During an interview with OncLive®, Visco discussed findings from the phase 2 FIL_V-RBAC study (NCT03567876), which evaluated venetoclax (Venclexta) added to bendamustine, rituximab (Rituxan), and intermediate-dose cytarabine (RBAC) in treatment-naive, older, or transplant-ineligible patients with MCL across 35 Italian centers, highlighting the manageable hematologic toxicity profile observed with RBAC and the minor incremental toxicity associated with venetoclax during consolidation.
“We observed that after a median follow-up of 45 months, the 2-year PFS [rate] of the high-risk group was 60%, [satisfying] the primary end point of the study. In the end, we observed that venetoclax conferred a survival advantage when consolidating patients with high-risk features, and specifically after 4 cycles of RBAC,” Visco explained. “In terms of toxicity, [we] didn’t see any unexpected adverse effects compared with the single drugs that have been used. The RBAC 500 regimen is well known for [its] hematological toxicity, which can be widely reduced by dose reductions along cycles, and venetoclax in consolidation basically conferred only minor hematological toxicity.”
Visco serves as an associate professor of Hematology in the Department of Medicine, Section of Hematology, at the University of Verona in Italy.
OncLive: What is the rationale for conducting this analysis within [the] treatment landscape of MCL?
One of the [major] unmet needs in MCL treatment is [how] to deal with [the] high-risk patients. High-risk patients have been treated with the standard regimen so far. FIL_V-RBAC, which was developed in Italy by the Fondazione Italiana Lymphoma, there was no trial dealing specifically with high-risk patients. The real [aim] of this trial was [to] stratify patients upfront between low risk and high risk and dedicate a specific treatment to high-risk patients, which was basically the primary end point of this study.
What were the design and enrollment criteria of the study?
Bendamustine-rituximab, combined with intermediate-dose cytarabine, has been and [remains] a standard initial regimen for older patients with MCL in [many] international guidelines. With this study, we aimed to investigate whether the addition of venetoclax to the RBAC regimen could improve progression-free survival of [patients] with high-risk MCL.
High-risk MCL [was] defined as having at least 1 of these features: a blastoid morphology, a high Ki-67 [proliferation index] defined as Ki-67 30% or higher, the presence of a TP53 gene mutation, or the 17p deletion, so a FISH-positive [result] for deletion of the gene involving the TP53 gene.
The study was conducted in Italy. It was a phase 2, multicenter, single-arm study involving 35 [institutions] from the Fondazione Italiana Lymphoma. Inclusion criteria were for histologically confirmed, treatment-naive patients with mantle cell lymphoma, age 65 or older.
Treatment was [conceived as] 4 cycles of RBAC for all patients and patients were stratified according to the risk profile during the screening phase. Patients [with] at least 1 of the risk factors that I mentioned before were treated with 4 RBAC [cycles] and then consolidated with venetoclax. The treatment of low-risk patients was different from the treatment [of] high-risk patients, because venetoclax was dedicated just to patients with high-risk features.
[When analyzing] the results, we could combine the 2 populations but also split them and see the real efficacy of RBAC itself in low-risk patients, and RBAC with the addition of venetoclax in high-risk patients.
We enrolled [155] consecutive patients [who] were screened for inclusion, of whom [140] were enrolled and analyzed for study end points. The median age of the whole population was 72 [years]. Most of the patients were male, as we always see in MCL, all were White, and 54 patients had a high-risk profile. Twenty percent had TP53 mutations, 14% had 17p deletions, 24% had [high] kinetics, and 9% had blastoid morphology.
What dosing considerations or practical adjustments do you recommend when administering the RBAC regimen?
In terms of RBAC, [I] always suggest to my students and the [oncologists] I see around Italy and Europe that it is very advisable to try to reduce the doses that have been published before. The original 500 [mg/m²] regimen was designed to be given over 3 days, with a third day of cytarabine on the third day of therapy. This, as per protocol in the study but also in real life when we use it, I believe should be avoided for most patients, unless the patient is very fit or tolerates the treatment well.
