CAR T-cell Therapies Produce Durable Remissions

Chimeric antigen receptor (CAR) T-cell therapies can lead to high rates of durable, complete remission in patients with B-cell precursor acute lymphoblastic leukemia (ALL), according to a pair of studies published in The New England Journal of Medicine.

The studies, which are some of the first to provide a longer-term assessment of the effectiveness of CAR T-cell therapies, focus on tisagenlecleucel (Kymriah, CTL019; Novartis), approved last year to treat patients up to age 25 with ALL, and 19-28z CAR T cells, under development at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, NY. Both therapies target CD19, which is highly expressed on ALL cells.

Shannon Maude, MD, PhD, and her team at Children's Hospital of Philadelphia in Pennsylvania published results from the phase II ELIANA trial of tisagenlecleucel, in which 75 patients with ALL were treated at 25 centers around the world (N Engl J Med 2018;378:439–48). The study achieved an overall remission rate of 81% by 3 months. At 6 months, event-free survival and overall survival were 73% and 90%, respectively, and they were 50% and 76%, respectively, at 12 months.

“What we learned from this study is that we are seeing very high remission rates in this population of patients for whom our other therapies had failed, and, more importantly, we are seeing durable remissions in a good fraction of patients as well,” Maude says. “It showed us that this highly specialized and personalized therapy can be implemented across institutions and around the world.”

The second study relates to findings of a phase I trial in which 53 adult patients with ALL received infusions of 19-28z CAR T cells (N Engl J Med 2018;378:449–59). After 21 days, 83% of patients had achieved complete remission. At 29 months, the median event-free and overall survival were 6.1 months and 12.9 months, respectively. Patients with a low disease burden fared best, with a median overall survival of 20.1 months, compared with 12.4 months among patients with a high disease burden.

“These results put into focus what the best situation is to treat these patients, what scenarios will allow these patients to achieve optimal outcomes, and how to manage these patients in the future,” while identifying patient groups for whom more effective CAR T-cell therapies are needed, explains Renier Brentjens, MD, PhD, who co-leads the study at MSKCC.

For Hagop Kantarjian, MD, of The University of Texas MD Anderson Cancer Center in Houston, “there's no doubt that CAR T cells are a major breakthrough in cancer therapy,” but he has concerns about their toxicity, high cost, and effectiveness in certain patients.

“These studies give us an idea of how to move in the future in terms of learning how to give the CAR T cells, giving them in minimal residual disease patients to have less toxicities and better efficacy,” he says.

Terry Fry, MD, of Children's Hospital Colorado in Aurora, says that although the studies provide clear evidence that some patients achieve durable remissions with CAR T-cell therapy, “the relapse rates and some of the challenges with manufacturing are issues that we need to deal with.”

“It's a fantastic therapy, it's really been transformative in terms of leukemia treatment, but I think we have to get past the initial enthusiasm,” he says. “I think now it's on us to manage expectations and be honest about where the therapy is at, and recognize that there are a lot of places to improve.” –Catherine Caruso

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