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Durable and high responses with the CD19 targeting CAR T-cell therapy tisagenlecleucel in adults with relapsed/refractory diffuse large B-cell lymphoma

Results of the JULIET trial demonstrate that tisagenlecleucel (CTL019), an investigational CAR T-cell therapy targeting CD19-expressing B cells, produces high response rates in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The responses to CTL019 were shown to be durable, with 95% of the complete responses (CRs) seen at month 3 being sustained at month 6. There were no treatment-related mortalities in this study, and the adverse events (AEs) associated with the therapy could be managed effectively.

DLBCL is the most common form of lymphoma, accounting for roughly one-third of all non-Hodgkin lymphoma cases. While the current therapy is successful for many patients, some fail and they face a poor prognosis with limited treatment options. The most effective second-line treatment option in this setting consists of an autologous stem cell transplantation  (ASCT), but this option is only feasible in about half of the cases. CTL019 is a CAR T-cell therapy that identifies and eliminates CD19-expressing B cells. JULIET is a single-arm, open-label, multicentre, global, pivotal phase 2 trial evaluating CTL019 in adult patients with relapsed/refractory DLBCL. In order to be eligible for enrolment in JULIET, patients had to be 18 years of age and had to have progressive DLBCL after 2 or more lines of chemotherapy. Patients also had to be ineligible for, or should have failed, an ASCT.

Among the 81 CTL019 infused patients with at least 3 months of follow-up, the best ORR was 53.1% with a CR in 40% of patients and with 13.6% of partial responses (PRs). At month 3, the CR rate was 32% with a PR rate of 6%. Among the 46 patients who were evaluable at 6 months, the CR rate was 30% and an additional 7% of patients had a PR. The response rates to CTL019 were shown to be consistent across the different prognostic subgroups, including in patients who received a prior ASCT and in patients with double-hit lymphoma. Both the median duration of response (DoR) and the median overall survival (OS) were not yet reached at the time of the analysis. At 6 months, the probability of being free of relapse was 73.5% and the 6-month probability of OS was 64.5%. Interestingly, almost all patients in CR at month 3 remained in CR for the remainder of the follow-up time. No patients proceeded to transplant while in response.

Most of the adverse events (AEs) with CTL019 were seen shortly after infusion. Overall, 86% of patients had grade 3/4 adverse events (AEs). Cytokine release syndrome (CRS) occurred in 58% of infused patients and reached grade 3/4 severity in 23%. In total, 15% of patients received anti-IL6 therapy, tocilizumab, for CRS management and 11% of patients received corticosteroids. Other grade 3/4 AEs of special interest included neurologic AEs (12%, managed with supportive care), cytopenia lasting for more than 28 days (27%), infections (20%) and febrile neutropenia (13%). Three patients died within 30 days of infusion, all due to disease progression.

In summary, CTL019 produced high response rates in this cohort of highly pre-treated relapsed/refractory DLBCL. The responses were durable, with 95% of the CRs at 3 months being sustained at 6 months. The study proved that centralized manufacturing of the CAR-T cells was feasible in this first global study of CAR T cell therapy. The CRS and other AEs emerging with CTL019 could be effectively managed by appropriately trained investigators without treatment-related mortality.


Schuster S, Bishop M, Tam C, 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 2017; Abstract #577.

Speaker Stephen Schuster


Prof. Stephen J. Schuster, MD,PhD, Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA


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