by fixed‑duration venetoclax produced a 2‑year progression‑free survival (PFS) of 60% (95% CI 48–74).

– Hematologic toxicity (neutropenia, thrombocytopenia) was the predominant grade ≥3 adverse event during venetoclax consolidation and maintenance; one treatment‑related death from tumour lysis syndrome occurred during induction.

Background: clinical context and unmet need

Mantle cell lymphoma (MCL) is a clinically heterogeneous B‑cell lymphoma that ranges from indolent presentations to aggressive disease characterized by high proliferation, blastoid morphology, and adverse genetic features such as TP53 mutation or 17p deletion. Older, fit patients who are ineligible for high‑dose chemotherapy and autologous stem cell transplantation represent a substantial clinical subgroup for whom optimizing front‑line regimens is critical. Standard immunochemotherapy regimens for such patients often include combinations of anti‑CD20 monoclonal antibody with alkylators and cytarabine; however, outcomes are worse in patients with high‑risk biological features and TP53 disruption. There is a clear unmet need for strategies that improve durability of response in this high‑risk population without unacceptable toxicity.

Study design

FIL_V‑RBAC is a multicentre, single‑arm, phase 2 study conducted at 35 Fondazione Italiana Linfomi centres in Italy (ClinicalTrials.gov NCT03567876). Treatment‑naive patients with histologically confirmed MCL who were aged ≥65 years and fit by a modified geriatric assessment (or younger than 65 but ineligible for high‑dose chemotherapy with ECOG ≤2) were enrolled and, after baseline assessment, classified into low‑risk or high‑risk groups based on presence of any of: blastoid morphology, Ki‑67 ≥30%, TP53 mutation, or 17p deletion.

Low‑risk patients received six 28‑day cycles of RBAC (rituximab 375 mg/m2 day 1; bendamustine 70 mg/m2 days 1–2; cytarabine 500 mg/m2 days 1–3). High‑risk patients received four cycles of RBAC followed by a fixed‑duration oral venetoclax consolidation (4 months at 800 mg/day) and maintenance (20 months at 400 mg/day). The predefined primary endpoint was 2‑year PFS in high‑risk patients who received at least one dose of RBAC.

Key findings

Patient population and follow‑up

Between Sept 2018 and July 2021, 155 patients were screened and 140 enrolled and analysed. Median age was 72 years (IQR 69–76); 76% were male and all participants were White. Fifty‑four patients (39%) met criteria for high‑risk disease: 28 (20%) had TP53 mutations, 19 (14%) had 17p deletions, 34 (24%) had Ki‑67 ≥30%, and 13 (9%) had blastoid morphology. Median follow‑up was 45 months (IQR 40–55).

Efficacy outcomes

In the prespecified high‑risk cohort, the 2‑year PFS was 60% (95% CI 48–74). Median PFS in the high‑risk group was 37 months (95% CI 19–not reached). These results indicate that the combination of cytarabine‑containing induction followed by fixed‑duration venetoclax achieved disease control in a population historically prone to early relapse.

Safety

Toxicity during venetoclax consolidation and maintenance was dominated by hematologic adverse events. During consolidation (n=43 assessed), grade ≥3 neutropenia occurred in 12 patients (28%), thrombocytopenia in three (7%), and skin reactions in three (7%). During maintenance (n=37 assessed), grade ≥3 neutropenia occurred in seven patients (19%), thrombocytopenia in two (5%), and anemia in two (5%). There was one treatment‑related death among the 140 patients: tumour lysis syndrome occurring during the first RBAC induction in a high‑risk patient.

Interpretation of effect size and clinical relevance

Achieving a 2‑year PFS of 60% in a high‑risk cohort enriched for TP53 disruption and high proliferation is clinically meaningful, given the poor historical outcomes in such subgroups with chemoimmunotherapy alone. The median PFS of 37 months suggests that fixed‑duration venetoclax consolidation plus maintenance can prolong disease control beyond induction, while allowing for an oral, time‑limited targeted component that is attractive for older patients.

