April 2, 2020 update: The results of the ZUMA-2 trial that were previewed at the 2019 American Society of Hematology annual meeting and that are reviewed in this article have now been published in the New England Journal of Medicine.
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Relapsed/refractory (R/R) mantle cell lymphoma (MCL) patients significantly benefited from chimeric antigen receptor (CAR) T-cell therapy, with durable complete responses and manageable adverse events, according to findings from the ZUMA-2 trial presented at the 2019 American Society of Hematology (ASH) annual meeting.
“Mantle cell lymphoma is a challenge,” says Brian T. Hill, MD, PhD, Director of Cleveland Clinic Cancer Center’s Lymphoid Malignancies Program and a co-author of the study. “Although many people are in remission for years, eventually MCL will recur, at which time it has been, historically, a very difficult disease to treat.
“Currently, BTK [Bruton’s tyrosine kinase] inhibitors are the best approach with, on average, 1-2 years of disease control,” he says. “However, once those drugs stop working, we know that patients have a very limited lifespan.”
In recent years there have been a series of breakthroughs with CAR T-cell therapies. This approach has shown remarkable activity in aggressive lymphomas, which prompted the development of the ZUMA-2 trial.
A new treatment avenue
This phase II multicenter study evaluated the safety and efficacy of KTE-X19, an autologous anti-CD19 CAR T cell therapy. It was tested in patients with R/R MCL who had received one to five prior therapies, including a BTK inhibitor.
Sixty adult patients were treated with KTE-X19. The results for patients who had at least 1 year of follow-up were presented at ASH. As of May 30, 2018, 28 patients had received CAR T-cell treatment with ≥ 1 year of follow-up. Eighty-six percent of patients were male, and the median age was 65 years. Eighty-two percent had stage IV disease, 50% had intermediate-high Mantle Cell Lymphoma International Prognostic Index scores, and 57% were refractory to their last therapy.
Following KTE-X19 treatment, Dr. Hill and his collaborators reported an investigator-assessed objective response rate (ORR) of 86% (95% confidence interval [CI], 67-96%) and a complete response rate of 57% (95% CI, 37-76%).
“As of May 30, 2018, 75% of responders remained in response and 64% of treated patients had ongoing responses,” the study authors wrote. “The 12-month estimates of duration of response, progression-free survival and overall survival were 83% (95% CI, 60-93%), 71% (95% CI, 50-84%), and 86% (95% CI, 66-94%), respectively, and the medians were not reached.”
During ASH, the full ZUMA-2 findings also were publically shared in an oral presentation. “This talk included the full experience of the 74 patients enrolled,” Dr. Hill notes. “Sixty-eight patients were treated with KTE-X19, and the primary efficacy analysis included 60 patients, which showed an ORR of 93%, with 67% complete responses.
“Fifty-seven percent of patients remained in remission after a medium follow-up of 12 months. So the overall survival rate at 12 months was 83%,” he explains. “These kinds of numbers are really unprecedented in R/R mantle cell lymphoma, particularly, in a very high-risk patient population who had been previously treated and had become resistant to BTK inhibitors.”
Manageable safety profile
In addition to strong efficacy findings, the researchers observed manageable adverse events among patients who received KTE-X19.
Grade 3 or 4 cytokine release syndrome (CRS) occurred in 18% of patients. Forty-six percent had grade 3 or 4 neurologic events. Researchers reported that all CRS events and the majority of neurologic events were reversible.
The median time to onset and resolution of CRS following treatment was 2 days and 13 days, respectively. In terms of neurologic events, the median time to onset and resolution was 6 days and 20 days, respectively.
These results will have practice-changing implications, offering patients that have few options a potentially effective therapy with manageable adverse events.
“For patients who have received extensive prior treatments, including BTK inhibitors, we would expect the survival to be measured in a couple of months,” Dr. Hill says. “All other approved or investigational agents have a short durability of response, making these findings particularly significant.
“And although the treatment is intense, it’s manageable with good supportive care,” he says. “While there is a high rate of side effects, they are generally self-limiting. Therefore, patients can recover and, ideally, be in a remission that could last for a long period of time.”
Moving forward, Dr. Hill and his colleagues are preparing to open an expanded-access protocol for CAR T-cell treatment in MCL that will allow more patients to utilize this promising therapy.
And as research continues in this patient population, there are important questions that require additional research. Building on the ZUMA-2 interim findings, Dr. Hill notes the need to examine the timing of treatment administration.
“The next step is to use this treatment before patients lose their response to BTK inhibitors, or even to give it before BTK inhibitors,” he says, “because we know that if you have a high burden of disease and more extensive prior therapy it’s more difficult to control.”
Another issue to be addressed is how to manage patients who may not able to handle the adverse events associated with CAR T-cell therapy.
“The treatment is not for everyone, and older, less fit patients may not be suitable candidates to receive such intensive therapy,” Dr. Hill says. “So we’re certainly in the early period of development of this exciting new therapy. Additional strategies to mitigate the risks of CRS and neurotoxicity is an area of active investigation.”