CAR T-Cell Therapy Creates Opportunities for Individualized Treatment in MCL

Alan P. Z. Skarbnik, MD

Treatment decisions in mantle cell lymphoma (MCL) have become more nuanced since the FDA approval of the CAR T-cell therapy brexucabtagene autoleucel (Tecartus) in the relapsed/refractory setting, explained Alan P. Z. Skarbnik, MD.

Previously, the treatment of choice for patients who recurred after high-dose therapy and transplant had been 1 of the 3 FDA-approved BTK inhibitors: ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Now, there is a decision-making process between BTK inhibitors and CAR T-cell therapy, which is driven by the time to relapse, disease burden, and overall performance status of the patient.

“If a patient recurs 8 or 9 years after transplant and doesn’t have a lot of disease, a BTK inhibitor may be a better choice at that point. That way, you can safeguard the risks of CAR T-cell therapy to a later time. I do have a number of patients who have very long remissions or disease control with BTK inhibitors in that setting,” said Skarbnik. “Patients who recur shortly after transplantation who have larger bulk of disease and are more symptomatic may be better candidates for CAR T-cell therapy.”

In an interview with OncLive®, Skarbnik, a hematologist/oncologist with Novant Health, discussed the data with available treatment options in relapsed/refractory MCL and shared some of the elements of treatment selection.

OncLive®: How do you approach treatment selection among the 3 FDA-approved BTK inhibitors in MCL?

Skarbnik: We have not had a head-to-head comparison trial between the 3 agents. All 3 agents are available and efficacious. All we have are cross-trial comparisons. The duration of response [DOR] in the acalabrutinib trial seems to be longer. However, patients were in earlier lines of therapy; the median number of prior lines of therapy was 2 vs 3 in the ibrutinib trial. That may contribute to the difference in DOR. Zanubrutinib has a very good DOR and depth of response.

All 3 drugs seem to be safe and well tolerated. They have different safety profiles, which is not [to say that] one is better than the other, but [rather] that you have to determine what adverse effects [AEs] will be better tolerated in a particular patient.

There is head-to-head comparison between zanubrutinib and ibrutinib in Waldenström macroglobulinemia. In terms of the safety profile, zanubrutinib seems to be better tolerated in that particular trial and in that particular disease. You may extrapolate that to other disease settings, because the mechanism of action of the drugs is the same throughout. The newer second-generation BTK inhibitors may be better tolerated than the first-generation BTK inhibitor ibrutinib, but we can’t say that yet with certainty. All 3 drugs are great. [The decision is going to come down to] physician’s choice.

How has CAR T-cell therapy affected the paradigm?

Brexucabtagene autoleucel was recently approved in MCL based on data from the ZUMA-2 study, which evaluated this treatment in patients with recurrent, relapsed/refractory MCL who had been previously exposed to BTK inhibitor. However, the approval did not require patients to have been exposed to a BTK inhibitor in the commercial setting. Now, it’s approved for second-line or [later] use, which is appropriate at this point, because even though BTK inhibitors are a great treatment option for patients with relapsed MCL, the best DOR we have seen so far is close to 26 months, which certainly is not ideal.

We try to treat MCL more aggressively in the frontline setting with high-dose cytarabine-containing induction regimens followed by high-dose chemotherapy and autologous stem cell transplant or rescue. This seems to give patients a longer remission and progression-free survival than other treatment approaches in the frontline setting.

The biggest concern here is for patients who recur shortly after that intensive therapy—those with recurrent disease 1 to 3 years after a stem cell transplant. These patients have a higher risk of resistance to second-line therapy, and are at a higher risk of early progression after second-line therapy. The treatment of choice up until now has been BTK inhibitors, which are easy to take and are readily available. The AEs are well tolerated, and [patients] do have a response [to this type of treatment].

The length of response is the issue here. We now have the option of CAR T-cell therapy in that setting. Again, that is going to depend on how soon the patient relapses after transplant and their disease burden. We also have to consider the overall performance status of the patient. Are they going to be a good candidate to withstand the AEs of CAR T-cell therapy, or are they a better candidate for a BTK inhibitor?

We don’t have long-term follow-up for the [ZUMA-2] trial yet. The true, long-term effect of CAR T-cell therapy in terms of efficacy and disease is not known yet. We don’t know if using CAR T-cell therapy prior to a BTK inhibitor changes the response rate or DOR. We don’t have those data. It is something we’ll have to look back at retrospectively and try to compare as best as we can.

Certainly, I would be more inclined to use CAR T-cell therapy in a younger patient who has early recurrence after frontline induction, especially if they undergo transplant, and certainly for those who recur after BTK inhibitors. Very few agents can salvage a patient [after that]. In terms of chemotherapy, [rituximab/bendamustine with low-dose cytarabine] seems to be the chemotherapy regimen that has better response rates in the BTK inhibitor–refractory or –relapsed setting. However, CAR T-cell therapy was studied specifically in that setting, so it’s a good option for those patients.