乌鸦传媒

Relapsed/refractory mantle cell lymphoma (MCL) patients treated with brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell product, in standard-of-care practice show outcomes similar to those in pivotal clinical trials.

CAR T-cell therapy was originally studied in diffuse large B-cell lymphoma, and later other B-cell lymphomas, including mantle cell lymphoma (MCL). The single-arm, phase II showed that brexu-cel induced durable remissions in a majority of patients with relapsed/refractory MCL, and led to FDA approval. However, patients treated in clinical trials often differ from those treated in standard-of-care practice.

In a recent study, researchers investigated the safety and efficacy of brexu-cel in patients with relapsed/refractory MCL in standard-of-care practice among U.S. Lymphoma CAR T Consortium centers. In the following interview, Michael D. Jain, MD, PhD, of the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center in Tampa, Florida, discusses the details of the team's study, which was published in the .

What does the study add to the literature?

Jain: MCL is a rare, very diverse disease that is extremely heterogeneous. All patients in the ZUMA-2 trial had a Bruton's tyrosine kinase (BTK) inhibitor beforehand. Remission was durable -- 50% to 60% at 1-2 years -- and a good proportion of patients are still in remission after 3 years. The best overall and complete response rates were 91% and 68%, respectively.

Clinical trials generally include highly selected patients. The ZUMA-2 trial size was small (68 patients), and therefore it was hard to look at subgroups. We set out to delineate the characteristics and outcomes of patients with relapsed/refractory MCL treated with brexu-cel in standard-of-care practice in a consortium of 16 centers with 189 patients in the registry.

The outcomes were just as good in standard-of-care practice as on the clinical trial. Compared with ZUMA-2, more patients with high-risk features and/or comorbidities were treated with brexu-cel in the standard-of-care practices. Two-thirds of patients (65%) would have been ineligible for ZUMA-2 because of disease status or comorbidities.

Despite this, safety and efficacy outcomes were comparable with ZUMA-2. The best overall and complete response rates were 90% and 82%, respectively.

We also found a higher risk of infectious deaths than previously observed in pivotal trials. The non-relapse mortality was 9.1% at 1 year, primarily because of infections. This finding sheds light that MCL patients who receive CAR T-cell therapy may be more fragile. Patients may remain in remission, but may be more liable to have infections later on, and should be watched more carefully.

Some high-risk features, such as TP53 mutation, complex karyotype, and blastoid/pleomorphic variant, were associated with shorter progression-free survival (PFS) after brexu-cel infusion. This had not been shown before. Comorbidities, common with CAR T-cell therapy, were not necessarily dependent on tumor biology.

What is the potential benefit of bridging therapy?

Jain: It takes 3 to 4 weeks to manufacture T cells for CAR T-cell therapy. This provides an opportunity to give patients additional bridging therapy. We found no negative impact of giving bridging therapy. No one knows the optimal bridging therapy, and we need to find agents to bridge better. We like pirtobrutinib, the first and only approved reversible BTK inhibitor.

What is the importance of your finding of high brexu-cel efficacy in patients not previously treated with BTK inhibitors?

Jain: In ZUMA-2, patients had to receive a BTK inhibitor to qualify for the trial. But the FDA label does not specify prior BTK inhibitor therapy -- just relapsed/refractory MCL. Our study provides a critical first set of data of brexu-cel efficacy in BTK inhibitor-naïve patients. This may inform which patients to treat with less pre-exposure and still have good outcomes with CAR T-cell therapy.

What strategies are needed to improve on CAR T-cell therapy for high-risk patients?

Jain: We found that tumor intrinsic features led to worse outcomes. A found similar results, with more complex genomics leading to treatment failures in CAR T-cell therapy for B-cell lymphoma patients. With earlier lines of therapy, perhaps we can shrink the tumor to lessen the burden. We need to understand the underlying biology better.

What is the advantage of avoiding bendamustine just before leukapheresis when CAR T-cell therapy is planned?

Jain: The purine analogy bendamustine leads to long-term deficits in T cells. The quality of T cells matters for the efficacy of CAR T-cell therapy. Bendamustine is a good chemotherapy for MCL, but it may reduce T-cell quality and render CAR T-cell therapy less effective.

In our study, we observed higher rates of manufacturing failure and failure to infuse in patients with bendamustine exposure within 6 months. In addition, patients with bendamustine use within 6 months or 6 to 24 months had inferior PFS [progression-free survival] and overall survival than those with remote or no bendamustine exposure.

What is your main message for practicing oncologists?

Jain: In patients with relapsed/refractory MCL, CAR T-cell therapy can generate durable remissions. If patients have relapsed disease, consider referral to a CAR T-cell center. If you plan to send a patient for CAR T-cell therapy for MCL, avoid bendamustine as holding therapy. BTK inhibitors are better options.

For 1 year after CAR T-cell therapy, patients can be immunosuppressed and have adverse events from infections, and therefore they should be watched prophylactically.

Read the study here and expert commentary about it here.