The CAR T-cell therapy tisagenlecleucel (Kymriah) showed similar real-world efficacy and safety findings to that of the JULIET trial in the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma.
Samantha M. Jaglowski, MD
The CD19-directed CAR T-cell therapy tisagenlecleucel (Kymriah) demonstrated similar real-world efficacy and safety findings to that of the pivotal JULIET trial in the treatment of adult patients with relapsed/refractory diffuse large B-cell lymphoma, according to an analysis of the PICTOR (CTL019B2401)/CIBMTR SC 17-08 registry presented at the 2019 ASH Annual Meeting.1
Results showed that the best overall response rate (ORR) was 58%, which included a complete response (CR) rate of 40% and a partial response (PR) rate of 18%.
The efficacy findings are overall comparable with the updated data from the phase II JULIET trial, which were published in the New England Journal of Medicine earlier this year. Specifically, in JULIET, the ORR with the agent was 52%, with a CR rate of 40% and a PR rate of 12%.2
“Tisagenlecleucel therapy real-world evidence confirms the efficacy data reported in the JULIET study,” Samantha M. Jaglowski, MD, associate professor in the Department of Internal Medicine, Ohio State University Comprehensive Cancer Center—James, said in a presentation during the conference. “Additionally, the safety profile [of the product] appears more favorable in the registry compared with the pivotal study.”
In May 2018, the FDA approved tisagenlecleucel for use in adult patients with relapsed/refractory large B-cell lymphoma—including DLBCL, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma—after ≥2 lines of systemic therapy.
The approval was based on earlier phase II JULIET findings, in which tisagenlecleucel reached an ORR of 50% (95% CI, 38%-62%) in adult patients with relapsed/refractory DLBCL.3 The CR rate was 32% and the PR rate was 18%; the median duration of response (DOR) had not yet been reached.
The Center for International Blood & Marrow Transplant Research (CIBMTR) Cellular Therapy (CT) Registry was created to capture long-term data from patients who have received CAR T-cell therapy. In September 2018, the CIBMTR and Novartis, the developer of tisagenlecleucel, created this post-marketing study of tisagenlecleucel in the real-world setting to collect long-term safety and efficacy data from patients receiving the CAR T-cell therapy.
The registry plans to follow patients with lymphoma (n = 1500) and acute lymphoblastic leukemia (n = 1000) who have been treated with tisagenlecleucel for 15 years; this includes patients receiving an out-of-specification (OOS) product. The first patient entered on the registry was infused in June 2018. Recommended visit assessments were pre-infusion, at months 3, 6, 12, and annually after infusion.
Efficacy and safety data were collected from patients with ≥3 months of follow-up. Additionally, cytokine release syndrome (CRS) as per the consensus American Society for Transplantation and Cellular Therapy criteria and neurotoxicity via the Immune Effector Cell—Associated Neurotoxicity Syndrome (ICANS) scale were reported. Tisagenlecleucel’s manufacturing product characteristics and cell product characterization by immunophenotyping were compared with clinical outcomes obtained in the registry. Investigators used descriptive summaries and univariate logistic regression analyses to evaluate the association of cells administered, cell viability, potency, transduction efficiency to overall response, CRS, and ICANS grade.
To date, 39 centers contributed findings for 116 patients with relapsed/refractory DLBCL through the registry. The efficacy data set included 80 patients, 75 of which were in a manufacturing set; safety data were available for 83 patients, 77 of which were in a manufacturing set. The total manufacturing set includes 102 patients.
The median age of the participants included in the analysis was 65 years (range, 15-89); in JULIET, Jaglowski noted that the median age was 56 years (range, 22-74). Sixty percent of patients were male and most patients were white (85.7%). Furthermore, 34.3%, 47.1%, 4.3%, and 14.3% of patients had an ECOG performance status of 0, 1, 2, and not reported, respectively. Forty-one percent of patients had double- or triple-hit lymphoma and 27% had transformed lymphoma; 32% and 61% of patients had refractory and relapsed disease, respectively. Twenty-four percent of patients had undergone prior autologous stem cell transplant; allogeneic stem cell transplant occurred in 4% of patients.
