MCL Landscape Adapts to Changes After CAR T-Cell Therapy Approval

James Gerson, MD

Despite the introduction of CAR T-cell therapy to the mantle cell lymphoma (MCL) armamentarium, induction therapy followed by stem cell transplant has maintained a role, said James Gerson, MD, who added that he continues to recommend transplant for patients, since they are still eligible for CAR T-cell therapy upon relapse on transplant.

“I tell patients that we have very long-term data that a consolidative transplant for those who are eligible leads to a prolonged remission,” Gerson explained. “If a patient can be in remission for 10 years, maybe 10 years from now we will have something that is even better and more tolerable than CAR T-cell therapy.”

In July 2020, the FDA approved brexucabtagene autoleucel (Tecartus) for the treatment of adult patients with relapsed/refractory MCL. The indication was based on findings from the phase 2 ZUMA-2 trial where brexucabtagene autoleucel, given as a single infusion, induced an 87% objective response rate and a 62% complete response rate in this patient population.

“Unlike in diffuse large B-cell lymphoma where more restrictions [with CAR T-cell therapy] exist, any patient with MCL who had 1 prior therapy and relapsed can go straight to CAR T-cell therapy,” Gerson said. “We can use BTK inhibitors to bridge them, but we don’t have to. There are a lot of possibilities.”

Though not yet planned, further studies evaluating CAR T-cell therapy in the frontline setting for patients with high-risk MCL may be worth exploring, said Gerson.

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on hematologic malignancies, Gerson, an assistant professor of clinical medicine at Penn Medicine, discussed navigating treatment selection amid the approval of CAR T-cell therapy in MCL and the role of transplant after induction therapy.

OncLive®: What induction regimens do you consider for your patients with MCL and how do you select between possible options?

Gerson: For young, fit patients, there is really no right answer for induction therapy because [treatment selection] is based on phase 2, nonrandomized data. Typically, induction therapy involves high-dose chemotherapy. I’m actually very intrigued by a recent publication from the French group that looked at obinutuzumab [Gazyva] with DHAP [dexamethasone, cytarabine, and cisplatin; O-DHAP] as frontline therapy for young patients prior to consolidative transplant. 

I’ve used a lot of R-DHAP [rituximab (Rituxan) plus DHAP], but I haven’t used this O-DHAP. I think there is rationale to be excited about that option. Even though it is a phase 2 trial, it should [yield] reasonable data to take to insurance and get approval for. Again, it is not something I’ve given, but I’m very compelled by it and it is something I will try in the coming months.

Then, [we] usually follow [induction therapy] with a stem cell transplant for patients who are eligible.

In the relapsed setting, second-line BTK inhibition is pretty much the standard of care now. There is no right answer between [ibrutinib (Imbruvica) and acalabrutinib (Calquence)]. Anecdotally and by some limited published data, ibrutinib seems to have a higher occurrence of adverse effects [AEs]. Acalabrutinib is a little bit different but seems to be more tolerable in the long run. I tend to tell patients that and then they tend to want the medication that probably has fewer AEs. A lot of us end up choosing acalabrutinib, but from an efficacy standpoint, we have no comparative data. The curves are pretty similar when we look between the 2 trials.

In the era of cellular therapy, what is the role of transplant in MCL?

The challenge, of course, is that with the FDA approval of brexucabtagene autoleucel and CAR T-cell therapy coming into MCL, it is hard to know if we should still be transplanting patients. No one knows the answer because it is obviously not something that has been explored. The only thing that is known is that patients who have been transplanted can still go forward with [CAR T-cell] therapy and respond quite well. Therefore, it is not that getting a transplant means a patient cannot get CAR T-cell therapy in the future.

[With that], I usually tell my patients not to skip transplant because of the approval of brexucabtagene autoleucel in the relapsed/refractory setting. That said, it is an individualized choice. Certainly, some patients might make that choice not to undergo a transplant now that CAR T-cell therapy is available to them should they relapse. Still, in my practice, I will still offer transplant to a patient who is young and fit as a consolidative measure after induction therapy.

Do you see CAR T-cell therapy gaining a more significant role in MCL? Will it eventually move into the frontline setting?

Right now, the label given to brexucabtagene autoleucel was very open, [encompassing] any relapsed/refractory patient [with MCL]. That is great not only for patients but for practicing physicians.

[Bringing CAR T-cell therapy to] the frontline setting will likely be investigated in the future, especially for high-risk patients with high MIPI [Mantle Cell Lymphoma International Prognostic Index] scores, TP53 mutations, blastoid variant MCL, or pleomorphic variant MCL. [These features] tend to [confer] worse outcomes. There are areas where using [CAR T-cell therapy] in the frontline setting is worth looking into.

It is completely up to the company whether they want to pursue it. Otherwise, it is going to be left to investigator-initiated trials, which are going to be difficult because of the cost associated with CAR T-cell therapy. Some centers may pursue using homegrown CAR T-cell therapy where the cost is much lower for some of these high-risk patients, but I hope the company will pursue such trials in the frontline setting.

What other regimens are potentially on the horizon in MCL and how could they best fit into the paradigm?

There are a lot of similarities between chronic lymphocytic leukemia [CLL] and MCL. A similar triplet strategy to ibrutinib, obinutuzumab, and venetoclax [(Venclexta) in CLL] is being looked at in frontline and relapsed/refractory MCL. That is incredibly exciting and could very well supplant typical [cytarabine]-based induction and transplant. We will need long-term follow-up, so we probably won’t know for many years.

Thankfully, with minimal residual disease [MRD], we will possibly be able to know much sooner, because if we can get a large percentage of patients into an MRD-negative state, that is a proxy for outcome. Again, we won’t know for probably about 10 years before we get that long-term follow-up, but we will have a good enough idea if we [should] use MRD as a surrogate end point.

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Eng J Med. 2020;382(14):1331-1342. doi:10.1056/NEJMoa1914347