Is There a New CAR T-Cell Treatment for Mantle Cell Lymphoma?

Mantle cell lymphoma (MCL) is a type of B-cell non-Hodgkin lymphoma with a typically poor prognosis. Even with an allogeneic stem cell transplant, patients can become resistant to chemotherapy. Most do not survive 4 or 5 years after diagnosis, and the 10-year survival rate hovers between 5% and 10%.

Chimeric antigen receptor (CAR) T-cell therapy has been making great inroads as targeted treatment for many types of cancers highly resistant to other treatments, by prolonging patient survival and increasing their quality of life. Until now, similar results have not been seen in patients with MCL. However, with their successful phase 2 ZUMA-2 trial results just published in the New England Journal of Medicine, a group of researchers led by Michael Wang, MD, from The University of Texas MD Anderson Cancer Center, are able to show that these patients can benefit from the specialized therapy.

In this study conducted in the United States and Europe, the patient population had relapsed/refractory progressive disease despite receiving Bruton’s tyrosine kinase (BTK) inhibitor therapy and from 3 to 5 prior therapies.

“BTK inhibitor therapy has greatly improved outcomes in patients with relapsed or refractory mantle cell lymphoma, yet patients who have disease progression after receiving the treatment are likely to have poor outcomes, with median overall survival of just 6 to 10 months,” the authors said.

The median patient age was 65 years (range, 38-79). They were evaluated for response to a single infusion of KTE-X19, an anti-CD19 CAR T-cell therapy, that was dosed at 2×10⁶ CAR T cells/kg of body weight. Seventy-four patients were enrolled between October 24, 2016, and April 16, 2019; the treatment was manufactured for 71 and ultimately administered to 68.

There was a follow-up after 60 patients were monitored for 7 months, at which time a primary efficacy analysis was conducted. The primary endpoint was objective response (complete [CR] or partial [PR]), which was confirmed via bone marrow evaluation and positron emission tomography-computed tomography.

Overall, 85% of the entire study cohort of 74 patients was able to reach an objective response to KTE-X19, 59% of whom had a CR. These numbers were even higher among the group of 60 patients. Ninety-three percent (95% CI, 84%-98%) achieved an objective response, which was evaluated by an independent radiologic review committee. And of this group, 67% (95% CI, 53%-78%) had a CR.

The median times to response were impressive, with there being 1 month (range, 0.8-3.1) to initial response and 3 months (range, 0.9-9.3) to CR. In addition, of the 42 patients who initially had a PR or stable disease (SD), 24 (21 who had a PR, 3 who had SD) progressed to a CR in a median 2.2 months (range, 1.8-8.3).

Progression-free (PFS) and overall survival (OS) results also show promise to treatment with KTE-X19. As of the data cutoff date, there was evidence of remission in 78% patients who had a CR, with similar results seen in 57% of patients from the primary efficacy analysis. Overall, at 12 months, the PFS and OS were 61% and 83%, respectively.

Common adverse events to the treatment of grade 3 or higher included cytopenias (94%) and infections (32%). Ninety-one percent also experienced cytokine release syndrome, with a median time to onset of 2 days (range, 1-13) for any grade and 4 days (range, 1-9) for at least grade 3, but none died as a result. According to the study authors, most symptoms were reversible.

“ZUMA-2 is the first multi-center, phase 2 study of CAR T-cell therapy for relapsed/refractory mantle cell lymphoma, and these efficacy and safety results are encouraging,” stated Wang. “Although this study continues, our reported results, including a manageable safety profile, point to this therapy as an effective and viable option for patients with relapsed or refractory mantle cell lymphoma.”

Reference

Wang M, Munoz J, Goy A, et al. KTE-X19 CAR T-Cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2020;382;1331-1342. doi: 10.1056/NEJM0a1914347.