The median time from diagnosis of DLBCL to CAR T-cell therapy was 15 months, and the median time from manufacturing start to infusion was 32 days. All patients were treated with the FDA-approved dose of tisagenlecleucel of 0.6 to 6 x 108; the median dose was 1.7 x 108 CAR+ viable T cells (range, 0.4-6.8 x 108).
The median number of prior therapies was 3 (range, 0-9). Prior to tisagenlecleucel treatment, patients were either resistant to primary induction (31.4%), experienced a second or later CR (5.7%), were in first relapse (25.7%), second relapse (31.4%), ≥third relapse (2.9%), or not reported/unknown (2.9%).
Of the 116 patients, lymphodepletion therapy was given via cyclophosphamide and fludarabine in most (89%), followed by bendamustine (5%), cyclophosphamide with cytarabine and a monoclonal antibody (4%), as well as nitrosourea, cyclophosphamide, and not reported (1% each).
Cell viability specification is ≥70% in all trials and commercial settings except in the United States, where it is ≥80%. Twenty-nine of the products manufactured were out-of-commercial specification due to low cell viability (<80%); 1 product also had low cell count (<0.6 x 108 CAR + viable T cells) and 1 had high cell count (>6.0 x 108 CAR + viable T cells).
However, efficacy and safety outcomes were similar to those with batches that met viability specifications. None of the manufacturing characteristics were linked with ORR or CRS and ICANS, and the analysis of cell viability did not correlate with best ORR.
At a median follow-up of 4.5 months (range, <1-10.5 months), results of the efficacy set also showed that the 3-month DOR was 75.2%. Additionally, the 3-month progression-free and overall survival (OS) rates were 61.6% and 79.6%, respectively.
In JULIET, the median DOR at 3 months was 76%; the 3- and 6-month PFS rates were 46% and 39%, respectively, and the 3- and 6-month OS rates were 83% and 61%, respectively.
Regarding safety, all-grade CRS occurred in 49% of patients. The majority of CRS AEs were of grades 1/2, no grade 3 cases were reported, and 1% and 2% of patients experienced grade 4 and 5 CRS, respectively.
In the JULIET trial, all-grade CRS was reported in 58% of patients, with grade 3/4 events occurring in 22% of cases.
“We hypothesize that the earlier administration of tocilizumab (Actemra) may have contributed to patients not progressing in terms of grade of CRS,” explained Jaglowski.
All-grade neurotoxicity was observed in 16% of patients; 10% were grades 1/2 events, 5% were grades 3/4, and 1% was not reported. In JULIET, all-grade neurologic events occurred in 21% of patients, 12% of which were grades 3/4.
The median time to CRS onset was 4 days (range, 2-14) and lasted 5 days on average; neurotoxicity was a median 8 days to onset (range, 4-27) and lasted for a median 14 days.
When the relationship between cell count and best overall response was analyzed, it was found that a lower cell count quartile was associated with a lower ORR, but this was not statistically significant in comparison with other quartiles. The cell count ranges were associated with the following ORRs (n = 75): 0.42 to 1.19 x 108 cells (28%; 95% CI, 10%-53%), 1.20 to 1.67 x 108 cells (68%; 95% CI, 43%-87%), 1.69—2.26 x 108 cells (68%; 43%-87%), and 2.27—6.79 x 108 cells (63; 38%-84%).
Additionally, the overall CRS rates varied by dose quartile: 1 (21%), 2 (37%), 3 (55%), and 4 (68%); grade ≥3 CRS occurred in 4% of patients, all of which occurred in the third quartile.
The association between lower cell dose and lower overall response needs to be further studied with a larger number of patients, and registration participation is highly encouraged to further advance insights, Jaglowski concluded.