Updated results from the phase II JULIET trial of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) presented at the 2017 ASH Annual Meeting confirmed results from an earlier interim analysis: A single infusion of tisagenlecleucel led to good response rates and durable remissions in a patient population that has few to no treatment options available.
As lead author Stephen J. Schuster, MD, from the Abramson Cancer Center at Penn Medicine in Philadelphia, reported during his presentation, 43 of 81 patients (53%) responded to tisagenlecleucel treatment, demonstrating that “the efficacy we saw in earlier trials was sustained.”
Tisagenlecleucel was the first chimeric antigen receptor (CAR) T-cell therapy approved by the U.S. Food and Drug Administration for the treatment of pediatric patients with B-cell precursor acute lymphocytic leukemia (ALL). According to Dr. Schuster, it is also a promising therapy for difficult-to-treat DLBCL. “This is a frustrating patient population because we feel that we can save lives in DLBCL, but not this population,” he told ASH Clinical News. “Patients who either don’t respond to secondline therapy and are refractory to immunochemotherapy or whose disease has progressed after transplant have no great existing therapy.”
As of March 8, 2017 (data cutoff), 147 patients were enrolled in the trial and 99 (median age = 56 years; range = 22-76 years) were infused with a single dose of tisagenlecleucel (median dose = 3.1×108 cells/kg; range = 0.1-6.0×108 cells/kg). Seventy-seven percent of patients had stage III or IV disease at study entry. The median number of prior lines of antineoplastic therapy was three (range = 1-6 therapies); 95 percent of patients received two or more therapies, and 51 percent received three or more. Nearly half (47%) had received autologous hematopoietic cell transplantation. Prior to infusion, 93 percent received lymphodepleting chemotherapy with fludarabine, cyclophosphamide, or bendamustine.
Dr. Schuster reported findings from the 81 patients infused with tisagenlecleucel who had been followed for at least three months.
Over a median follow-up of 29 months (range not reported), the best overall response rate (ORR; primary endpoint) was 53.1 percent (p<0.0001), which included 32 complete remissions (CRs; 39.5%) and 11 partial remissions (PRs; 13.6%).
Three months after tisagenlecleucel infusion, the ORR was 38 percent (32% CRs, 6% PRs), and these rates remained stable at six months post-infusion (ORR=37%, with 30% CRs and 7% PRs). Response at three months was “key,” Dr. Schuster said, with “95 percent of patients who were in CR at three months likely to stay in CR for years.”
Median overall survival (OS) and median duration of response were not reached, the six-month probability of OS was 64.5 percent (95% CI 51.5-74.8; p value not reported), and the six-month probability of being relapse-free was 73.5 percent (95% CI 52.0-86.6; p value not reported).
Safety analysis showed that 86 percent of all 99 patients who received tisagenlecleucel experienced a grade 3 or 4 adverse event (AEs). As with other CAR T-cell therapies, the most common any-grade AE was cytokine release syndrome (CRS), which occurred in 58 percent of infused patients; CRS was grade 3/4 in 23 percent of patients. Fifteen percent of these patients received tocilizumab, and 11 percent of patients received corticosteroids to manage CRS, “with good response,” Dr. Schuster noted. Though neurologic events occurred in 21 percent of patients (12% were grade 3/4), there were no deaths related to cerebral edema, the researchers added. Three deaths occurred within 30 days of infusion, all of which were considered related to disease progression (not treatment or treatment-related AEs).
The findings from this study are limited by the small number of patients and the lack of a comparator arm. Dr. Schuster added that the JULIET investigators are now looking at the causes for treatment failure in the patients who did not respond to tisagenlecleucel infusion. “Loss of CD19 is the most common reason for failure in ALL, but accounts for only 10 to 20 percent of treatment failure in DLBCL,” he said. “In JULIET, the majority of [treatment failures] were because the tumor cells upregulated inhibitory ligands. … We have started a trial ‘rescuing’ patients whose disease progressed during T-cell expansion with the checkpoint inhibitor pembrolizumab.”
The authors report financial relationships with Novartis, which also provided funding for the study.
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. Abstract 577. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.