Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults

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Abstract

Anti-CD19 chimeric antigen receptor T cells (CAR) are a well-established treatment option for children and young adults suffering from relapsed/refractory B-lineage acute lymphoblastic leukemia. Bridging therapy is used to control disease prior to start of lymphodepletion before CAR infusion and thereby improve efficacy of CAR therapy. However, the effect of different bridging strategies on outcome, side effects and response to CAR therapy is still poorly understood. In this retrospective, multinational study, real-world data were collected from 14 different sites in Germany, Austria and Switzerland on 88 patients receiving 93 2nd-generation CAR therapies. Bridging therapy was classified into the categories 1) no systemic therapy (15/93 treatments), 2) low-intensity therapy (38/93 treatments) and 3) high-intensity therapy (39/93 treatments). We analyzed the impact of bridging regimens on clinical outcome. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time of eligibility compared to patients treated with a low-intensity or no systemic bridging therapy. They suffered significantly more from bacterial adverse events and mucositis. Overall survival was significantly better for patients who did not receive any bridging therapy in comparison to patients who had been treated with a low- or high-intensity bridging regimen. In conclusion, in this retrospective cohort, high-intensity bridging therapy has not improved the outcome in terms of overall and progression-free survival in comparison to a low-intensity therapy. Yet, high-intensity bridging therapy was associated with more adverse events. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13045-024-01659-x.

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Most cited references 9

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Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Shannon Maude, Theodore Laetsch, Jochen Buechner … (2018)

In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

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Chimeric antigen receptor T cells for sustained remissions in leukemia.

Shannon Maude, Noelle Frey, Pamela Shaw … (2014)

Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

Jae H. Park, Isabelle Rivière, Mithat Gonen … (2018)

BACKGROUND CD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients. METHODS We conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19–28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. RESULTS A total of 53 adults received 19–28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden. CONCLUSIONS In the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19–28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, [Related object:] NCT01044069.)

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Author and article information

Contributors

Tobias Feuchtinger: tobias.feuchtinger@uniklinik-freiburg.de

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 17 January 2025

Publication date PMC-release: 17 January 2025

Publication date Collection: 2025

Volume: 18

Electronic Location Identifier: 8

Affiliations

[1 ]Bavarian Cancer Research Center (BZKF), R/R ALL Study Group, Bavaria, Germany

[2 ]Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. Von Hauner Children’s Hospital, University Hospital, LMU Munich, ( https://ror.org/02jet3w32) Munich, Germany

[3 ]Department of Pediatrics, Division for Stem Cell Transplantation, Immunology and Intensive Care, Goethe University Frankfurt, University Hospital, ( https://ror.org/04cvxnb49) Frankfurt, Germany

[4 ]Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, ( https://ror.org/02qb3f692) Vienna, Austria

[5 ]Department of Pediatric Hematology and Oncology, University Children’s Hospital Muenster, ( https://ror.org/01856cw59) Muenster, Germany

[6 ]Division of Pediatric Stem Cell Therapy, Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, ( https://ror.org/024z2rq82) Duesseldorf, Germany

[7 ]Department of Pediatrics and Adolescent Medicine, University Hospital Erlangen, ( https://ror.org/0030f2a11) Erlangen, Germany

[8 ]Department of Medicine III, LMU University Hospital, LMU Munich, ( https://ror.org/05591te55) Muenchen, Bavaria Germany

[9 ]Department of Internal Medicine 5, Hematology and Oncology, Friedrich-Alexander University of Erlangen-Nuremberg, ( https://ror.org/00f7hpc57) Erlangen, Bavaria Germany

[10 ]Pediatric Hematology and Oncology and Stem Cell Transplantation, University Children’s Hospital Wuerzburg, ( https://ror.org/000ph9k36) Würzburg, Germany

[11 ]Department of Pediatrics and Children’s Cancer Research Center, TUM School of Medicine, Children’s Hospital Munich Schwabing, Technical University of Munich, ( https://ror.org/02kkvpp62) Munich, Germany

[12 ]Department of Oncology and Children’s Research Center, University Children’s Hospital Zurich, ( https://ror.org/035vb3h42) Zurich, Switzerland

[13 ]Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, ( https://ror.org/01zgy1s35) Hamburg, Germany

[14 ]Department of Pediatrics I, University Hospital Schleswig-Holstein, ( https://ror.org/01tvm6f46) Campus Kiel, Kiel, Germany

[15 ]Department of General Pediatrics, Hematology and Oncology, University Children’s Hospital Tübingen, ( https://ror.org/03esvmb28) Tübingen, Germany

[16 ]Department of Pediatric Oncology and Hematology, Charité Universitaetsmedizin Berlin, ( https://ror.org/001w7jn25) Berlin, Germany

[17 ]Department of Pediatric Hematology, Oncology and Stem Cell Transplantation, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, ( https://ror.org/0245cg223) Freiburg, Germany

Article

Publisher ID: 1659

DOI: 10.1186/s13045-024-01659-x

PMC ID: 11742544

PubMed ID: 39825416

SO-VID: ccb251cf-e0fa-4e30-8897-bb55f9cdba8d

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Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

History

Date received : 5 November 2024

Date accepted : 30 December 2024

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b-all,car t cells,bridging therapy

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: b-all, car t cells, bridging therapy

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Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults

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Karger: Oncology

Most cited references 9

Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Chimeric antigen receptor T cells for sustained remissions in leukemia.

Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia

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