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

John E Levine; Stephan A Grupp; Michael A Pulsipher; Andrew C Dietz; Susana Rives; G Douglas Myers; Keith J August; Michael R Verneris; Jochen Buechner; Theodore W Laetsch; Henrique Bittencourt; Andre Baruchel; Michael W Boyer; Barbara De Moerloose; Muna Qayed; Stella M Davies; Christine L Phillips; Timothy A Driscoll; Peter Bader; Krysta Schlis; Patricia A Wood; Rajen Mody; Lan Yi; Mimi Leung; Lamis K Eldjerou; Carl H June; Shannon L Maude

doi:10.1136/jitc-2020-002287

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

J Immunother Cancer. 2021 Aug;9(8):e002287. doi: 10.1136/jitc-2020-002287.

Authors

John E Levine^{1

2}, Stephan A Grupp^{3

4}, Michael A Pulsipher⁵, Andrew C Dietz⁵, Susana Rives^{6

7}, G Douglas Myers⁸, Keith J August⁸, Michael R Verneris^{9

10}, Jochen Buechner¹¹, Theodore W Laetsch^{3

4

12

13}, Henrique Bittencourt^{14

15}, Andre Baruchel¹⁶, Michael W Boyer¹⁷, Barbara De Moerloose^{18

19}, Muna Qayed²⁰, Stella M Davies^{21

22}, Christine L Phillips^{21

22}, Timothy A Driscoll²³, Peter Bader²⁴, Krysta Schlis²⁵, Patricia A Wood²⁶, Rajen Mody²⁷, Lan Yi²⁶, Mimi Leung²⁶, Lamis K Eldjerou²⁶, Carl H June^{28

29}, Shannon L Maude^{30

4}

Affiliations

¹ Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, Michigan, USA.
² Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁴ Division of Oncology, Center for Childhood Cancer Research and Cancer Immunotherapy Program, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
⁵ Section 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 Department 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 Department of BMT and Cellular Therapy, Children's Hospital Colorado, University of Colorado, Boulder, Colorado, USA.
¹¹ Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway.
¹² Department 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 Hematology Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine, Montreal, Québec, Canada.
¹⁵ Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Québec, Canada.
¹⁶ Pediatric Hematology-Immunology Department, University Hospital Robert Debré (APHP) and Université de Paris, Paris, France.
¹⁷ Department of Pediatrics and Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
¹⁸ Department 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 Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA.
²² Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
²³ Department 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 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.
²⁶ Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA.
²⁷ Department 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 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
³⁰ Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA maude@chop.edu.

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.

Keywords: chimeric antigen; hematologic neoplasms; pediatrics; receptors.

Publication types

Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Antineoplastic Agents, Immunological / pharmacology
Antineoplastic Agents, Immunological / therapeutic use*
Child
Child, Preschool
Female
Humans
Male
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Receptors, Antigen, T-Cell / therapeutic use*

Substances

Antineoplastic Agents, Immunological
Receptors, Antigen, T-Cell
tisagenlecleucel

Associated data

ClinicalTrials.gov/NCT02435849
ClinicalTrials.gov/NCT02228096