© Phil McCarten 2017
Stephen J. Schuster, MD Photo courtesy of ASH
ATLANTA—The first chimeric antigen receptor (CAR) T-cell therapy approved in the US to treat children and young adults with leukemia is also producing high response rates in lymphoma, according to investigators of the JULIET trial.
They reported that tisagenlecleucel (formerly CTL019) produced an overall response rate (ORR) of 53% and a complete response (CR) rate of 40% in patients with diffuse large B-cell lymphoma (DLBCL).
Additionally, researchers say the stability in the response rate at 3 and 6 months—38% and 37%, respectively—indicates the durability of the therapy.
At 3 months, 32% of patients who achieved CR remained in CR. At 6 months, 30% remained in CR.
Researchers believe these results confirm the durable clinical benefit reported previously.
Stephen J. Schuster, MD, of the University of Pennsylvania in Philadelphia, presented the JULIET data at the 2017 ASH Annual Meeting (abstract 577).
“Only about half of relapsed diffuse large B-cell lymphoma patients are eligible for transplant,” Dr Schuster said. “[O]f those patients, only about a half respond to salvage chemotherapy, and a significant number of patients relapse post-transplant. So there is really a large unmet need for these patients, and CAR T-cell therapy is a potential agent [for them].”
The JULIET trial was a global, single-arm, phase 2 trial evaluating tisagenlecleucel in DLBCL patients. Tisagenlecleucel (Kymriah™) consists of CAR T cells with a CD19 antigen-binding domain, a 4-1BB costimulatory domain, and a CD3-zeta signaling domain.
The trial was conducted at 27 sites in 10 countries across North America, Europe, Australia, and Asia. There were 2 centralized manufacturing sites, one in Europe and one in the US.
Patients had to be 18 years or older, have had 2 or more prior lines of therapy for DLBCL, and have progressive disease or be ineligible for autologous stem cell transplant (auto-SCT). They could not have had any prior anti-CD19 therapy, and they could not have any central nervous system involvement.
The primary endpoint was best ORR using Lugano criteria with assessment by an independent review committee. Secondary endpoints included duration of response, overall survival (OS), and safety.
Study design and enrollment
Patients were screened and underwent apheresis with cryopreservation of their leukapheresis products during screening, which “allowed for enrollment of all eligible patients,” Dr Schuster said.
Patients could receive bridging chemotherapy while they awaited the manufacture of the CAR T cells.
“What’s important to note is that, early on in the trial, there was a shortage of manufacturing capacity, and this led to a longer-than-anticipated interval between enrollment and treatment,” Dr Schuster said. “This interval decreased as manufacturing capacity improved throughout the trial.”
When their CAR T cells were ready, patients were restaged, lymphodepleted, and received the tisagenlecleucel infusion. The dose ranged from 0.6 x 108 to 6.0 x 108 CAR-positive T cells.
The infusion could be conducted on an inpatient or outpatient basis at the investigator’s discretion, Dr Schuster said.
As of the data cutoff in March 2017, investigators enrolled 147 patients and infused 99 with tisagenlecleucel.
Forty-three patients discontinued before infusion, 9 because of an inability to manufacture the T-cell product and 34 due to death (n=16), physician decision (n=12), patient decision (n=3), adverse event (n=2), and protocol deviation (n=1). Five patients were pending infusion.
There were 81 patients with at least 3 months of follow-up or earlier disease progression evaluable for response.
Patient characteristics
Patients were a median age of 56 (range, 22–76), and 23% were 65 or older. All had an ECOG performance status of 0 or 1, 80% had DLBCL, and 19% had transformed follicular lymphoma.
Fifteen percent had double or triple hits in CMYC, BCL2, and BCL6 genes, and 52% had germinal center B-cell type disease.
Forty-four percent had 2 prior lines of therapy, 31% had 3 prior lines of therapy, and 19% had 4 to 6 prior lines of therapy. All were either refractory to or relapsed from their last therapy.
Forty-seven percent had undergone prior auto-SCT.
Eighty-nine of the 99 patients infused with tisagenlecleucel received bridging therapy, and 92 received lymphodepleting therapy.
Twenty-six patients were infused as outpatients, and 20 remained as outpatients for 3 or more days after the infusion.
Efficacy
The trial met its primary endpoint with an ORR of 53% tested against the null hypothesis of 20% or less. Forty percent of patients achieved a CR, and 14% had a partial response.
The ORR was consistent across all subgroups, including age, sex, lines of prior antineoplastic therapy, cell of origin, and rearranged MYC/BCL2/BCL6.
“The durability of response, however, which is really the message, is shown by the stability between 3- and 6-month response rates, 38% and 37%, respectively,” Dr Schuster said. “The response rate at 3 months is really indicative of the long-term benefit of this treatment approach.”
The investigators observed no apparent relationship between tumor response at month 3 and dose. And they observed responses at all dose levels.
The very early response may be due, to a certain extent, to the chemotherapy, according to Dr Schuster.
“The effect of the T cells becomes evident as you follow these patients over time,” he said.
The median duration of response and overall response have not been reached. And 74% of patients were relapse-free at 6 months.
“Importantly, almost all the complete responders at month 3 remained in complete response,” Dr Schuster said.
Safety
Adverse events of special interest that occurred within 8 weeks of the infusion included:
- Cytokine release syndrome (CRS)—58% all grades, 15% grade 3, 8% grade 4
- Neurologic events—21% all grades, 8% grade 3, 4% grade 4
- Prolonged cytopenia—36% all grades, 15% grade 3, 12% grade 4
- Infections—34% all grades, 18% grade 3, 2% grade 4
- Febrile neutropenia—13% all grades, 11% grade 3, 2% grade 4
No deaths occurred due to tisagenlecleucel, CRS, or cerebral edema.
Fifty-seven patients developed CRS. The median time to onset of CRS was 3 days (range, 1–9), and the median duration of CRS was 7 days (range, 2–30).
Twenty-eight percent of patients developed hypotension that required intervention, 6% requiring high-dose vasopressors. Eight percent were intubated, and 16% received anticytokine therapy—15% with tocilizumab and 11% with corticosteroids.
Investigators did not observe a relationship between dose and neurological events. However, they did detect a higher probability of CRS with the higher doses of tisagenlecleucel.
They also noted that dose and exposure were independent.
Dr Schuster indicated that these data are the basis for global regulatory submissions.
Manufacture of tisagenlecleucel was centralized, and investigators believe the trial shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and centralized manufacturing.
Novartis Pharmaceuticals, the sponsor of the trial, is now able to commercially manufacture the CAR T cells in 22 days.
Dr Schuster disclosed research funding and consulting fees from Novartis and Celgene.
