Impressive Responses Seen With Tisagenlecleucel in DLBCL in JULIET Trial

Stephen J. Schuster, MD

Treatment with tisagenlecleucel (Kymriah) continues to excite the possibilities seen with chimeric antigen receptor (CAR) T-cell therapy with impressive responses seen with the therapy in patients with&nbsp;relapsed/refractory diffuse large B-cell lymphoma (DLBCL). In the phase II JULIET trial, an overall response rate (ORR) of 53.1%&nbsp;(95% CI, 42-64;P<.0001) was observed, according to findings presented at the ASH Annual Meeting.&nbsp;

These responses occurred in 81 infused patients and included a complete response (CR) rate of 39.5% and a partial response (PR) rate of 13.6%. The CR rate for all 81 patients at month 3 was 32% and the PR rate was 6%. The rates were 30% and 7%, respectively, among patients evaluable at 6 months (n = 46).

&ldquo;What is important is not the overall response rate. What&rsquo;s important is the response rate at 3 months, because most of those patients will stay in remission for years,&rdquo; lead investigator Stephen Schuster, MD, professor of hematology/oncology at the University of Pennsylvania Abramson Cancer Center, said when presenting the results at ASH.

In August 2017, the FDA approved the CD19-directed therapy tisagenlecleucel for the treatment of children and adults up to age 25 with B-cell precursor acute lymphoblastic leukemia, making it the first CAR T-cell therapy approved for use in the United States.

Based on the JULIET trial, Novartis, the manufacturer of tisagenlecleucel filed a supplemental biologics license application (sBLA) with the FDA to expand the indication for tisagenlecleucel to include adults with relapsed/refractory DLBCL who are ineligible for autologous stem cell transplant (auto-SCT). The FDA granted a breakthrough therapy designation for tisagenlecleucel in this population in April 2017.

Patients in JULIET were enrolled at 27 study centers in 10 countries on 4 continents. At the March 8, 2017, data cutoff, 147 patients were enrolled, 99 of whom were infused with a single dose of tisagenlecleucel transduced cells (median, 3.1 x 10⁸cells; range, 0.1-6.0 x 10⁸). Ninety percent of patients received bridging therapy. Before infusion, patients underwent restaging and 93% received lymphodepleting chemotherapy.

The median patient age was 56 years (range, 22-76) and 77% of patients had stage III/IV disease at baseline. Forty-seven percent of patients had received auto-SCT. Patients had received a median of 3 (range, 1-6) prior lines of antineoplastic therapy, with 95% of patients having received at least 2 lines of therapy and 51% having received 3 or more.&nbsp;

The investigators observed consistent response rates across prognostic subgroups, including prior auto-SCT and patients with double-hit lymphoma. The median duration of response had not been reached. The probability of being relapse-free at 6 months was 73.5% (95% CI, 52.0-86.6). Among the patients achieving a CR or a PR, none proceeded to allogenic- or auto-SCT.

Median overall survival (OS) had not been reached, with the probability of OS at 6 months being 64.5% (95% CI, 51.5-74.8). Among responders, tisagenlecleucel was detected in peripheral blood by quantitative PCR for up to 367 days.

The incidence of adverse events of special interest (AESI) was evaluated in 99 patients. Common AESIs included cytokine release syndrome (CRS; 58%; grade 3, 15%; grade 4, 8%), neurological events (21%; grade 3, 8%; grade 4, 4%), prolonged cytopenia (36%; grade 3, 15%; grade 4, 12%), infections (34%; grade 3, 18%; grade 4, 2%), and febrile neutropenia (13%; grade 3, 11%; grade 4, 2%).&nbsp;

There were no deaths due to tisagenlecleucel, CRS, or cerebral edema. Twenty-six patients were infused as outpatients, with 20 of these patients remaining outpatients for &ge;3 days after infusion.

Interim results from the JULIET trial were previously reported in June 2017 at the 2017 International Conference on Malignant Lymphoma biennial meeting in Lugano, Switzerland. At a median follow-up of 3.7 months, the ORR was 59% (95% CI, 44.2%-72.4%;P<.0001) in 51 patients, with a 43% CR rate and 16% PR rate.&nbsp;

Schuster noted in his concluding remarks that the international trial importantly demonstrated &ldquo;the feasibility of globally distributing these cells that are manufactured centrally,&rdquo; adding, &ldquo;this technology is exportable.&rdquo;

Reference:

Schuster SJ, Bishop MR, Tam CS, et al. Primary analysis of Juliet: A global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Presented at: ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 577.