JULIET Analysis Finds Durable Responses With Tisagenlecleucel in DLBCL

Half of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) responded to tisagenlecleucel, and approximately two-thirds of responders are expected to remain progression-free at one year, according to updated results from the phase IIa JULIET trial. The findings were published in the New England Journal of Medicine.

“The high and durable response rates are promising … but the potential longterm toxic effects require further analysis,” lead author Stephen Schuster, MD, from the Perelman School of Medicine at the University of Pennsylvania, and colleagues wrote.

Tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy that targets and eradicates CD19-expressing B cells, was approved by the U.S. Food and Drug Administration in May 2018 for the treatment of relapsed or refractory DLBCL based on earlier results from the JULIET trial.

With this update, the investigators evaluated response rates and response duration in 165 adults with DLBCL who were enrolled from 27 sites in 10 countries. Ultimately, 111 patients (median age = 56 years; range = 22-76 years) received CAR T-cell infusion; 30 percent of enrolled patients discontinued the study without receiving an infusion, mostly as a result of disease progression and death.

Participants had previously been treated with at least two lines of therapy (including rituximab and an anthracycline) and had either a relapse after or were ineligible for autologous hematopoietic cell transplantation (HCT). JULIET also included patients who had DLBCL that had transformed from follicular lymphoma or who had double- or triple-hit lymphoma. Patients who had previously received CD19-directed therapy or had received an allogeneic HCT were excluded from the trial.

The study protocol allowed for bridging therapy between leukapheresis and CAR T-cell manufacturing and infusion. Ninetytwo percent of patients received bridging therapy with rituximab, gemcitabine, dexamethasone, and other agents.

Prior to infusion of tisagenlecleucel, patients also received one cycle of lymphodepleting chemotherapy with either fludarabine and cyclophosphamide or bendamustine.

The median time from enrollment to infusion was 54 days (range not provided), and patients were infused with a single dose of tisagenlecleucel (median = 3.0×108 cells; range = 0.1-6.0×108 cells). The CAR T-cell therapy was centrally manufactured via cryopreserved apheresis and a global supply chain.

All 111 patients who received a CAR T-cell infusion were included in the safety analysis; the efficacy analysis included the 93 patients who had follow-up of at least three months.

Over a median follow-up of 14 months (range = 0.1-26 months), the best overall response rate (ORR) was 52 percent; the majority of responses were complete responses (CRs; 40%) and the remaining were partial responses (PRs; 12%). Response rates were consistent across prognostic subgroups, the researchers noted, including age, previous response status, and molecular subtype.

At three months, the ORR was 38 percent, and the CR rate was 32 percent. At six months, ORRs and CR rates were 33 percent and 29 percent, respectively, suggesting that most early responses were durable.

Among the 37 patients who had a CR, four patients had stable disease and 12 had a PR at one month after CAR T-cell infusion, which improved to a CR within a median of two months (range = 1-17 months), the authors noted. Also, more than half of patients with a PR converted to a CR (n=13/24; 54%). According to these observations, the authors predicted that 79 percent of patients who had a CR and 65 percent of all responders were likely to remain relapse-free one year after infusion.

At the time of data cutoff, the median response duration had not been reached (range = 10 months to not reached). Similarly, the median progression-free survival (PFS) had not been reached, yet the estimated 12-month PFS was 83 percent among patients who responded at three months. Achieving a CR increased the probability of 12-month overall survival (OS), the researchers added: The estimated 12-month OS rate was 49 percent among all treated patients, but 90 percent among those who achieved a CR.

The authors noted that the adverse events (AEs) were similar to those experienced with other CAR T-cell products. The most common AEs included cytokine release syndrome (CRS) in 64 patients (58%); 23 patients (22%) had grade 3 or 4 CRS. See TABLE for incidence of other AEs of interest.

Three participants died within 30 days of tisagenlecleucel infusion; however, deaths were not considered related to the study drug or CRS. The investigators noted no new deaths for reasons other than disease progression since earlier reports from JULIET.

Limitations of the study include its small sample size, the sizable proportion of patients who discontinued study participation, the lack of a control group, and the open-label design.

The authors report relationships with Novartis, which supported the study.

Reference

Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56.

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