Long-term clinical outcomes of tisagenlecleucel in the JULIET trial

October 2021 Pharma News Jolien Blokken

In the primary analysis of the international phase II JULIET trial of tisagenlecleucel, the best overall response rate was 52% and the complete response rate was 40% in adult patients with relapsed or refractory aggressive B-cell lymphomas. Long-term clinical outcomes with a median follow-up of 40.3 months, now confirm the durable activity and manageable safety profile of tisagenlecleucel.

Expert opinion of Prof. Gregor Verhoef, Haematologist, UZ Leuven

In general, patients with relapsed or refractory large B-cell lymphomas (LBCL) have poor outcomes with traditional therapies. However, CAR T-cell products could demonstrate efficacy with acceptable toxicity profiles. In the primary analysis of the international, single-arm, phase II JULIET trial of tisagenlecleucel (median time from infusion to data cut-off 14 months), the best overall response rate was 52% and the complete response rate was 40%, among 93 adults with relapsed or refractory (R/R) LBCL. Updated, long-term follow-up data of the full adult patient population with R/R aggressive B-cell lymphoma who were given tisagenlecleucel (tisa-cel) in the JULIET study were recently published in Lancet Oncology.

JULIET study design

JULIET is a multicentre, open-label, single-arm, phase II trial that enrolled patients at 27 treatment sites in ten countries across four continents. Adult patients with histologically confirmed relapsed or refractory LBCL who had previously received at least two lines of therapy, including rituximab and an anthracycline, and had either relapsed after, were ineligible for, or did not consent to, autologous haematopoietic stem-cell transplantation were eligible for the study.  Patients who had LBCL that had transformed from follicular lymphoma and patients who had high-grade B-cell lymphoma with MYC rearrangements combined with either BCL2 rearrangements, BCL6 rearrangements, or both BCL2 and BCL6 rearrangements were also eligible. Following leukapheresis, bridging chemotherapy was permitted at the discretion of the treating physician. Before tisa-cel infusion, patients could receive one cycle of lymphodepleting chemotherapy consisting of either intravenous fludarabine (25 mg/m²) and intravenous cyclophosphamide (250 mg/m²) once daily for three days or intravenous bendamustine (90 mg/m²) once daily for 2 days. Patients received a single intravenous infusion of tisa-cel at a dose ranging from 0.1 × 10⁸ viable CAR T cells to 6.0 × 10⁸ viable CAR T cells (target dose 5 × 10⁸ viable CAR T cells), in either the inpatient or outpatient setting.

Results

As of February 20, 2020, 115 patients had received tisa-cel, with a median follow-up of 40.3 months and a maximum follow-up of 52.6 months from the time of infusion to data cut-off. Most of them (N= 101) received tisa-cel in the inpatient setting while 14 patients received tisa-cel in the outpatient setting. The overall response rate, as assessed by an independent review committee, was 53.0%. Interestingly, 39% of patients had a complete response as their best overall response. The median duration of response in the full analysis set was not estimable. However, the estimated proportion of patients with a response at 36 months after response onset was 60.4%. The median progression-free survival (PFS) was 2.9 months and the median overall survival (OS) was 11.1 months. Both median PFS and median OS was not reached for patients who had a complete response at three or six months. Patients with high lactate dehydrogenase concentrations, low platelet counts, or both, before infusion appear to represent a high-risk, less responsive population. Tisa-cel cells underwent in-vivo expansion following infusion and showed persistence of the CAR transgene for up to 1,370 days in responding patients and 1,000 days in non-responding patients.

The safety profile of tisa-cel observed in this long-term follow-up analysis was largely consistent with previous reports and no new or unexpected safety signals were detected. The most common grade 3–4 adverse events were anaemia (39%), decreased neutrophil count (34%), decreased white blood cell count (32%), decreased platelet count (28%), cytokine release syndrome (23%), neutropenia (20%), febrile neutropenia (17%), hypophosphataemia (13%), and thrombocytopenia (12%). The most common treatment-related serious adverse events were cytokine release syndrome (27%), febrile neutropenia (6%), pyrexia (5%), pancytopenia (3%), and pneumonia (3%). No treatment-related deaths were reported. The final analysis of the JULIET trial is expected when the last patient infused with tisa-cel completes 5 years of follow-up.

Conclusion

At a median follow-up of 40.3 months, tisagenlecleucel continued to show durable activity in adult patients with relapsed or refractory aggressive large B-cell lymphomas, including patients with DLBCL not otherwise specified, high-grade B-cell lymphoma, and transformed follicular lymphoma. No unexpected safety signals were detected and no deaths were attributed to tisagenlecleucel.

Reference

Schuster SJ, Tam CS, Borchmann P, et al. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021. https://doi.org/10.1016/S1470-2045(21)00375-2

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