Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Kris M Mahadeo¹, Sajad J Khazal², Hisham Abdel-Azim³, Julie C Fitzgerald⁴, Agne Taraseviciute⁵, Catherine M Bollard⁶, Priti Tewari⁷, Christine Duncan⁸, Chani Traube⁹, David McCall², Marie E Steiner¹⁰, Ira M Cheifetz¹¹, Leslie E Lehmann⁸, Rodrigo Mejia¹², John M Slopis¹³, Rajinder Bajwa¹⁴, Partow Kebriaei¹⁵, Paul L Martin¹⁶, Jerelyn Moffet¹⁶, Jennifer McArthur¹⁷, Demetrios Petropoulos², Joan O'Hanlon Curry², Sarah Featherston², Jessica Foglesong², Basirat Shoberu¹⁸, Alison Gulbis¹⁹, Maria E Mireles¹⁹, Lisa Hafemeister², Cathy Nguyen², Neena Kapoor³, Katayoun Rezvani^#¹⁵, Sattva S Neelapu^#²⁰, Elizabeth J Shpall^#¹⁵; Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network

Affiliations

¹ Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. kmmahadeo@mdanderson.org.
² Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Pediatrics, Blood and Marrow Transplantation Program, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁴ Department of Anesthesiology and Critical Care, Division of Critical Care, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵ Department of Pediatrics, Division of Hematology-Oncology, University of Washington, Seattle Children's Hospital, Seattle, WA, USA.
⁶ Center for Cancer and Immunology Research and Department of Pediatrics, Children's National and The George Washington University, Washington DC, USA.
⁷ Department of Pediatrics, Stem Cell Transplantation, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
⁸ Pediatric Hematology-Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA.
⁹ Department of Pediatric Critical Care, Weil Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.
¹⁰ Department of Pediatrics, Division of Critical Care, University of Minnesota, Masonic Children's Hospital, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Pediatrics, Division of Critical Care, Duke Children's Hospital, Duke University, Durham, NC, USA.
¹² Department of Pediatrics, Critical Care, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Pediatrics, Neurology, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Pediatrics, Division of Blood and Marrow Transplantation, Nationwide Children's Hospital, the Ohio State University, Columbus, OH, USA.
¹⁵ Department of Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁶ Department of Pediatrics, Division of Blood and Marrow Transplant, Duke Children's Hospital, Duke University, Durham, NC, USA.
¹⁷ Department of Pediatrics, Division of Critical Care, St. Jude's Children's Research Hospital, Memphis, TN, USA.
¹⁸ Department of Pharmacy, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
¹⁹ Department of Pharmacy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Lymphoma and Myeloma, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

^# Contributed equally.

PMID: 30082906
PMCID: PMC7096894
DOI: 10.1038/s41571-018-0075-2

Review

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Kris M Mahadeo et al. Nat Rev Clin Oncol. 2019 Jan.

. 2019 Jan;16(1):45-63.

doi: 10.1038/s41571-018-0075-2.

Authors

Affiliations

¹ Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. kmmahadeo@mdanderson.org.
² Department of Pediatrics, Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
³ Department of Pediatrics, Blood and Marrow Transplantation Program, Keck School of Medicine, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁴ Department of Anesthesiology and Critical Care, Division of Critical Care, University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
⁵ Department of Pediatrics, Division of Hematology-Oncology, University of Washington, Seattle Children's Hospital, Seattle, WA, USA.
⁶ Center for Cancer and Immunology Research and Department of Pediatrics, Children's National and The George Washington University, Washington DC, USA.
⁷ Department of Pediatrics, Stem Cell Transplantation, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA.
⁸ Pediatric Hematology-Oncology, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA.
⁹ Department of Pediatric Critical Care, Weil Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.
¹⁰ Department of Pediatrics, Division of Critical Care, University of Minnesota, Masonic Children's Hospital, University of Minnesota, Minneapolis, MN, USA.
¹¹ Department of Pediatrics, Division of Critical Care, Duke Children's Hospital, Duke University, Durham, NC, USA.
¹² Department of Pediatrics, Critical Care, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹³ Department of Pediatrics, Neurology, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Department of Pediatrics, Division of Blood and Marrow Transplantation, Nationwide Children's Hospital, the Ohio State University, Columbus, OH, USA.
¹⁵ Department of Stem Cell Transplantation and Cellular Therapy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁶ Department of Pediatrics, Division of Blood and Marrow Transplant, Duke Children's Hospital, Duke University, Durham, NC, USA.
¹⁷ Department of Pediatrics, Division of Critical Care, St. Jude's Children's Research Hospital, Memphis, TN, USA.
¹⁸ Department of Pharmacy, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
¹⁹ Department of Pharmacy, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
²⁰ Department of Lymphoma and Myeloma, CARTOX Program, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

^# Contributed equally.

PMID: 30082906
PMCID: PMC7096894
DOI: 10.1038/s41571-018-0075-2

Abstract

In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19⁺ acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

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Figures

**Fig. 1. Proposed algorithm for the diagnosis and management of CAR T cell-related haemophagocytic lymphohistiocytosis and/or macrophage-activation syndrome.**
Chimeric antigen receptor (CAR) T cell-related haemophagocytic lymphohistiocytosis (HLH) and macrophage-activation syndrome (MAS) are serious, life-threatening complications of CAR T cell therapy and should be suspected when a patient has a serum ferritin level >10,000 ng/ml in association with grade ≥3 organ toxicities (liver, kidney, or lung) per Common Terminology Criteria for Adverse Events (version 5.0) and/or evidence of haemophagocytosis in the bone marrow or other organs. Patients should be managed as recommended for grade 3 cytokine-release syndrome (CRS) with close monitoring of inflammatory markers and organ function. If no clinical and laboratory improvement is observed after 48–72 hours, consider HLH management according to the HLH-2004 protocol.

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References

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Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Affiliations

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

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Abstract

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