CAR T-Cell Therapy Makes Significant Inroads in Lymphoma: Kymriah and Yescarta Show Durable Remissions

Phoebe Starr

February 2018, Vol 8, No 2 - ASH 2017 Highlights


The data for CD19-directed chimeric antigen receptor (CAR) T-cell therapy continue to show excellent and durable responses in patients with lymphoma who have no other treatment options. Two studies presented at ASH 2017 provide encouraging news for 2 new drugs, including long-term follow-up of the pivotal ZUMA-1 study of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta), and primary results from the JULIET study of tisagenlecleucel (Kymriah).

Both drugs were approved by the FDA in 2017, and were the first 2 gene therapies approved in the United States. Tisagenlecleucel is indicated for pediatric patients with B-cell acute lymphocytic leukemia (ALL), and axicabtagene ciloleucel is indicated for adults with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). The JULIET study results suggest that tisagenlecleucel may receive a new FDA indication for lymphoma.

ZUMA-1 Study

Updated results from the ZUMA-1 clinical trial show that patients with refractory DLBCL continue to have durable responses to the CD19-directed CAR T-cell therapy axicabtagene ciloleucel after >1 year. Furthermore, investigators identified 2 potential mechanisms of resistance—loss of CD19 and PD-L1 expression—paving the way for strategies to overcome resistance.

“Long-term follow-up of ZUMA-1 confirms that these responses can be durable, and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remission at 6 months tend to stay in remission,” said lead investigator Sattva S. Neelapu, MD, Deputy Department Chair ad interim, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX. “We saw no late-onset cytokine release syndrome [CRS] or neurological toxicity due to treatment. Durable responses were observed with and without detectable CAR-T,” added Dr Neelapu.

ZUMA-1 is the largest study to date with a CD19-directed CAR T-cell therapy (ie, axicabtagene ciloleucel). Patients received low-dose conditioning chemotherapy using fludarabine and cyclophosphamide for 3 days, followed by a single infusion of their own re-engineered T-cells through axicabtagene ciloleucel.

“We confirmed the feasibility and reliability of centralized manufacturing and coordination of the leukapheresis procedures and shipping from multiple centers across the country,” said Dr Neelapu.

With longer follow-up, no new treatment-related CRS, neurologic events, or grade 5 adverse events have been reported. Serious adverse events that occurred after 6 months were predominantly infections in 10 patients, all of which resolved by the data cut-off date.

JULIET Study

Primary analysis of the JULIET study showed that a single infusion of the CAR T-cell therapy tisagen­lecleucel achieved durable remissions in nearly 50% of adults with relapsed or refractory DLBCL.

“JULIET shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and central manufacturing. If this therapy is approved [for lymphoma], the sponsor is gearing up for large-scale production for DLBCL in 2018,” said lead investigator Stephen J. Schuster, MD, Director, Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia.

JULIET was conducted at 27 sites in 10 countries. T-cells were manufactured at 2 sites, 1 in the United States and 1 in Germany, with a turnaround time of approximately 22 days. Of the 147 enrolled patients, 99 received the CAR T-cell infusion. Dr Schuster reported findings for 81 patients who received tisagenlecleucel manufactured in the United States.

At 3 months, the best ORR was 53%, and the complete response was 40%. At 6 months, the ORR was 37%, and the complete response was 30%. Nearly 75% of patients were relapse-free at 6 months. The median duration of response and overall survival were not reached at that time.

“The ORR at 3 months is important, because most of those patients will stay in remission for years. I anticipate that we will continue to see durable responses at 3 years,” said Dr Schuster. “This is in the context of an expected median survival of 4 months in relapsed or refractory DLBCL, showing that CAR T-cell therapy represents a breakthrough therapy in a setting with a large unmet need,” he added.

Adverse events of special interest were evaluated in 99 patients. CRS occurred in 58% of patients, and grade 3 or 4 CRS in 23% of patients. Neurologic events occurred in 21% of patients, and grade 3 or 4 neurologic events in 12%. No treatment-related deaths, CRS, or cerebral edema were reported. Overall, 26% of patients received CAR T-cell therapy on an outpatient basis, and 77% of them remained outpatients for ≥3 days after the infusion.

“This suggests that it is possible to give CAR T-cell therapy on an outpatient basis,” said Dr Schuster.

“The JULIET trial, along with ZUMA-1, shows striking responses that are remarkably similar, even though there are differences in the two products,” said Renier J. Brentjens, MD, PhD, Director, Cellular Therapeutics, Memorial Sloan Kettering Cancer Center, New York, who moderated the press conference.

“The initial hoopla was about the high response rates in B-[cell] ALL, but the lingering question was, ‘how durable are these responses, and can they be extrapolated to other B-cell malignancies?’ These trials show that the answer is affirmative,” added Dr Brentjens.