Tisagenlecleucel Granted Approval in Europe for DLBCL, ALL

Tisagenlecleucel has gained approval from the European Commission as a treatment for adult patients with diffuse large B-cell lymphoma that is relapsed or refractory after 2 or more lines of systemic therapy, or patients up to 25 years of age with B-cell acute lymphoblastic leukemia that is refractory, in relapse posttransplant, or in second or later relapse.

Carl June, MD

Tisagenlecleucel (Kymriah) has gained approval from the European Commission as a treatment for adult patients with diffuse large B-cell lymphoma (DLBCL) that is relapsed or refractory after 2 or more lines of systemic therapy, or patients up to 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse posttransplant, or in second or later relapse, Novartis, the manufacturer of the CAR T-cell therapy, has announced.

The approval in DLBCL was based on data from the phase II JULIET study. Updated data from the trial presented at the 2018 European Hematology Association (EHA) Congress showed that at a median follow-up of 14.1 months, tisagenlecleucel achieved an objective response rate (ORR) of 52% (95% CI, 41-62) in adult patients with relapsed/refractory DLBCL.1The ORR included a complete response (CR) rate of 40% and a partial response (PR) rate of 12%. This response was durable, as the duration of response had not been reached at data cutoff.

These response rates were consistent across all subgroups, including patients receiving prior allogeneic stem cell transplantation, and in patients having double-hit lymphoma. Additionally, the 12-month relapse-free survival (RFS) rate in patients with a CR was 78.5% (95% CI, 60%-89%) and the 12-month RFS rate in all responders was 65% (95% CI, 49%-78%). No patients proceeded to transplant while in response.

The ALL approval was based on data from the phase II ELIANA trial. Updated data from the pivotal trial published in February 2018 in theNew England Journal of Medicine showed that at a median follow-up of 13.1 months, tisagenlecleucel induced an ORR of 81% in children and young adults with relapsed/refractory B-cell ALL.2

In an analysis of 75 infused patients with 3 or more months of follow-up, 60% of patients achieved CR and 21% of patients achieved CR with incomplete blood count recovery following tisagenlecleucel infusion. By day 28, investigators detected no minimal residual disease among responding patients.

"When the University of Pennsylvania and Novartis agreed to work together to develop CAR-T therapy, our main goal was clear and ambitious to address unmet needs for patients and to extend, improve and save lives," Carl June, MD, the Richard W. Vague Professor in Immunotherapy in the Department of Pathology and Laboratory Medicine at Penn and Director of the Center for Cellular Immunotherapies in the Abramson Cancer Center, said in a statement. "We are proud that our efforts in CAR-T now offer the European blood cancer community a breakthrough that brings new hope."

At the EHA Congress, Peter Borchmann, MD, of the Department of Internal Medicine, University Hospital of Cologne in Cologne, Germany, discussed long-term results from the JULIET trial that were updated after an additional 8 months of follow-up since the last presentation of JULIET results at the 2017 ASH conference in December. JULIET is single-arm open-label global phase II trial (NCT02445248) of tisagenlecleucel in adult patients with relapse/refractory DLBCL, who were ineligible for or had failed autologous stem cell transplant (ASCT).

Of the 165 adult patients enrolled in JULIET, 111 patients were infused with a single dose of tisagenlecleucel (median, 3.0×108cells [range, 0.1-6.0×108cells]). 92% of patients received bridging therapy and 93% received lymphodepleting chemotherapy. Median follow-up from infusion to data cutoff was 14 months with a maximum follow-up of 23 months. Median age of the patients was 56 years (range, 22-76). Nearly a quarter (23%) of patients were older than 65.

At study entry, 76% of infused patients had stage III/IV disease, 17% had double/triple hit mutations in MYC/BCL2/BCL6. Germinal center B-cell disease was present in 57% of patients, and 41% had activated B-cell molecular subtypes. The patients had received a median of prior 3 lines of antineoplastic therapy (range, 1-6), with 95% undergoing ≥2 prior treatments, including prior ASCT in 49% of patients.

