Value in Using CAR T Cells for DLBCL

The CD19-targeting chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah; Novartis), recently approved for young patients with acute lymphoblastic leukemia, triggers remissions in adults with relapsed and refractory diffuse large B-cell lymphoma (DLBCL), according to data presented at the 2017 American Society of Hematology Annual Meeting in Atlanta, GA, held December 9–12.

The new results come from the single-arm, phase II JULIET trial, in which patients with relapsed or refractory DLBCL in 10 countries received CAR T cells produced at manufacturing facilities in the United States or Germany. All recipients had undergone at least two previous chemotherapy regimens and either were ineligible for autologous stem cell transplants or didn't benefit from this therapy. At the meeting, the study's lead author, Stephen Schuster, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, presented data on the subset of patients who received CAR T cells produced in the United States.

At the 3-month time point, 32% of 81 patients showed complete responses and 6% showed partial responses. For the 46 patients evaluated after 6 months, the complete response rate was 30% and the partial response rate was 7%, indicating that nearly all of those who responded to the therapy at 3 months remained relapse-free at 6 months and beyond. The median duration of response and median overall survival weren't reached.

Side effects were common, with 86% of patients suffering grade 3 or 4 adverse events, the most common of which was cytokine release syndrome, occurring in 58% of the patients. In addition, 12% of patients developed grade 3 or 4 neurologic symptoms, 27% had cytopenia, and 20% developed infections. Although three patients died from progressive disease during the trial, none died due to the treatment, Schuster reported.

Concurrent with the presentation, Schuster and colleagues published results in The New England Journal of Medicine from a different phase II study of tisagenlecleucel (N Engl J Med 2017;377:2545–54). It showed remissions in 18 of 28 patients with relapsed or refractory DLBCL or follicular lymphoma. In that study, unlike in the JULIET trial, the treatments all occurred at one site, but “the JULIET study shows the feasibility of globally distributing these cells,” Schuster told conference attendees.

Novartis has submitted an application for tisagenlecleucel's approval for DLBCL. Another CD19-targeting CAR T-cell therapy, axicabtagene ciloleucel (Yescarta; Kite), was approved in October for relapsed or refractory DLBCL.

If the FDA greenlights tisagenlecleucel, Marco Davila, MD, PhD, of the Moffitt Cancer Center in Tampa, FL, said he would recommend the therapy for his patients. “The durability of these responses is quite high,” said Davila, who wasn't connected to the study. However, he cautioned that the size of an effective dose isn't clear. The patients in the JULIET trial received between 10 million and 600 million cells. “I don't know as a clinician what is the appropriate dose,” he said.

“The fact that we have another immune-based approach against lymphoma is great,” said Jonathan Schatz, MD, of the University of Miami Miller School of Medicine in Florida, who also wasn't part of the study. Still, how long the benefits of the therapy will last—and thus the role of CAR T cells in DLBCL treatment—remains uncertain, he said. “Is this potentially curative therapy for patients by itself, or is it something that will salvage patients who have relapsed so they go on to allogeneic transplant?” –Mitch Leslie

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