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February 15, 2019

Longer-Term JULIET Results Confirm Sustained Response With Tisagenlecleucel in Relapsed/Refractory DLBCL

Surabhi Dangi-Garimella, PhD
A median 19-month follow-up of the JULIET trial—a single-arm, open-label, multicenter, global, pivotal phase 2 trial of the chimeric antigen receptor-T cell therapy tisagenlecleucel directed against CD19-expressing B cells—has found a 40% complete response and a manageable safety profile in adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).
A median 19-month follow-up of the JULIET trial—a single-arm, open-label, multicenter, global, pivotal phase 2 trial of the chimeric antigen receptor (CAR)-T cell therapy tisagenlecleucel directed against CD19-expressing B cells—has found a 40% complete response (CR) and a manageable safety profile in adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL).1

Tisagenlecleucel (Kymriah) was FDA approved in May 2018 for the treatment of adult patients with R/R large B-cell lymphoma following at least 2 prior line of therapy.

Conducted across 27 sites in 10 countries, the JULIET trial enrolled 167 patients with R/R DLBCL at the cutoff date of May 21, 2018, and 115 of them received an infusion of CD19-directed CAR T cells (dose range 0.1 x 108 to 6 x 108 cells). Eligibility criteria included at least 18 years of age; at least 2 lines of prior therapy, including an anti-CD20 antibody and an anthracycline; and were ineligible for or had failed autologous stem cell transplant (ASCT). Primary trial endpoint was overall response rate (ORR), as a sum total of the CR and partial response as assessed by an independent review committee. Secondary endpoints included duration of response, overall survival, and safety.

About 90% of infused patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median time from infusion to data cutoff was 19.3 months. Median age was 56 years (range, 22-76 years); 23% were aged ≥65 years. At study entry, 77% of infused patients had stage III/IV disease; 55% and 43% had germinal center and activated B-cell molecular subtypes, respectively. Over half of the patients had received at least 3 prior lines of antineoplastic therapy (range, 1-6) and about the same number had undergone a prior ASCT.

Of the 99 patients who were evaluated who had at least 3 months of follow-up, ORR was 54% (95% CI, 43%-64%), with 40% CR. Further, ORR was consistent across prognostic subgroups that were evaluated, including prior ASCT, gender, age, and molecular subtype.

Median duration of response (DOR) was not reached at the time of data analysis, and DOR was not influenced by age or R/R status, the study found. No relapses were observed beyond 11 months after infusion. The median OS for all infused patients was 11.1 months (95% CI, 6.6 months-not evaluable [NE]) and was not reached for patients in CR (95% CI, 21 months-NE). The OS probability was 48% (95% CI, 38%-57%) at 12 months and 43% (95% CI, 33%-53%) at 18 months, and, similar to DOR, was not influenced by the patient’s age or R/R status.

“These findings are consistent with what we’ve shown in our single-site studies here at Penn, which is that the majority of patients who go into remission stay in remission,” said Stephen J. Schuster, MD, director of the Lymphoma Program at the Abramson Cancer Center of the University of Pennsylvania, who is the principle investigator for the JULIET trial.2

The authors compared the survival curves from their current study with those of the SCHOLAR-1 study3 and the CORAL study,4 and found that patients enrolled in JULIET performed much better in terms of overall survival. The OS probability was about 30% and 25% for SCHOLAR-1 and CORAL at 12 months, respectively, and 25% and 20% at 24 months, respectively.

More than half (57%) of patients experienced cytokine release syndrome, 34% of which were grade 3/4. Prolonged (>28 days) cytopenias were observed in 45% patients, 34% of which were high-grade (3/4); a majority (17%) of infections in 37% of patients were grade 3. Twenty percent of treated patients experienced neurological adverse events, including a single case of grade 2 cerebral edema, which was detected without a contrast computed tomography (CT) scan, which disappeared following a contrast CT scan after 24 hours.

The authors report that there were no treatment-related deaths following their last data presentation at the Congress of the European Hematology Association in June this year.5

References
  1. Schuster SJ, Bishop MR, Tam C, et al. Sustained disease control for adult patients with relapsed or refractory diffuse large B-Cell lymphoma: an updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel. In: Proceedings from the American Society of Hematology; December 1-3, 2018; San Diego, CA. Abstract 1684.
  2. Global trial shows CAR T therapy can lead to durable remissions in non-Hodgkin’s lymphoma [press release]. Philadelphia, PA: Penn Medicine; November 30, 2018. newswise.com/articles/view/704664/?sc=dwhr&xy=10014716. Accessed December 4, 2018.
  3. Crump M, Neelapu SS2, Farooq U, et al. Outcomes in refractory diffuse large B-cell lymphoma: results from the international SCHOLAR-1 study. Blood. 2017;130(16):1800-1808. doi: 10.1182/blood-2017-03-769620.
  4. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30(36):4462-4469. doi: 10.1200/JCO.2012.41.9416.
  5. Borchmann P, Tam CS, Ulrich Jager, et al. An updated analysis of Juliet, a global pivotal phase 2 trial of tisagenlecleucel in adult patients with relapsed or refractory (r/r) diffuse large b-cell lymphoma (DLBCL). In: Proceedings from the 23rd Congress of the European Hematology Association; June 14-17, 2018; Stockholm, Sweden. Abstract S799.


 
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