ATLANTA (FRONTLINE MEDICAL NEWS) Responses 3 months after chimeric antigen receptor (CAR) T-cell therapy look durable in adults with transplant-ineligible relapsed/refractory diffuse large B-cell lymphoma (DLBCL), according to updated results from the single-arm, global, phase 2 JULIET trial.

Fully 95% of patients who had a complete response to CTL019 (tisagenlecleucel; Kymriah) at 3 months maintained that complete response at 6 months, Stephen J. Schuster, MD, said at the annual meeting of the American Society of Hematology.

“The failure rate beyond 6 months’ remission is very low,” Dr. Schuster said during a press briefing. This is the take-home message from the JULIET trial , he stressed, not the fact that the study met its primary endpoint (best overall response rate, 53%; 95% confidence interval, 42%-64%; P less than .0001).

Patients with relapsed/refractory DLBCL tend to face a very poor prognosis, noted Dr. Schuster of Perelman School of Medicine and Abramson Cancer Center, University of Pennsylvania, Philadelphia. High-dose chemotherapy followed by autologous stem cell transplantation “is capable of long-term survival, but in very few patients,” he said. A dismal 8% of patients completely respond to salvage treatment and only about one in five partially respond. Both levels of response are short-lived, with a median survival of about 4 months.

Meanwhile, CTL019 therapy has produced durable complete remissions in children with lymphoblastic leukemia and in adults with chronic lymphocytic leukemia, Dr. Schuster and his associates wrote in an article simultaneously published in the New England Journal of Medicine ( 2017 Dec 10. doi: 10.1056/NEJMoa1708566 ). 

To test the CAR T-cell therapy in relapsed/refractory DLBCL, they enrolled affected adults who had received at least two prior lines of antineoplastic treatment and who were not candidates for autologous stem cell transplantation.

Treatment consisted of a single CTL019 infusion(median dose, 3.1 × 108 cells; range, 0.1 × 108 to 6.0 × 108 cells), usually after lymphodepleting chemotherapy. Previously, patients had received a median of three lines of therapy, and about half had undergone autologous stem cell transplantation.

Median time from infusion to data cutoff in March 2017 was 5.6 months. Among 81 patients followed for at least 3 months before data cutoff, best overall response rate was 53% and 40% had a complete response. Overall response rates were 38% at 3 months and 37% at 6 months. Rates of complete response as confirmed by 18F-fluorodeoxyglucose–positron-emission tomography (PET) were 32% at 3 months and 30% at 6 months. These findings highlight the predictive power of 3-month response to CTL019 therapy in relapsed/refractory DLBCL, Dr. Schuster said. Among all responders, 74% remained relapse free at 6 months, meaning that median duration of response and median overall survival were not reached at data cutoff.

Dr. Schuster also reported that 26% of patients were infused as outpatients, which he called “easy to do” and appropriate as long as patients who become febrile are admitted and monitored for cytokine release syndrome. Three-quarters of patients who were infused as outpatients were able to remain home for at least 3 days afterward, he said.

Adverse events typified those of CAR T-cell therapy, including cytokine release syndrome (all grades: 58%; grade 3-4: 23%) and neurological toxicities (all grades: 21%; grade 3-4: 12%). The current labeling for CTL019 in children and young adults with acute lymphoblastic leukemia also includes a boxed warning for these toxicities. Tisagenlecleucel, the first-ever approved CAR T-cell therapy, is made by using a lentiviral vector to genetically engineer a patient’s own T-cells to express a CAR for the pan-B-cell CD19 antigen. These anti-CD19 CAR T-cells are then expanded in the laboratory, frozen for shipping purposes, and infused back into patients. In October 2017, Novartis submitted a biologics license application to the Food and Drug Administration to expand the label for CTL019 to include transplant-ineligible relapsed/refractory DLBCL.

Novartis Pharmaceuticals anticipates large-scale production in 2018, Dr. Schuster said. Manufacturing time has been cut to 22 days from the 30-day turnaround used in the trial, he reported.

Dr. Schuster also said that he sees no point in retreating patients whose relapsed/refractory DLBCL doesn’t respond to tisagenlecleucel, and that JULIET did not test this approach. “If someone fails therapy and you retreat, you don’t see success, in my experience,” he said. “If patients respond and then fail later, then you retreat and you may succeed.”

Novartis Pharmaceuticals sponsored JULIET. Dr. Schuster disclosed consultancy and research funding from Novartis and ties to Celgene, Gilead, Genentech, and several other pharmaceutical companies.

SOURCE: Schuster S et al. ASH 2017 Abstract 577 .


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