Elsevier

The Lancet Oncology

Volume 20, Issue 12, December 2019, Pages 1710-1718
The Lancet Oncology

Articles
Patient-reported quality of life after tisagenlecleucel infusion in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia: a global, single-arm, phase 2 trial

https://doi.org/10.1016/S1470-2045(19)30493-0Get rights and content

Summary

Background

The ELIANA trial showed that 61 (81%) of 75 paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia achieved overall remission after treatment with tisagenlecleucel, a chimeric antigen receptor targeted against the CD19 antigen. We aimed to evaluate patient-reported quality of life in these patients before and after tisagenlecleucel infusion.

Methods

ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA. Patients with B-cell acute lymphoblastic leukaemia aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis who were in second or greater bone marrow relapse, chemorefractory, relapsed after allogeneic stem-cell transplantation, or were otherwise ineligible for allogeneic stem-cell transplantation were enrolled. Patients received a single intravenous administration of a target dose of 0·2–5 × 106 transduced viable T cells per kg for patients weighing 50 kg or less or 0·1–2·5 × 108 transduced viable T cells for patients weighing more than 50 kg. The primary outcome, reported previously, was the proportion of patients who achieved remission. A prespecified secondary endpoint, reported here, was patient-reported quality of life measured with the Pediatric Quality of Life Inventory (PedsQL) and European Quality of Life-5 Dimensions questionnaire (EQ-5D). Patients completed the questionnaires at baseline, day 28, and months 3, 6, 9, and 12 after treatment. The data collected were summarised using descriptive statistics and post-hoc mixed models for repeated measures. Change from baseline response profiles were illustrated with cumulative distribution function plots. The proportion of patients achieving the minimal clinically important difference and normative mean value were reported. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT02435849.

Findings

Between April 8, 2015, and April 25, 2017, 107 patients were screened, 92 were enrolled, and 75 received tisagenlecleucel. 58 patients aged 8–23 years were included in the analysis of quality of life. At baseline, 50 (86%) patients had completed the PedsQL questionnaire and 48 (83%) had completed the EQ-5D VAS. Improvements in patient-reported quality-of-life scores were observed for all measures at month 3 after tisagenlecleucel infusion (mean change from baseline to month 3 was 13·3 [95% CI 8·9–17·6] for the PedsQL total score and 16·8 [9·4–24·3] for the EQ-5D visual analogue scale). 30 (81%) of 37 patients achieved the minimal clinically important difference at month 3 for the PedsQL total score and 24 (67%) of 36 patients achieved this for the EQ-5D visual analogue scale.

Interpretation

These findings, along with the activity and safety results of ELIANA, suggest a favourable benefit–risk profile of tisagenlecleucel in the treatment of paediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukaemia.

Funding

Novartis.

Introduction

Acute lymphoblastic leukaemia represents 75–80% of acute leukaemias in children and is the most common paediatric cancer in the USA.1, 2 Approximately 85% of children diagnosed with acute lymphoblastic leukaemia have B-cell lineage.3 With current multiagent chemotherapy, the survival at 5 years for paediatric acute lymphoblastic leukaemia is almost 90%, but is lower in adolescents and young adults.4 However, outcomes are poor for children who relapse or are refractory to standard treatments.5, 6

Patient-reported quality of life is an increasingly important component in the assessment of new oncology therapies. Certain symptoms and functional losses in patients with cancer might not be measurable with clinical tests or procedures.7, 8, 9, 10, 11 Previous studies in children with acute lymphoblastic leukaemia have generally reported a substantial decline in patient-reported quality of life during active therapy (usually lasting years) followed by improvements in patients who achieved remission.12, 13, 14, 15, 16, 17, 18 Quality of life in children with acute lymphoblastic leukaemia treated with chimeric antigen receptor-expressing T cells (CAR T cells) has not been previously reported and might be different from that in children given cytotoxic chemotherapy, given the distinct toxicity profiles and different durations of therapy.19

