Elsevier

The Lancet Oncology

Volume 22, Issue 10, October 2021, Pages 1403-1415
The Lancet Oncology

Articles
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

https://doi.org/10.1016/S1470-2045(21)00375-2Get rights and content

Summary

Background

In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort.

Methods

In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing.

Findings

Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported.

Interpretation

Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy).

Funding

Novartis Pharmaceuticals.

Introduction

Patients with relapsed or refractory large B-cell lymphomas (LBCL) have poor outcomes with traditional therapies. Although new treatments, such as polatuzumab vedotin, an antibody–drug conjugate, and tafasitamab, a cytolytic antibody, have been introduced, CD19-directed chimeric antigen receptor (CAR) T-cell therapies have shown improved, durable outcomes in patients with relapsed or refractory B-cell malignancies. Notably, the US Food and Drug Administration have approved three therapeutic products (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) for the treatment of relapsed or refractory LBCL. All three CAR T-cell products have shown efficacy with acceptable toxicity profiles.1, 2, 3, 4, 5

Tisagenlecleucel has shown durable responses and a manageable safety profile in patients with relapsed or refractory LBCL.4, 5, 6 In the primary analysis of the international, single-arm, phase 2 JULIET trial of tisagenlecleucel (median time from infusion to data cutoff 14 months), the best overall response rate was 52% (95% CI 41–62; 48 patients) and the complete response rate was 40% (37 patients) among 93 adult patients with relapsed or refractory LBCL.4 The most common grade 3 or 4 adverse events of interest were cytokine release syndrome, neurological events, cytopenias lasting more than 28 days, infections, and febrile neutropenia.4 Response rates did not differ substantially across major patient demographic and prognostic subgroups; however, given the small patient population, there were an insufficient number of events to evaluate subgroups with adequate power.4

Research in context

Evidence before this study

We searched PubMed for interventional clinical trials (excluding reviews) published in any language between database inception and Dec 1, 2020, using the search terms “CD19” AND “chimeric antigen receptor” AND “lymphoma.” Historically, the prognoses for patients with relapsed or refractory diffuse large B-cell lymphomas (DLBCL) have been poor. With the approval of three CD19-directed chimeric antigen receptor (CAR) T-cell products (tisagenlecleucel, axicabtagene ciloleucel, and lisocabtagene maraleucel) by the US Food and Drug Administration and the approval of two CD19-directed CAR T-cell products by the European Medicines Agency (tisagenlecleucel and axicabtagene ciloleucel) for the treatment of relapsed or refractory DLBCL, CAR T-cell therapies have transformed the treatment landscape for B-cell malignancies; all three CAR T-cell products have produced durable responses and shown toxicity profiles that compare favourably with those of conventional therapies (eg, salvage chemotherapy). Beyond the 2-year follow-up study of the ZUMA-1 trial, our search results revealed few reports of long-term clinical outcomes and correlative analyses of biomarkers with efficacy and safety.

Added value of this study

At a median follow-up of 40·3 months, our results showed that tisagenlecleucel continues to have durable activity in adult patients with relapsed or refractory aggressive B-cell lymphomas. Notably, our analyses showed that patients who had a complete response at any time had long-term durability of response and survival benefits. No unexpected safety signals were detected and no deaths were attributed to tisagenlecleucel. We also did comprehensive correlative analyses of pre-infusion and post-infusion biomarkers that suggested that a subset of patients with increased serum lactate dehydrogenase concentrations at baseline, severe cytokine release syndrome, or severe neurological events had poorer outcomes in this study.

Implications of all the available evidence

These data, along with data from studies of other approved or investigational CD19-directed CAR T-cell therapies, support the use of CAR T-cell therapy in the treatment of patients with relapsed or refractory aggressive B-cell lymphomas. Our correlative analyses of predictive biomarkers of activity and toxicity could provide further guidance on patient selection and help to identify patient subsets at risk of poorer activity or safety outcomes.

Here, we report an updated, long-term follow-up analysis of the full adult patient population with relapsed or refractory aggressive B-cell lymphoma who were given tisagenlecleucel in the JULIET study. We also aimed to do comprehensive correlative analyses of pre-infusion and post-infusion biomarkers with activity and safety.

Section snippets

Study design and participants

JULIET is a multicentre, open-label, single-arm, phase 2 trial that enrolled patients at 27 treatment sites (academic medical centres) in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA) across four continents, which closed to accrual on Feb 20, 2018 (the date of last patient infusion). The study design has been previously described.4

Briefly, adult patients (aged ≥18 years) with histologically confirmed relapsed or refractory LBCL

Results

Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled into our study. As of Feb 20, 2020, 115 had received tisagenlecleucel, with a median follow-up of 40·3 months (IQR 37·8–43·8) and a maximum follow-up of 52·6 months from the time of infusion to data cutoff. Patient demographics and baseline characteristics of all 115 patients evaluable for efficacy and safety are summarised in table 1. 101 patients received tisagenlecleucel in the inpatient setting and 14 patients received

Discussion

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. Notably, the median progression-free survival and the median overall survival of patients with a complete response at 3 months, 6 months, or both, were not reached. These analyses show that patients who have

Data sharing

Where available, the following anonymised patient-level data and information will be provided for each clinical study: the raw dataset (the dataset collected for each patient in the clinical trial); the analysis-ready dataset (the dataset Novartis used for the analysis); the protocol with any amendments, which can be found in this study's appendix; the annotated case report form (blank case report form with descriptions of the data collected and how they are described in the dataset); the

Declaration of interests

SJS is an adviser or consultant for Acerta, AlloGene, AstraZeneca, BeiGene, Celgene (Juno), Genentech (Roche), LoxoOncology, Novartis, and Tessa Therapeutics; reports honoraria from Acerta, AlloGene, AstraZeneca, BeiGene, Celgene, Genentech (Roche), LoxoOncology, Novartis, Nordic Nanovector, Pfizer, and Tessa Therapeutics; reports steering committee participation for AbbVie, Celgene, Novartis, Juno, Nordic Nanovector, and Pfizer; reports research support from AbbVie, Acerta, Celgene (Juno),

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