I always suggest [avoiding] the third day of cytarabine and to give the cycle in a 2-day fashion. In this way, you can evaluate hematotoxicity and then possibly lower the doses of cytarabine and bendamustine. This is what I suggest usually, because you have to consider that RBAC itself is one of the most powerful regimens we have, and has the advantage of not being followed by maintenance rituximab. It’s a 1-shot therapy, then in 4 to 6 months, you end up with your induction regimen. What we have demonstrated here [is] that even by reducing the dose, this is a very [effective] regimen, especially in low- or standard-risk patients.
What unmet needs within this field really persist that are important to note within this treatment paradigm with RBAC and beyond?
The unmet needs in MCL still [are in] high-risk patients. The main point has been and is going to be in the [results in] the TP53-mutated patients. These patients do not achieve prolonged remissions with standard immunochemotherapy. These patients have demonstrated [an] inferior survival when treated upfront with combination therapies, including BTK inhibitors covalent BTK inhibitors. These patients also have a dismal survival with CAR-T cell therapy or pirtobrutinib [Jaypirca].
When we look at [the] MCL field, the [main] high-risk factor and matter of consideration is the TP53 mutation. We need to study [this] more. We need to define [these] mutations better. One mutation can be different from another. We need to consider how the mutation [relates] with other known risk factors, [including] clinical and histopathological risk factors, because usually they combine together.
We need to cluster these patients in [a] high-risk group that will be well defined and find a way to treat them differently from the beginning, as we [have tried] to do with our trial.
What current trials do you think could have the potential to move the treatment paradigm one way or the other in the field of MCL?
The European Mantle Cell Network has 2 main trials ongoing in patients with MCL upfront. The first study [is a phase 2 trial (20225018089600)] which is enrolling an elderly population similar to the RBAC [population], and it is randomly assigning [patients to] a chemotherapy-free combination based on rituximab, ibrutinib, and venetoclax.2 It is evaluating BTK and BCL2 inhibitors, completely chemotherapy-free, vs the combination of bendamustine-rituximab plus ibrutinib, plus maintenance in both arms. This trial in the elderly population will tell us how patients will deal with chemotherapy-free combinations, including a triplet combination of chemotherapy-free drugs upfront in the elderly population.
The second trial, which is going to give us very important information, is the [phase 2] CARMAN trial [2022-502405-15-00], [which] is randomly assigning younger patients upfront — high-risk patients upfront, and selectively high[-]risk patients between CAR T[-cell therapy] with brexucabtagene autoleucel [Tecartus] after a short course of ibrutinib plus rituximab vs the standard of care. I believe these trials will give us important information, both in the elderly population and [in] younger patients with high-risk features.
References
- Visco C, Tabanelli V, Sacchi MV, et al. 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. Published online September 17, 2025. doi:10.1016/S2352-3026(25)00252-2
- Herold S, Schmidt C, Visco C, et al. The MCL elderly III trial protocol: an international, randomized, open-label phase II trial to investigate the combinations of venetoclax, ibrutinib and rituximab or bendamustine, ibrutinib and rituximab in patients with treatment naive mantle cell lymphoma not eligible for dose-intensive treatment. BMC Cancer. 2025;25(1):1370. doi:10.1186/s12885-025-14803-8
- Marie-Kristin Tilch, Schmidt C, Marek Trneny, et al. Trials in progress: carman - an international, randomized phase II study evaluating early treatment intensification in patients with high risk mantle cell lymphoma using CAR-T-cell treatment after an abbreviated induction therapy with rituximab and ibrutinib and 6 months ibrutinib maintenance (Arm A) as compared to standard of care induction and maintenance (Arm B). Blood. 2024;144(suppl 1):4422.3-4422.3. doi:10.1182/blood-2024-206931
