Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Background

Tisagenlecleucel, an anti-CD19 chimeric antigen receptor T cell therapy, has demonstrated efficacy in children and young adults with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) in two multicenter phase 2 trials (ClinicalTrials.gov, NCT02435849 (ELIANA) and NCT02228096 (ENSIGN)), leading to commercialization of tisagenlecleucel for the treatment of patients up to age 25 years with B-ALL that is refractory or in second or greater relapse.

Methods

A pooled analysis of 137 patients from these trials (ELIANA: n=79; ENSIGN: n=58) was performed to provide a comprehensive safety profile for tisagenlecleucel.

Results

Grade 3/4 tisagenlecleucel-related adverse events (AEs) were reported in 77% of patients. Specific AEs of interest that occurred ≤8 weeks postinfusion included cytokine-release syndrome (CRS; 79% (grade 4: 22%)), infections (42%; grade 3/4: 19%), prolonged (not resolved by day 28) cytopenias (40%; grade 3/4: 34%), neurologic events (36%; grade 3: 10%; no grade 4 events), and tumor lysis syndrome (4%; all grade 3). Treatment for CRS included tocilizumab (40%) and corticosteroids (23%). The frequency of neurologic events increased with CRS severity (p<0.001). Median time to resolution of grade 3/4 cytopenias to grade ≤2 was 2.0 (95% CI 1.87 to 2.23) months for neutropenia, 2.4 (95% CI 1.97 to 3.68) months for lymphopenia, 2.0 (95% CI 1.87 to 2.27) months for leukopenia, 1.9 (95% CI 1.74 to 2.10) months for thrombocytopenia, and 1.0 (95% CI 0.95 to 1.87) month for anemia. All patients who achieved complete remission (CR)/CR with incomplete hematologic recovery experienced B cell aplasia; however, as nearly all responders also received immunoglobulin replacement, few grade 3/4 infections occurred >1 year postinfusion.

Conclusions

This pooled analysis provides a detailed safety profile for tisagenlecleucel during the course of clinical trials, and AE management guidance, with a longer follow-up duration compared with previous reports.

Related collections

Most cited references 46

Record: found
Abstract: found
Article: not found

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).

0 comments Cited 1461 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Stephen Schuster, Michael R. Bishop, Constantine Tam … (2018)

Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.

0 comments Cited 1178 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

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.).

0 comments Cited 1112 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Journal ID (hwp): jitc

Journal ID (publisher-id): jitc

Title: Journal for Immunotherapy of Cancer

Publisher: BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )

ISSN (Electronic): 2051-1426

Publication date Collection: 2021

Publication date (Electronic): 5 August 2021

Volume: 9

Issue: 8

Electronic Location Identifier: e002287

Affiliations

[1 ]departmentBlood and Marrow Transplant Program , University of Michigan , Ann Arbor, Michigan, USA

[2 ]departmentTisch Cancer Institute , Icahn School of Medicine at Mount Sinai , New York, New York, USA

[3 ]departmentDepartment of Pediatrics , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA

[4 ]departmentDivision of Oncology , Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children’s Hospital of Philadelphia , Philadelphia, Pennsylvania, USA

[5 ]departmentSection of Transplantation and Cellular Therapy , Children's Hospital Los Angeles Cancer and Blood Disease Institute, University of Southern California Keck School of Medicine , Los Angeles, California, USA

[6 ]departmentDepartment of Pediatric Hematology and Oncology , Hospital Sant Joan de Déu de Barcelona , Barcelona, Spain

[7 ]Institut de Recerca Sant Joan de Déu , Barcelona, Spain

[8 ]Children’s Mercy Hospital Kansas City , Kansas City, Missouri, USA

[9 ]Division of Pediatric Blood and Marrow Transplant, University of Minnesota , Minneapolis, Minnesota, USA

[10 ]departmentDepartment of BMT and Cellular Therapy, Children’s Hospital Colorado , University of Colorado , Boulder, Colorado, USA

