Two Treatment Strategies Transform the Mantle Cell Lymphoma Paradigm

Peter Martin, MD

The introduction of BTK inhibitors into the armamentarium of relapsed or refractory mantle cell lymphoma (MCL) years ago, caused a shift in the way oncologists treat the disease. Today, chimeric antigen receptor (CAR) T-cell therapies are transforming the landscape yet again, according to Peter Martin, MD.

The current standard for patients with relapsed/refractory MCL has been the BTK inhibitors ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanabrutinib (Brukinsa), which were approved for use in this population in November 2013, October 2017, and November 2019, respectively. However, no phase 3 clinical trials comparing the agents have been done, making it difficult to choose among the options available, said Martin.

Beyond BTK inhibitors, CAR T-cell therapies have also emerged in this field. “CAR T-cell therapies are an interesting area of research in MCL,” said Martin. “Some of that comes from a place of optimism and hope; we are almost willing this modality to be the next [big thing in the space].”

In an interview with Targeted Oncology, Martin, chief of the Lymphoma Program at the Meyer Cancer Center and an associate professor of medicine at Weill Cornell Medicine, discussed the current MCL treatment landscape and the future of the field.

TARGETED ONCOLOGY: Could you discuss the current frontline treatment landscape for patients with MCL?

Martin: The current frontline treatment for MCL is interesting in that, now more than ever, there is no single standard of care. In other lymphomas, the standards of care are fairly established, but in MCL we basically just have a series of options. Broadly speaking, in terms of acceptability, it has been reasonable to treat younger, healthier patients with more intensive therapies. In older patients or those with multiple comorbidities, [treatment approaches are] a little bit less intense. The goal of therapy in all of those strategies is to minimize the impact of the lymphoma on [a patient’s] life. Also, we need to minimize the impact of treatment on their lives, as well. That's a loaded statement, but intensive therapies have a short-term impact that can be quite significant. The hope is that these treatments will result in a long treatment-free interval.

The caveat in all of this is that not only are there multiple acceptable, less-intensive frontline strategies, but we're also moving into an era where we're recognizing that some of those strategies don’t serve some patients well. Some patients have [variants] of MCL where they don't really benefit from those treatments, while others have [variants] of MCL that may not require intensive strategies. That's where we're starting to see the emergence of those non-chemotherapy approaches and it will be exciting to see where that goes. Obviously, in chronic lymphocytic leukemia (CLL), for example, non-chemotherapy strategies have been the standard of care and have seen some use MCL, as well.

TARGETED ONCOLOGY: Shifting to the relapsed/refractory setting, and how do you navigate among the available options?

Right now, for patients with previously treated MCL, it's probably true that most clinicians around the world are using BTK inhibitors because 3 different agents in multiple trials have proven efficacy, particularly in the second-line setting; these agents are relatively welltolerated, as well. There may be certain scenarios in which chemotherapy might also be reasonable. In the average person, a BTK inhibitor would be a reasonable strategy. That may change as we see BTK inhibitors used more in the frontline setting, but right now, that’s still experimental.

TARGETED ONCOLOGY: What factor do you consider when choosing among the available BTK inhibitors?

Currently, 3 BTK inhibitors have been approved by the FDA for use in patients with MCL: ibrutinib, acalabrutinib, and zanubrutinib. These agents all have really revolutionized the way MCL is treated. [However], no randomized, phase 3 trials have been done to compare these agents yet in this disease, so we don't know if 1 agent is more or less effective than the other. We don't know how the safety profiles compare between these agents in someone with MCL, in particular. You can extrapolate some of those data from other settings or lymphomas, but it’s not always so straightforward given that different patient populations might have different backgrounds and they also might be on medications for different lengths of time. For example, in CLL, patients will be on these medications for many, many years.

There are some scenarios where you might choose 1 agent over another. For example, some medications have drug-drug interactions and can't be taken with certain medications. It appears that acalabrutinib and zanubrutinib may be associated with a little bit less of a bleeding risk and cardiac arrhythmias; however, we don't know that for sure. Head-to-head trials [need to be conducted] to [truly understand that]. Certainly, for someone with a high risk of cardiac problems, [we would] choose 1 of [those 2 agents rather than] ibrutinib.

All these drugs are being studied in combinations and we'll have to be careful not to necessarily substitute 1 for another in those combinations because of the potential for drug–drug interactions in all of these settings.

TARGETED ONCOLOGY: How do you see CAR T-cell therapy impacting the paradigm?

Martin: Existing data on CAR T-cell therapy, such as those in the ZUMA-2 trial, prove that [this approach] can be effective [in MCL], even in patients who have been previously treated with BTK inhibitors, so [there’s] a population that responds well to this treatment; that's very exciting.

Smaller trials have included patients with MCL with other CAR T cells and suggest [this approach is] active; it's maybe a class effect [being seen with] CD19-targeted CAR T-cells and that is exciting and promising. There are obviously going to be differences between all of these CAR T cells. I don’t know which one is going to be the best for which scenario.

That's going to take more time and more experience. I suspect that, initially, CAR T cells will be used in the area in which they are being studied, which is primarily in patients who have received prior BTK inhibitors. For oncologists, that will be important because oftentimes when patients with MCL are receiving BTK inhibitors they work, and then suddenly they stop working; to some degree, that's predictable. Patients with very high-risk MCL don't tend to be on BTK inhibitors for a long time. We're all getting increasingly better at identifying those patients who cannot achieve really durable benefits from BTK inhibitors. Just as when I'm starting someone on frontline therapy, I'm thinking about what might come next. Going forward, when we're starting somebody on a BTK inhibitor, we should all be thinking, “Is this somebody that's going to need CAR T cells in the future? If so, how do I prepare for that?”

TARGETED ONCOLOGY: Is there anything else that you would like to add?

Martin: MCL is something that [creates] a lot of debate. People are willing to debate pretty freely and passionately. That's important; that we won't just become complacent and lethargic about how people are treated. We all feel strongly about making therapy [options] better. Everyone has their own biases about how that should happen, which is really critical and is the basis for scientific testing. I like having people challenge assumptions and there are a number of assumptions that are open to challenge [in the field].

For example, 1 assumption that is open to challenge is that everyone needs chemotherapy. Another assumption is every young person [should receive] intensive therapy. Those are questions that are being asked in randomized trials right now because they're good questions. We could use more trials like that. Again, there are so many questions: Which is the best BTK inhibitor to use? Will CAR T cells solve all of our problems? Or, which patients will have their problems solved [by CAR T-cell therapy]? How will we take care of patients who have had CAR T cells?