New Understandings of Treatments, End Points, and Disease Biology Expand MCL Horizons

Establishing treatment approaches for patients with high-risk disease or TP53 mutations, demystifying the disease’s heterogeneity, utilizing novel artificial intelligence (AI) tools, and exploring novel treatment combinations are all core issues the mantle cell lymphoma (MCL) field is racing to address, according to Lore Gruenbaum, PhD.

In an interview with OncLive®, Gruenbaum detailed ongoing research on MCL and its potential impact. Additionally, she covered other noteworthy developments such as the April 2026 FDA approval of brexucabtagene autoleucel (Tecartus; brexu-cel), the phase 2 OASIS-II trial (NCT04802590), novel treatment combination approaches, and the integration of end points such as minimal residual disease (MRD).^1,2

“There's going to be a place for CAR [chimeric antigen receptor] T-cell therapy if we can define the patients who are likely to have a functional cure with CAR T-cell therapy, which [will be possible if researchers] can predict long-term outcomes and a good prognosis for patients before they relapse,” Gruenbaum said.

Gruenbaum is the chief scientific officer and senior vice president of research at Blood Cancer United.

OncLive: What are the key areas of focus for MCL research right now?

Gruenbaum: We're seeing some efforts [to move CAR T-cell therapy into the frontline setting] in other disease spaces; [however,] it’s not what I'm hearing from experts in the MCL field. Especially at Blood Cancer United, [where we have] an MCL initiative specifically focused on helping accelerate novel therapies, [the focus is on] high-risk disease and TP53 mutations. [High-risk disease and TP53 mutations] are unmet needs across many indications, not just in MCL.

[Other focuses are] being able to tailor treatments [to patients], and we're in this good situation where it seems we can move away from chemoimmunotherapy to [treatments] that are chemotherapy-free in the frontline. How much can we limit treatment duration? We haven't talked about MRD yet, but there's a big discussion [in MCL] with many trials looking at fixed-duration approaches vs MRD-driven approaches to limit the impact on the patient's quality of life.

What are the critical unmet needs in MCL? What next steps are needed to address them?

First and foremost, we are always looking to better understand resistance. The challenge in MCL, as in many other cancers, is that whenever a new therapy is introduced, the disease’s biology will change. [Thus, current] research goes back to the more basic discoveries and really understanding these new disease mechanisms, [including] resistance mapping in terms of understanding how the characteristics of different contributing clones change. [Current MCL research also revolves] around better understanding the tumor microenvironment, which is something that we are appreciating more and more now, along with the complexity of the interaction between cancer cells and the surrounding myeloid cells.

Another important area [of MCL research is] heterogeneity, not just interpatient heterogeneity, but also intrapatient heterogeneity. This is where the novel tools that we have through AI-based models can help describe the evolution of disease on one hand, and there are also algorithms that can help in clinical practice in assessing, for example, the risk for relapse based on molecular markers.

One area that is of particular interest is spatial analysis. The ability that we have now with new technologies allows for extensive characterization of mechanisms at DNA, RNA, and protein levels, and we can do this for single cells, which allows us to appreciate the heterogeneity and the complexity of [MCL]. Knowing what happens in single cells, but also knowing what happens inside these cells, relates in a spatial pattern [is important]. This is something where there's a lot more work to do. It will be essential for understanding relapse and also understanding how our detection and the informative use of MRD can move forward. Ideally, we would like to have MRD assessments guide clinical decision-making and potentially also help drive drug development.

We've seen [MRD-guided drug development and decision-making] in multiple myeloma pave the way for how this can be done. To understand the complexities around MRD and novel [technologies], standardizing of what you do and also understanding what's biologically meaningful vs what you can measure most sensitively [is important]. There are a lot of questions to address [in MCL]; we have our work cut out for ourselves for a few more years.

How will the full FDA approval of brexu-cel influence the MCL treatment paradigm? What is the future of BTK inhibitor-based regimens in MCL?

We need both. BTK [Bruton tyrosine kinase] inhibitors are clearly going to be an essential tool that will be part of our armamentarium. At the same time, if we talk about CAR T-cell therapy, we have approved agents, but there are other interesting targets out there. For example, CAR T-cell therapy against the BAFF receptor is currently in clinical trials and has shown interesting, promising results. We saw them at the 2025 ASH Annual Meeting and Exposition, and although the trial [had a] small number of patients, it is important to look at alternative targets.³

There's going to be a place for CAR T-cell therapy if we can define the patients who are likely to have a functional cure with CAR T-cell therapy, which [will be possible if researchers] can predict long-term outcomes and prognosis for patients before they relapse. This is where these novel targets and small-molecule targets that are in the works are going to play an important role moving forward.

What ongoing clinical trials in MCL are you interested in? What should the future of MCL research look like?

There are a number of trials that are ongoing and interesting. The trials that I'm watching are certainly the trials looking at BCL-2 inhibitors like sonrotoclax [BGB-11417], where we’ve seen early data in heavily pretreated patients, which will be something interesting to watch moving forward. There are a number of trials that are looking at quadruplet combinations or larger combination studies that are going to be interesting to see additional data from.

For example, the OASIS-II trial [is evaluating] a time-limited, fixed-duration treatment. [OASIS-2] is an interesting trial where we're looking at combinations with BTK inhibitors and anti-CD20s in addition to venetoclax [Venclexta]. There are some trials around using CAR T-cell therapy for intensification after induction for patients who are high-risk to see whether you can drive patients into MRD response. Then on the other side, [there are trials evaluating] MRD-guided de-escalation, starting off with a triplet combination and looking at MRD monitoring in a way that really informs patient outcomes.

International collaboration with experts is important, [especially for these rarer diseases]. [International collaboration] is something that we try to encourage, since, based on the different regulatory landscapes and approvals, you can get different insights from different trials. We find that often the large European trials are really critical and drive lots of insights. We’ve seen the insight that we don't necessarily need transplants in MCL, but we do need maintenance, driven by the large phase 3 TRIANGLE study [NCT02858258], for example. There are several of these larger studies that are happening in Europe that are informative for the field. International collaboration and the support for these collaborative studies are particularly important when you’re looking at these smaller indications [like MCL].

References

1. US FDA grants full approval of Kite’s Tecartus for adult patients with relapsed or refractory mantle cell lymphoma. News release. Gilead. April 2, 2026. Accessed May 4, 2026. https://www.gilead.com/company/company-statements/2026/us-fda-grants-full-approval-of-kite-tecartus-for-adult-patients-with-relapsed-or-refractory-mantle-cell-lymphoma
2. Study of ibrutinib + CD20 antibody and venetoclax in patients with untreated mantle cell lymphoma. ClinicalTrials.gov. Updated March 3, 2026. Accessed May 4, 2026. https://clinicaltrials.gov/study/NCT04802590
3. Budde E, Del Real M, Baird J, et al. BAFFR-CAR T cells (PMB-CT01) demonstrate durable responses and manageable toxicities in relapsed/refractory B-cell lymphomas with prior CD19-directed therapy failure or CD19-negative disease. Blood. 2025;146(suppl 1):268. doi:10.1182/blood-2025-268