Evolving Approaches With BTK Inhibition and Targeted Therapy Seek to Improve Outcomes in High-Risk MCL

As high-risk biological features continue to drive poor outcomes in mantle cell lymphoma (MCL), new targeted combinations and frontline BTK inhibition are offering promising therapeutic shifts, according to Christine Ryan, MD.

“We're seeing exciting advancements in the management of MCL,” Ryan said in an interview with OncLive®.

In the interview, Ryan discussed the limitations of current first-line MCL treatment strategies, especially for patients with high-risk disease; recent advances in the treatment paradigm; and the evolving role of BTK inhibition for eligible patients.

Ryan is a physician at Dana-Farber Cancer Institute, as well as an instructor in medicine at Harvard Medical School, both in Boston, Massachusetts.

OncLive: What are the most pressing unmet needs in MCL?

Ryan: MCL is a subtype of lymphoma that we still consider incurable, so our need [to discover more treatment] is clear, and it's a large one. Some patients can achieve a durable first remission, but unfortunately, when the lymphoma comes back, it is harder to treat and harder to get back into a durable remission.

Another area of unmet need within MCL is patients with high-risk disease. There are several different ways to think about high-risk disease features in [patients with] MCL. One of the most common [high-risk disease features] is by genetic status, specifically the TP53 gene. Patients with TP53-aberrant disease tend to have a poor prognosis, but there are other biological features that we have identified that also make the disease more aggressive and difficult to treat. For patients with those higher-risk biological features, there is also a great need for improving outcomes.

How do you currently approach the management of high-risk MCL in your clinical practice?

There are several different factors [for management of high-risk MCL] that we consider. Starting with histology, for example, blastoid and theomorphic histology tend to behave more aggressively. Moving on from that, there are features like the Ki-67 proliferation rate; patients in whom [Ki-67 proliferation rate] is elevated also tend to have more aggressive disease. One cutoff [for Ki-67 proliferation rate] is at 30%, and another cutoff is at 50%. Regardless, elevated Ki-67 proliferation rate tends to be an adverse biological factor [for high-risk MCL].

Regarding genetics themselves, the TP53 gene is one that we focus on and test for. [The TP53 gene] is a growing area of investigation, because likely there are other genetic signatures. Some have been identified already, [and there are] panels of genes that likely contribute to conferring that higher-risk biology.

Regarding how to treat [patients with high-risk MCL], ideally, we would be enrolling them onto clinical trials, because their ideal treatment is still an open question. Recently, we have seen exciting data with a chemotherapy-free triplet targeted regimen. This is called the phase 2 BOVen trial [NCT03824483] regimen, combining the BTK inhibitor zanubrutinib [Brukinsa] with the BCL-2 inhibitor venetoclax [Venclexta] and the anti-CD20 antibody obinutuzumab [(Gazyva) in the frontline setting]. [In the BOVen trial,] we saw in the initial cohort excellent early outcomes with this regimen. That being said, for many [high-risk] patients, the question remains about whether a chemotherapy-free regimen or a targeted plus chemotherapy regimen is the best approach. We need large, ideally randomized clinical trials to answer that question.

With the field of MCL management increasingly moving toward chemotherapy-free regimens, how do you see the role of BTK inhibitors evolving, particularly in younger patients?

One of the biggest changes [in MCL management] recently has been increasing inclusion of BTK inhibitors in frontline therapy in younger patients. Previously, we considered patients transplant eligible or ineligible. For transplant-eligible patients, the phase 3 TRIANGLE study [NCT02858258] was an important study that established the role of adding BTK inhibitors in the frontline setting. The results [of the study] showed that the addition of the BTK inhibitor [ibrutinib (Imbruvica)] in the induction and maintenance settings achieved superior outcomes vs the previous standard-of-care regimen, which was without a BTK inhibitor and with the inclusion of autologous transplant. By including the BTK inhibitor [in the MCL frontline setting], we can omit autologous transplant for many patients, if not all, and still achieve the same, if not superior, outcomes.

Adding in the BTK inhibitor in the frontline setting is a component that I consider for my younger patients [with MCL]. There are a lot of nuances to those results. The chemotherapy backbone that was used in that study is not the standard chemotherapy backbone we use at our institution and that other institutions use. Several different induction chemotherapy regimens have been studied and established.

References

1. Kumar A, Soumerai J, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation. Blood. 2025;145(5):497-507. doi:10.1182/blood.2024025563
2. Dreyling M, Doorduijn J, Giné E, et al. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024;403(10441):2293-2306. doi:10.1016/S0140-6736(24)00184-3