CAR T-Cell Therapy Induces Sustained Responses in DLBCL
Mark L. Fuerst
Six months after receiving a single dose of tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy that targets CD-19, high response rates persist among adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), according to a new study.
The latest interim analysis of the international JULIET trial, presented at the 2017 American Society of Hematology, showed that for 46 patients with at least 6 months of follow-up, the overall response rate was 37 percent, with 30 percent achieving a complete remission (CR) and 7 percent achieving a partial response (Abstract 577).
The CTL019 product was the first FDA-approved CAR T-cell therapy, and it is indicated for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia refractory or in second or later relapse.
In an earlier analysis, tisagenlecleucel was studied in a single-center, phase II study in relapsed/refractory CD19+ lymphomas at the University of Pennsylvania, Philadelphia, and it led to an overall response rate (ORR) of 64 percent (18/28 patients) and CR of 57 percent (16/28 patients). In a DLBCL cohort, the ORR was 50 percent (7/14 patients) and CR of 43 percent (6/14 patients). All patients in CR remained in CR at median follow-up of 29 months.
In the new study, the CAR T-cell therapy produced high response rates with 95 percent of CRs at 3 months being sustained at 6 months in a cohort of highly pretreated adult patients with relapsed/refractory DLBCL, which confirm the findings of the earlier interim analysis.
“While we don't completely understand why these remissions are so durable, it's exciting and will change how this disease is treated when conventional therapies fail,” said lead author Stephen Schuster, MD, Professor of Hematology/Oncology in the Perelman School of Medicine at the University of Pennsylvania and the Penn Abramson Cancer Center. “We are going to be able to offer patients who don't respond to standard therapies a form of therapy that may, after a single treatment, relieve symptoms and save lives.”
DLBCL is the most common form of lymphoma, accounting for roughly one-third of all non-Hodgkin lymphoma cases. Those patients who do not respond to current treatments face a poor prognosis with limited treatment options. Primary therapy will fail in about one-third of people with DLBCL, and half of these patients will not be candidates for stem cell transplantation, which is considered the best second-line treatment approach. These patients would be candidates for CAR T-cell therapy.
“Patients with relapsed/refractory DLBCL have a poor prognosis, a low rate of response to salvage therapy, and short survival, with a median overall survival of 4 months,” noted Schuster. Standard of care for these patients is high-dose chemotherapy followed by autologous stem cell transplant (ASCT).
Details of Juliet Trial
JULIET is the first global CAR T-cell trial in DLBCL, conducted in 27 sites in 10 countries across North America, Europe, Australia, and Asia, with centralized manufacturing of tisagenlecleucel in two centers. This single-arm, open-label, phase II trial included patients who had received two or more lines of prior chemotherapy and had disease progression, or had failed to respond or were ineligible for ASCT.
Of the 147 patients enrolled, 99 patients, median age was 56 years, were infused with a single dose of CTL019 transduced cells (median, 3.1 × 108 cells). Prior to infusion, patients underwent restaging, and 93 percent received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 5.6 months. Three-quarters of patients had stage III or IV disease with a median of three prior lines of antineoplastic therapy; about half had prior ASCT.
Among 81 infused patients with 3 or more months follow-up, the best ORR was 53.1 percent, with 39.5 percent CR and 13.6 percent PR. At month 3, the CR rate was 32 percent and the PR rate was 6 percent. Among the 46 patients evaluable at 6 months, the CR rate was 30 percent and PR rate was 7 percent.
“Durability of responses is shown by the stability between 3- and 6-month response rates. Response at 3 months is indicative of the long-term benefit of this treatment,” Schuster stated.
Response rates were consistent across prognostic subgroups, including those who received prior ASCT and those with double-hit lymphoma, he said. Median duration of response was not reached; the 6-month probability of being relapse-free was 73.5 percent. Median overall survival was not reached; the 6-month probability of overall survival was 64.5 percent.
“Almost all patients in CR at month 3 remained in CR. No patients proceeded to transplant while in response,” he said. “We anticipate seeing durable remissions that will last for years.”
He noted that CTL019 was detected in peripheral blood by quantitative PCR for up to 367 days in responders.
Most of the adverse events were seen shortly after infusion and included CRS and neurotoxicities, which tended to be transient and self-limiting, he said. There were no deaths attributable to CTL019, CRS, or neurological events.
Schuster said several factors set this trial apart from other investigations of CAR T-cell therapies. The therapy was done on an outpatient basis for many patients (26%) and the manufacturing process allowed investigators to generate CAR T cells from previously collected and frozen blood cells, permitting successful shipment around the world.
“Once the CAR T cells were generated, we could freeze them again, allowing us to hold the product until patients were clinically ready to receive them,” he said. “These are very sick patients, so this gives the treating physician some flexibility to schedule therapy when it's best for each patient.”
Patients in the JULIET trial who responded to therapy continue to be followed carefully for recurrence of their lymphoma and recovery of their immune system.
These data served as the basis for global regulatory submissions, and large-scale production of tisagenlecleucel for relapsed/refractory DLBCL is projected in 2018. A target of 22-day manufacturing time has been achieved in the commercial setting.