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Tisagenlecleucel induces durable responses in relapsed, refractory DLBCL
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ATLANTA — Treatment with the chimeric antigen receptor T-cell therapy tisagenlecleucel led to durable responses among highly pretreated patients with relapsed and refractory diffuse large B-cell lymphoma, according to results of the global JULIET trial presented at the ASH Annual Meeting and Exposition.
“Patients with large B-cell lymphoma who failed available therapies, either with relapsed or primary resistant disease, have very poor prognosis,” Stephen Schuster, MD, professor of hematology/oncology at Perelman School of Medicine of University of Pennsylvania and Penn's Abramson Cancer Center, said during a press conference. “Response rate to existing and available therapies is about 8% for complete response and 18% for partial response, but these tend to be short lived. Median survival for these patients is about 4 months.”
Up until this point, salvage chemotherapy has been standard of care for these patients, with responding patients undergoing stem cell transplantation.
“If you have 100 patients with DLBCL, only about half of them will be eligible for transplant, and only half of those will have a response to chemotherapy and be able to go on to transplant,” Schuster said. “Those who are transplanted will have a relapse rate so, in the end, transplant is capable of long-term survival, but in very few patients.”
Tisagenlecleucel (Kymriah, Novartis) — the first FDA-approved chimeric antigen receptor (CAR) T-cell therapy — is composed of a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
A single-center, phase 3 study of tisagenlecleucel in relapsed/refractory CD19-positive lymphomas at University of Pennsylvania showed an ORR of 64% and a complete response rate of 57%. Further, all patients with complete response remained in response at a median follow-up of 29 months.
“Recall that median OS for this group of patients is about 4 months, whereas these patients have not relapsed after a median follow-up of 29 months,” Schuster said. “So, this therapy clearly has the power to fulfill the unmet need for patient with DLBCL that is not responsive to our current therapies.”
To assess the efficacy of tisagenlecleucel outside of a single center, researchers conducted the first global CAR T-cell trial in DLBCL at 27 sites in 10 countries.
Researchers enrolled 147 patients, 99 (median age, 56 years; range, 22-76; 77% stage III-IV disease) of whom received a single infusion of CD19-transduced cells (median, 3.1 x 108 cells).
Patients had received a median of three (range, 1-6) prior lines of therapy, and 47% of patients underwent autologous stem cell transplantation.
Median time from infusion to data cutoff was 5.6 months. Best ORR per independent review committee served as the study’s primary endpoint.
Among 81 infused patients with at least 3 months of follow-up, the best ORR was 53%, with a complete response rate of 39.5%.
At 3 months, the ORR was 38% and complete response rate was 32%. These rates appeared stable at 6 months, with an ORR of 37% and complete response rate of 30%.
“Most of the patients in response at 3 months will stay in remission for years,” Schuster said. “There is 95% stability between 3 and 6 months. To see the effect of the cells, it is important to look at the data at 3 months, 6 months and beyond.”
Median duration of response and median OS had not yet been reached.
“What I anticipate is, like in our single-center study at Penn, we’ll see durable remission lasting years,” Schuster said. “This is in response to a single treatment.”
Among all 99 patients, cytokine release syndrome occurred among 58% at any grade, 15% at grade 3 and 8% at grade 4. Neurological events of any grade occurred among 21% of patients, including 8% that were grade 3 and 4% grade 4.
Researchers reported no deaths related to treatment, cytokine release syndrome or cerebral edema.
Further, Schuster noted that 26 patients were infused with the CAR T cells as outpatients, 20 of whom (77%) remained outpatients for more than 3 days following the infusion.
“Chemotherapy was lighter in this protocol, so we were able to treat a quarter of patients as outpatients,” Schuster said. “Many of them would develop fever and be admitted several days later for observation, but it was easy to give as an outpatient.”
Overall, these results confirm the durable benefit with this CAR T-cell therapy observed in the single-center study.
Further, the manufacturing time of the CAR T cells decreased from 30 days to 22 days, showing the technology continues to improve, Schuster said.
“JULIET shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing,” he said. “These data have been submitted in the U.S. and the European Union to the regulatory agencies for approval. The sponsor of the study, Novartis, is gearing up for large-scale production of this in 2018.” – by Alexandra Todak
Reference:
Schuster SJ, et al. Abstract 577. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta.
Disclosures: Novartis sponsored this study. Schuster reports consulting roles with and research funding from Celgene, Genentech, Gilead, Janssen, Nordic Nanovector, Novartis, Merck and Seattle Genetics. Please see the abstract for all other authors’ relevant financial disclosures.