Centrally manufactured CAR T cells were provided using cryopreserved apheresis and a global supply chain. The primary endpoint of JULIET was best ORR (CR + PR) per independent review committee. Efficacy results were reported for 93 patients in the main cohort having at least 3 months’ follow-up or earlier discontinuation and the safety cohort included all 111 infused patients.

The median overall survival (OS) among all infused patients was 11.7 months (95% CI, 6.6-NE), with a 12-month OS rate of 49%. Median OS was not reached for patients in CR (95% CI, 17.9-NE), and the 12-month OS rate was 95% for these patients. The response status at 3 months indicated durable clinical benefit; the estimated progression-free survival rate at 12 months was 83% for patients with CR or PR at 3 months.

Grade 3 cytokine release syndrome (CRS) occurred in 14% of patients, with 8% of patients experiencing grade 4. Grade 3 neurological adverse events (AEs) occurred in 7% of patients, with 5% experiencing grade 4. Three patients died ≤30 days of infusion due to disease progression, as reported in the preliminary analysis. No additional deaths have occurred and no deaths were attributed to tisagenlecleucel, CRS, or cerebral edema.

ELIANA, the first pediatric global CAR-T cell therapy registration trial, is a single-cohort, multicenter, study of tisagenlecleucel in children and young adults with relapsed or refractory B-cell ALL. Patients aged 3 to 21 years with least 5% lymphoblasts in bone marrow at screening received a single median weight-adjusted dose of 3.1 × 106transduced viable T cells per kg of body weight. The median total dose of transduced cells was 1.0 × 108(range, 0.03 × 108to 2.6 × 108).

Event-free survival was 73% at 6 months (95% CI, 60-82) and 50% at 12 months (95% CI, 35-64) among the 61 patients who responded to treatment. Overall survival (OS) in all 75 patients was 90% (95% CI, 81-95) at 6 months and 76% (95% CI, 63-86) at 12 months.

Investigators detected CAR T-cells in patients up to 20 months after initial infusion, with a median persistence of 168 days (range, 20-617) at data cutoff. All patients in the trial received a single infusion of tisagenlecleucel.

All responding patients demonstrated B-cell aplasia, an on-target effect of treatment with tisagenlecleucel. Evaluable patients with a response at day 28 had a median time to maximum expansion of 10 days (range, 5.7-28). Six patients with no response had a median time to maximum expansion of 20 days (range, 13-63).

Nearly all patients (95%) experienced any-grade treatment-related adverse events (TRAE). The most common non-hematologic TRAEs were CRS (77%), pyrexia (40%), decreased appetite (39%), febrile neutropenia (36%) and headache (36%).

Three-quarters of patients experienced a grade 3/4 TRAE, including 21% who experienced grade 3 CRS and 25% who experienced grade 4. Investigators managed CRS using prior site education on implementation of the CRS treatment algorithm. Thirty-five (47%) patients were admitted to the intensive care unit for management of CRS.

Forty percent of patients experienced neurological events within 8 weeks of infusion. Ten patients (13%) had grade 3 neurological events that were managed with best supportive care. There was no incidence of grade 4 neurological events or cerebral edema reported.

"Bringing Kymriah to patients in the European Union advances the treatment paradigm in an unprecedented way and delivers a lifesaving therapy to young patients with ALL who have not been successfully treated with existing therapies, and who have limited options left," Peter Bader, MD, head of the Division for Stem Cell Transplantation and Immunology and principal investigator of the ELIANA study at the University Hospital for Children and Adolescents in Frankfurt/Main, said in a statement.

In August 2017, tisagenlecleucel became the first CAR T-cell therapy approved by the FDA when the agency authorized the treatment’s use for patients up to 25 years of age with B-cell precursor acute lymphoblastic leukemia that is refractory or in second or later relapse. The FDA approved tisagenlecleucel in May 2018 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 or more lines of systemic therapy.


  1. Borchmann P, Tam CS, Jager U, 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). Presented at: 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract S799.
  2. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia.N Engl J Med.2018; 378:439-448.