Lore Gruenbaum, PhD, discusses hot topics in mantle cell lymphoma, such as recently approved CAR T-cell therapies and where she sees the field moving next.
With the recent
The full approval of brexu-cel was based on data from the phase 2 ZUMA-2 trial (cohorts 1 and 2, NCT02601313; cohort 3, NCT04880434).2,3 Data from the trial showed that evaluable patients in cohort 3 (n = 86) and cohort 1 (n = 60) achieved overall response rates of 91% (95% CI, 82.5%-95.9%) and 87% (95% CI, 75%-94%), respectively.1 Moreover, patients from each cohort experienced complete response (CR) rates of 79% (95% CI, 69.0%-87.1%) and 62% (95% CI, 48%-74%), respectively.
In an interview with OncLive®, Gruenbaum touched on the significance of the approval, developments in adjacent indications she has her eye on, critical unmet needs in MCL management that need to be addressed, and novel agents, such as bispecific antibodies and Bruton tyrosine kinase (BTK) degraders, that could continue to impact the treatment paradigm.
Gruenbaum is the chief scientific officer and senior vice president of research at Blood Cancer United.
Gruenbaum: MCL is a small indication, but at the same time, it is also a complex indication. It is generally considered an aggressive form of non-Hodgkin lymphoma [NHL]. [However], one of the challenges in the field is that it ranges from manifesting as a more indolent disease to what we would consider classical, aggressive Hodgkin lymphoma, to transformed disease. [Thus, MCL] is actually a heterogeneous disease, and we are seeing a range of exciting new treatment options, both with approvals that we have with targeted agents that have moved into the first-relapse [setting] and are now moving into frontline therapy and combinations.
We saw the full approval of brexu-cel recently, so we now have 2 approved CAR [chimeric antigen receptor] T-cell therapy options [for MCL] with brexu-cel and lisocabtagene maraleucel [liso-cel; Breyanzi]. We’re also seeing a lot of interesting advances with bispecific antibodies in this space, also in a number of different combination regimens. What we’re seeing overall is that there are a good number of approved or emerging treatment options for the more indolent and classical forms [of MCL], but at the same time, there are high-risk patients—in particular, patients with TP53 mutations and blastoid morphology—who are not getting the same benefits from those treatments.
There are key questions [that need to be addressed]: How do we clearly define this population of patients as high risk? This is [a question] that I know is being discussed in the field. [Another important question is:] What are the best treatment options for this [high-risk] population?
At the other end of the spectrum, there is the never-ending discussion around cures and functional cures. How do you define a patient as cured? What is it? Is it 15 years in complete response? What is the appropriate definition? Then associated with [these questions is] the increasing role of time-limited therapy. [Ultimately, these] are the big themes that we see, the needs, the unmet needs, but also the tremendous opportunities where we see a lot of movement in the clinical development space [for MCL].
It is always good when there are more options available for patients. As we have learned, certainly in aggressive large B-cell lymphoma and other indications with CAR T-cell therapies, having different choices for patients based on both their individual comorbidities and their life situation is important. [Individualized therapy] is certainly the case with CAR T-cell therapy, which provides a perspective that patients might have an outcome of 1-and-done [treatment], where patients achieve either a long-term remission, a cure, or something resembling a functional cure.
At the same time, we know there are many factors that can limit the eligibility or the accessibility to [CAR T-cell therapy]. [However], it is encouraging and great to see accelerated approvals being converted to full approvals, especially in these experiences we’ve had recently, considering that [full approvals] are not always a given since at the time of the accelerated approvals, we do not always fully appreciate the long-term toxicities associated with treatments.
When it comes to sequencing, what do you do [following CAR T-cell therapy]? Bispecific antibodies are interesting. In this case, bispecific antibodies are not as advanced [in MCL as in] other indications, such as diffuse large B-cell lymphoma and follicular lymphoma, at least when it comes to FDA approvals. There are some interesting signs that bispecific antibodies, possibly in different combinations, could be effective, at least for some patients [with MCL] who relapse after CAR T-cell therapy. We’re going to see those similar discussions and experimental work, as well as clinical work, to really help us determine the optimal sequencing [for MCL treatments].
Should we use our best, strongest tool, early in the game, when we also know the patient’s immune system [generally] might be in much better shape than later? Or do we make sure we have the option available later and use [a treatment] that interferes less with the patient’s quality of life or has an adverse effect profile that is better fitted to what the patient needs?
Bispecific antibodies definitely will. CAR T-cell therapy will be interesting because we know from other CAR T efforts that there’s a lot happening in this field, including the allogeneic CAR T-cell therapies moving forward. We’ve also just seen the in vivo CAR T-cell therapy data in the multiple myeloma space. [These] are interesting new developments that ultimately will affect almost every disease where we can potentially use CAR T-cell therapy.
The positioning [of CAR T-cell therapy in] MCL remains to be seen, [especially as] there are many good, targeted therapies. We also know that the BTK degraders and second-generation BCL2 inhibitors are coming. We all know the drawbacks that the venetoclax [Venclexta] has in terms of the toxicity profile, but we’re seeing with sonrotoclax [BGB-11417], for example, interesting data coming up [for the BCL2 inhibitor]. These novel agents are providing options that really have improved tolerability and increased flexibility in combinations. We’re [evaluating] what the right combinations are for frontline therapy [with these new agents]. We now have the luxury [of trying] to intensify treatment, in particular when we’re thinking about high-risk patients.
On the other hand, we can also de-escalate the intensity of these therapies for the frail, older patient [who] also [may not]…need that aggressive treatment. [MCL] has this rich space of targeted agents and their combinability, which probably is going to lessen the pressure on CAR T-cell therapy moving up to the first line.