Expert commentary: strengths, limitations and context

Strengths

FIL_V‑RBAC establishes a prospectively defined, risk‑adapted therapeutic strategy at diagnosis and evaluates the feasibility of adding a BCL‑2 inhibitor in older, fit patients. The multicentre design and relatively mature follow‑up (median 45 months) strengthen the validity of the observed PFS data. Use of objective, prespecified high‑risk criteria (TP53 mutation/17p deletion, Ki‑67 ≥30%, blastoid morphology) is a pragmatic framework for clinical stratification.

Limitations

Key limitations include the single‑arm design and lack of a randomized control arm treated with RBAC alone; therefore, observed outcomes must be contextualized against historical benchmarks and are subject to selection and temporal biases. The study population was exclusively White, which limits generalizability. Detailed molecular minimal residual disease (MRD) data are not reported in the summary; such data would help link depth of response to long‑term outcomes. Finally, fixed dosing and schedule of venetoclax were pragmatic but not compared to alternative sequencing (for example, concurrent vs sequential) or combinations with other targeted agents such as BTK inhibitors.

Biological plausibility and mechanistic considerations

Venetoclax targets BCL‑2, an antiapoptotic protein frequently expressed in mature B‑cell malignancies. Preclinical and clinical data have shown single‑agent activity of venetoclax in MCL and synergy with chemotherapy and other targeted agents in lymphoma models. In patients with TP53 disruption, direct exploitation of apoptotic pathways by BCL‑2 inhibition provides a biologically plausible rationale to overcome chemo‑resistance driven by deficient p53‑dependent apoptosis, though TP53 mutant disease remains challenging and may still display shorter durations of response.

How this fits into current practice

The risk‑adapted approach promoted by FIL_V‑RBAC supports routine upfront assessment of proliferation index and TP53 status in newly diagnosed MCL to inform therapeutic planning. For older patients unfit for transplantation and with high‑risk features, adding fixed‑duration venetoclax after cytarabine‑containing induction is a reasonable option supported by this phase 2 evidence, pending confirmation. However, clinicians should weigh hematologic toxicity risk, monitor for tumor lysis syndrome (particularly during induction and venetoclax initiation), and consider patient comorbidities and drug interactions when prescribing venetoclax.

Future directions

Confirmatory randomized trials are required to establish causality and quantify the incremental benefit of venetoclax after RBAC versus RBAC alone, ideally with stratification by TP53 status, Ki‑67, and MRD kinetics. Combination strategies that pair venetoclax with BTK inhibitors (for example, ibrutinib, acalabrutinib) have shown promise in other B‑cell malignancies and warrant exploration in high‑risk MCL. Integration of MRD monitoring could allow response‑adapted therapy duration, potentially limiting toxicity while preserving efficacy. Finally, broader inclusion of diverse populations and harmonized reporting of molecular features will improve generalizability.

Conclusion

FIL_V‑RBAC provides the first prospective evidence that a risk‑adapted strategy in MCL, with addition of fixed‑duration venetoclax following a cytarabine‑containing induction, can produce meaningful PFS in older patients with high‑risk disease. Toxicities were manageable in most patients, with hematologic adverse events predominating. While promising, these findings should be validated in randomized studies and complemented by molecular response assessments to optimize patient selection and treatment duration.

Funding and trial registration

Funding: Fondazione Italiana Linfomi‑Ente del Terzo Settore, Leukemia and Lymphoma Society, Ministry of Health (Italy), and AbbVie.

ClinicalTrials.gov: NCT03567876

References

1. Visco C, Tabanelli V, Sacchi MV, et al; Fondazione Italiana Linfomi. Rituximab, bendamustine, and cytarabine followed by venetoclax in older patients with high‑risk mantle cell lymphoma (FIL_V‑RBAC): a multicentre, single‑arm, phase 2 study. Lancet Haematol. 2025 Oct;12(10):e777‑e788. doi:10.1016/S2352‑3026(25)00252‑2. PMID: 40975105.

2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Mantle Cell Lymphoma. Version 2.2024. Accessed 2025.

Thumbnail image prompt

A realistic, clinical thumbnail: an older patient and a hematologist reviewing a laptop showing a PET/CT image and molecular test results; a small inset shows a blister pack of oral pills labeled “venetoclax” and an infusion bag labeled “RBAC”; cool clinical color palette, high detail, photographic realism, shallow depth of field, journal cover style.