CAR T-Cell Therapy KTE-C19 Emerges Successful in Aggressive B-Cell Lymphoma
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Chimeric antigen receptor (CAR) T-cell therapy proceeds to have extraordinaire showings in patients with aggressive hematologic malignancies and no other good treatment options. Interim results of the pivotal phase II ZUMA-1 trial, the very first multicenter trial of the experimental CAR T-cell therapy KTE-C19, demonstrated finish and durable remissions in some patients with aggressive diffuse large B-cell lymphoma (DLBCL) and other lymphomas refractory to chemotherapy or recurring after autologous stem cell transplant.
At an interim analysis of ZUMA-1, more than 75% of patients with DLBCL responded to KTE-C19, and almost half had a finish response. Remissions are ongoing after twelve months on the phase I ZUMA-1 trial, and some patients treated on an earlier single-institution trial at the National Cancer Institute are still in accomplish response after several years.
“The accomplish response rate is sixfold higher compared with historical outcomes in this patient population,” said co-lead author Sattva S. Neelapu, MD, of The University of Texas MD Anderson Cancer Center, Houston, who introduced these results at the late-breaker session at the two thousand sixteen American Society of Hematology (ASH) Annual Meeting & Exposition. 1
Dr. Neelapu continued: “This is the very first pivotal multicenter examine of anti-CD19 CAR T cells in refractory aggressive non-Hodgkin lymphoma. We had a 99% success rate in manufacturing the genetically engineered T cells, with a 17-day turnaround time.”
Albeit these are titillating results (and in fact an audience member said, “This is the best explore at the meeting,”), CAR T-cell therapy requires skill and education to supply and can be harsh on patients. Adverse events of concern are cytokine-release syndrome, which is potentially fatal, and neurologic events.
“It is critical to educate physicians and staff at different centers on how to manage the side effects,” Dr. Neelapu emphasized. “The ZUMA-1 investigators had extensive education in the management of adverse events before the examine was conducted. It is critical for all providers who take care of these patients to be familiar with management algorithms for cytokine-release syndrome and neurologic events before proceeding with CAR T-cell treatment.”
CAR T-cell therapy utilizes each patient’s own T cells, extracted by leukapheresis, and the patient undergoes conditioning chemotherapy. The T cells are sent to a processing facility, where they are genetically engineered with CD19 receptors that seek out cancer cells; the T-cell population is then expanded and infused back into the patient. KTE-C19 and CTL-019 are engineered to target the CD19 antigen. Manufacturers of both agents are expected to file for U.S. Food and Drug Administration (FDA) approval in 2017.
Other groups are investigating CAR T cells directed to different antigens, including CD20 and CD44.
ZUMA-1 enrolled one hundred eleven patients with DLBCL and primary mediastinal B-cell lymphoma or transformed follicular lymphoma, and one hundred one received KTE-C19 infusions. Among the one hundred eleven patients enrolled, manufacturing was successful in 99%, 91% received treatment (Ten could not be treated), and the turnaround time was about seventeen days from leukapheresis to delivery of the KTE-C19 product to the clinical site.
About 50% of patients were sixty years old, 44% had high- or high-intermediate-risk disease, 85% had stage III or IV disease, 77% were refractory to second-line therapy, and 20% relapsed after prior therapy, and 3% were refractory to first-line therapy.
The interim analysis was based on data cutoff as of August 24, 2016; ninety three patients (73 with DLBCL, twenty with other forms of lymphoma) were evaluable for overall response at one month; sixty two of these patients (51 with DLBCL) were evaluable for the prespecified interim analysis endpoint of best overall response rate with at least three months of follow-up.
Novel Immunotherapy for Aggressive Hematologic Malignancies
- Anti-CD19 CAR T-cell therapy achieved accomplish and durable responses in aggressive DLBCL and other lymphomas, according to interim results of a pivotal phase II trial.
- The manufacturer of this therapy is expected to file for FDA approval in 2017.
- Adverse events proceed to be a challenge with this therapy, so practice and education are significant in managing patients being treated with this therapy.
The fresh findings report positive results of the fifty one patients with diffuse large B-cell lymphoma evaluable for best overall response rate with at least three months of follow-up. The overall response rate in these patients was 76%, and the rate of accomplish response was 47%.
In subgroups of special interest, the finish response rate was 75% in twelve patients who relapsed after autologous stem cell transplant and 47% (23 of 49) in patients refractory to second-line or higher therapy. “The treatment effect was similar across all subgroups, and accomplish responses are durable in the majority of the patients,” Dr. Neelapu told conference listeners.
The safety analysis was based on ninety three patients—73 with DLBCL who received CAR T-cell therapy at least one month before. “Adverse effect management was effectively implemented across twenty two sites, most with no prior CAR T-cell therapy practice,” Dr. Neelapu exposed.
The rate of grade three or higher adverse events was 93% in the DLBCL cohort and 90% in the cohort with primary mediastinal B-cell lymphoma or transformed follicular lymphoma, the majority of these events were due to cytopenias related to the conditioning chemotherapy. Grade three or higher cytokine-release syndrome occurred in 14% and 10%, respectively. Grade three neurologic events occurred in 25% and 45%, respectively. Grade three or higher neurologic events occurred in 25% and 45%, respectively. Cytokine-release syndrome and neurologic events were generally reversible.
Audience interest in this probe was high, judging by the many questions following Dr. Neelapu’s presentation. Attendees asked about how to supply CAR T cells, the lack of durability of partial responses, and why patients practice neutropenia and cytopenia. Dr. Neelapu’s response to the latter question was that cytopenias are expected because of the conditioning chemotherapy. “The best conditioning regimen is an ongoing area of explore. Most investigators are using cyclophosphamide and fludarabine,” he concluded.
Andrew Zelenetz, MD
Speaking from the audience, Andrew Zelenetz, MD, of Memorial Sloan Kettering Cancer Center, Fresh York, said the delay in getting CAR T cells to the patient is a concern. “The three weeks knock patients out of the picture who need instantaneous treatment.”
“The turnaround time is a big issue for patients with aggressive disease,” acknowledged Dr. Neelapu. “The good news is that of the one hundred eleven patients enrolled, 91% were able to be treated with this 17-day turnaround time.”
Selina Luger, MD
ASH session co-moderator, Selina Luger, MD, of the University of Pennsylvania, Philadelphia, who was not involved in the probe, said that the responses are similar to those in other studies of CAR T-cell therapy and were not that surprising. “What is remarkable is not the actual effect, but the fact that they were able to do this in a multicentered style among many centers with no previous practice.”
“CAR T-cell therapy is not for the faint of heart. This novel technology can be applied effectively at many centers, even those with no practice in T-cell therapy. The hope is that we can bring this out to the broader community,” said ASH President Charles Abrams, MD, commenting on this abstract during a premeeting ASH webinar. Dr. Abrams is Director of the Blood Center for Patient Care and Discovery at the University of Pennsylvania and Children’s Hospital of Philadelphia. ■
Disclosure: Dr. Neelapu has served as an advisor and received research funding from Kite Pharma, the maker of KTE-C19 and sponsor of ZUMA-1. Dr. Luger reported no potential conflicts of interest.