Research in context

Evidence before this study

Tisagenlecleucel is an anti-CD19 chimeric antigen receptor therapy that induced complete remission in 81% of children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia treated in the ELIANA trial, and had a manageable safety profile. Before our study, there was a paucity of information about quality of life in patients treated with chimeric antigen receptor therapy. We searched PubMed for articles published in English between inception and March 20, 2019, with the following search terms: “quality of life” or “patient reported outcomes” and “chimeric antigen receptor” or “tisagenlecleucel.” The search yielded one publication providing an overview of the opportunities and challenges of incorporation of patient-reported outcomes in clinical trials of chimeric antigen receptor cell therapy. We did not identify any papers reporting the results of patient-reported outcomes or quality of life in patients receiving this therapy.

Added value of this study

We present patient-reported quality-of-life data that were prospectively collected and analysed in the global, single-arm, open-label, phase 2 ELIANA trial of tisagenlecleucel for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia. Our study findings suggest that broad-based clinically meaningful improvements in patient-reported quality of life occur as soon as 1–3 months after treatment with tisagenlecleucel and persist for 12 months. To our knowledge, these results represent the first report of patient-reported quality of life associated with a novel treatment that has demonstrated remarkable efficacy in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia.

Implications of all the available evidence

Tisagenlecleucel was approved by the US Food and Drug Administration in 2017 and European Medicines Agency in 2018 for children and young adults up to age 25 years with B-cell acute lymphoblastic leukaemia that is refractory or in second or greater relapse. The rapid improvement in patient-reported quality of life scores presented here suggest that tisagenlecleucel is a promising treatment option for this patient population. Clinical trials of tisagenlecleucel in earlier lines of therapy are warranted.

Tisagenlecleucel (approved by the US Food and Drug Administration) is an autologous immunocellular therapy consisting of CD3 T cells that have undergone ex-vivo T-cell activation, gene modification, expansion, and formulation in infusible cryomedia.20 The transgene expressed via lentiviral vector transduction is a CAR targeted against the CD19 antigen.

The ELIANA trial assessed the efficacy and safety of tisagenlecleucel in children and young adult with relapsed or refractory B-cell acute lymphoblastic leukaemia. Efficacy analyses demonstrated that 61 (81%) of 75 patients who received the infusion achieved complete remission with or without complete blood count recovery within 3 months. Safety analyses showed that 52 (69%) of 75 patients had treatment-related grade 3–4 adverse events within 8 weeks of tisagenlecleucel infusion, which decreased to 12 (17%) of 75 after 8 weeks.20 In this study, we aimed to evaluate the impact of a single one-time infusion of tisagenlecleucel on patient-reported quality of life.

Section snippets

Study design and participants

ELIANA, a global, single-arm, open-label, phase 2 trial, was done in 25 hospitals across Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Norway, Spain, and the USA (appendix p 7). The entry criteria of this trial have previously been described.20 Briefly, the treatment population consisted of paediatric and young adult patients aged at least 3 years at the time of screening and 21 years or younger at the time of initial diagnosis with B-cell acute lymphoblastic leukaemia who

Results

Between April 8, 2015, and April 25, 2017, 107 patients were screened for the ELIANA trial, 92 were enrolled, 75 received tisagenlecleucel, and 58 were aged 8–23 years and included in this analysis (figure 1). 50 (86%) of 58 patients had completed PedsQL data and 48 (83%) had completed EQ-5D VAS data at baseline, and, of 48 (83%) of 58 patients with treatment response, 43 (90%) had PedsQL data and 40 (83%) had EQ-5D VAS data at baseline (table 1). The median follow-up of this group of patients

Discussion

The findings from this study suggest that rapid improvements in broad aspects of patient-reported quality of life occurred after one-time treatment with tisagenlecleucel. To our knowledge, this is the first report on patient-reported quality of life after CAR T-cell therapy for patients with relapsed or refractory B-cell acute lymphoblastic leukaemia. Patients began to report improvements in patient-reported quality-of-life scores at day 28 after tisagenlecleucel therapy across most domains. By

Data sharing

Novartis is committed to sharing with qualified external researchers, access to patient-level data, and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymised to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on //www.clinicalstudydatarequest.com

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