[11 ]departmentDepartment of Pediatric Hematology and Oncology , Oslo University Hospital , Oslo, Norway

[12 ]departmentDepartment of Pediatrics and Harold C. Simmons Comprehensive Cancer Center , The University of Texas Southwestern Medical Center , Dallas, Texas, USA

[13 ]Pauline Allen Gill Center for Cancer and Blood Disorders, Children’s Health , Dallas, Texas, USA

[14 ]departmentHematology Oncology Division, Charles-Bruneau Cancer Center , CHU Sainte-Justine , Montreal, Québec, Canada

[15 ]departmentDepartment of Pediatrics, Faculty of Medicine , University of Montreal , Montreal, Québec, Canada

[16 ]departmentPediatric Hematology-Immunology Department , University Hospital Robert Debré (APHP) and Université de Paris , Paris, France

[17 ]departmentDepartment of Pediatrics and Internal Medicine , University of Utah , Salt Lake City, Utah, USA

[18 ]departmentDepartment of Pediatric Hematology-Oncology and Stem Cell Transplantation , Ghent University Hospital , Ghent, Belgium

[19 ]Cancer Research Institute Ghent (CRIG) , Ghent, Belgium

[20 ]Aflac Cancer and Blood Disorders Center, Emory University , Atlanta, Georgia, USA

[21 ]departmentDepartment of Pediatrics , University of Cincinnati , Cincinnati, Ohio, USA

[22 ]Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center , Cincinnati, Ohio, USA

[23 ]departmentDepartment of Pediatric Transplant and Cellular Therapy, Children’s Health Center , Duke University Medical Center , Durham, North Carolina, USA

[24 ]Division for Stem Cell Transplantation and Immunology, Hospital for Children and Adolescents, University Hospital Frankfurt , Frankfurt, Germany

[25 ]departmentDepartment of Pediatrics , Stanford University School of Medicine , Stanford, California, USA

[26 ]Novartis Pharmaceuticals Corporation , East Hanover, New Jersey, USA

[27 ]departmentDepartment of Pediatrics , Division of Pediatric Hematology Oncology, Michigan Medicine , Ann Arbor, Michigan, USA

[28 ]Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA

[29 ]departmentDepartment of Pathology and Laboratory Medicine , Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania, USA

Author notes

[Correspondence to ] Dr Shannon L Maude; maude@ 123456chop.edu

Author information

John E Levine http://orcid.org/0000-0002-5611-7828

Susana Rives http://orcid.org/0000-0002-5658-1831

Jochen Buechner http://orcid.org/0000-0001-5848-4501

Theodore W Laetsch http://orcid.org/0000-0002-8497-3138

Barbara De Moerloose http://orcid.org/0000-0002-2449-539X

Shannon L Maude http://orcid.org/0000-0003-2210-8736

Article

Publisher ID: jitc-2020-002287

DOI: 10.1136/jitc-2020-002287

PMC ID: 8344270

PubMed ID: 34353848

SO-VID: 34f4cf66-2796-4b08-8d7b-51e95bb768ff

License:

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 10 June 2021

Funding

Funded by: These studies and writing assistance were funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. Representatives of the sponsor participated in study design, collection, data interpretation, and development/submission of the manuscript.;

Custom metadata

special-feature unlocked

Keywords: pediatrics,receptors,chimeric antigen,hematologic neoplasms

Data availability:

Keywords: pediatrics, receptors, chimeric antigen, hematologic neoplasms

Comments

Comment on this article

scite_

Cited by 15

See all cited by

Most referenced authors 1,392

See all reference authors

Pooled safety analysis of tisagenlecleucel in children and young adults with B cell acute lymphoblastic leukemia

Read this article at

Abstract

Background

Methods

Results

Conclusions

Related collections

Functional role of amyloid

Most cited references 46

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

Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Chimeric antigen receptor T cells for sustained remissions in leukemia.

Author and article information

Journal

Affiliations

Author notes

Author information

Article

History

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 235

Cited by 15

Most referenced authors 1,392