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Curated Papers > Recent high-impact research on "CAR-T therapy" (IF ≥ 30, last 5 years)

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

Literature Information ​

DOI10.1038/s41571-018-0075-2
PMID30082906
JournalNature reviews. Clinical oncology
Impact Factor82.2
JCR QuartileQ1
Publication Year2019
Times Cited109
KeywordsChimeric Antigen Receptor T Cell Therapy, Pediatrics, Acute Lymphoblastic Leukemia, Toxicity, Management Guidelines
Literature TypeConsensus Development Conference, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Review
ISSN1759-4774
Pages45-63
Issue16(1)
AuthorsKris M Mahadeo, Sajad J Khazal, Hisham Abdel-Azim, Julie C Fitzgerald, Agne Taraseviciute, Catherine M Bollard, Priti Tewari, Christine Duncan, Chani Traube, David McCall, Marie E Steiner, Ira M Cheifetz, Leslie E Lehmann, Rodrigo Mejia, John M Slopis, Rajinder Bajwa, Partow Kebriaei, Paul L Martin, Jerelyn Moffet, Jennifer McArthur, Demetrios Petropoulos, Joan O'Hanlon Curry, Sarah Featherston, Jessica Foglesong, Basirat Shoberu, Alison Gulbis, Maria E Mireles, Lisa Hafemeister, Cathy Nguyen, Neena Kapoor, Katayoun Rezvani, Sattva S Neelapu, Elizabeth J Shpall

TL;DR ​

In 2017, CAR T cell therapy for relapsed/refractory CD19+ acute lymphoblastic leukemia became the first gene therapy approved in the USA, demonstrating high response rates but also significant toxicities that necessitate careful monitoring. This paper presents consensus guidelines from experts to enhance the care of pediatric patients undergoing CAR T cell therapy, emphasizing the importance of a multidisciplinary approach to improve patient outcomes as this treatment becomes routine.

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Chimeric Antigen Receptor T Cell Therapy · Pediatrics · Acute Lymphoblastic Leukemia · Toxicity · Management Guidelines

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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Primary Questions Addressed ​

  1. What specific monitoring protocols are recommended for detecting early toxicities in paediatric patients undergoing CAR T cell therapy?
  2. How do the management guidelines differ for patients with varying levels of disease severity or comorbidities receiving CAR T cell therapy?
  3. What role do multidisciplinary teams play in the management of adverse effects associated with CAR T cell therapy in children?
  4. How can healthcare infrastructure be optimized to support the safe administration of CAR T cell therapy in paediatric populations?
  5. What are the long-term follow-up care considerations for children who have received CAR T cell therapy, particularly regarding late-onset toxicities?

Key Findings ​

Research Background and Purpose ​

Chimeric Antigen Receptor T cell (CAR-T) therapy has emerged as a significant treatment modality for pediatric patients with certain hematological malignancies. However, the management of these patients during and after therapy poses unique challenges due to the complexity of the treatment and the potential for severe adverse effects. The purpose of this consensus statement is to provide comprehensive management guidelines for pediatric patients undergoing CAR-T therapy, addressing both the therapeutic and supportive care aspects.

Main Methods/Materials/Experimental Design ​

The consensus was developed through a collaborative effort involving experts from the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network. The process included:

  1. Literature Review: An extensive review of existing literature and clinical practices related to CAR-T therapy in pediatric populations.
  2. Expert Consensus: Gathering insights from specialists in pediatric oncology, hematology, and supportive care to develop recommendations based on clinical experiences and available evidence.
  3. Guideline Development: Structuring the guidelines according to levels of evidence and grades of recommendation, ensuring clarity and applicability in clinical settings.
Mermaid diagram

Key Results and Findings ​

The guidelines emphasize several critical areas of management for pediatric patients receiving CAR-T therapy:

  • Pre-Treatment Assessment: Comprehensive evaluation of the patient's medical history, potential comorbidities, and psychosocial factors.
  • Monitoring During Treatment: Close observation for acute toxicities, including cytokine release syndrome (CRS) and neurotoxicity, with specific protocols for grading and managing these events.
  • Post-Treatment Care: Recommendations for follow-up care, including monitoring for long-term effects and psychosocial support.
  • Multidisciplinary Approach: Emphasizing the importance of a coordinated care team, including oncologists, nurses, pharmacists, and mental health professionals.

Main Conclusions/Significance/Innovation ​

The guidelines provide a structured framework to enhance the safety and efficacy of CAR-T therapy in pediatric patients. By standardizing management practices, these recommendations aim to reduce complications, improve patient outcomes, and support healthcare providers in delivering high-quality care. The innovation lies in the comprehensive nature of the guidelines, which integrate clinical evidence with expert opinion to address the multifaceted needs of this vulnerable population.

Research Limitations and Future Directions ​

While the guidelines are based on the best available evidence, limitations include:

  • Lack of Extensive Randomized Trials: Many recommendations are derived from expert consensus rather than large-scale randomized controlled trials, which may affect the strength of some recommendations.
  • Variability in Practice: Differences in institutional practices and patient populations may limit the generalizability of the guidelines.

Future research should focus on:

  • Conducting large-scale clinical trials to validate the effectiveness of these management strategies.
  • Exploring long-term outcomes in pediatric patients post-CAR-T therapy to inform future guidelines.
  • Investigating the psychosocial impacts of CAR-T therapy on patients and families to enhance supportive care strategies.

References ​

  1. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. - Sattva S Neelapu;Frederick L Locke;Nancy L Bartlett;Lazaros J Lekakis;David B Miklos;Caron A Jacobson;Ira Braunschweig;Olalekan O Oluwole;Tanya Siddiqi;Yi Lin;John M Timmerman;Patrick J Stiff;Jonathan W Friedberg;Ian W Flinn;Andre Goy;Brian T Hill;Mitchell R Smith;Abhinav Deol;Umar Farooq;Peter McSweeney;Javier Munoz;Irit Avivi;Januario E Castro;Jason R Westin;Julio C Chavez;Armin Ghobadi;Krishna V Komanduri;Ronald Levy;Eric D Jacobsen;Thomas E Witzig;Patrick Reagan;Adrian Bot;John Rossi;Lynn Navale;Yizhou Jiang;Jeff Aycock;Meg Elias;David Chang;Jeff Wiezorek;William Y Go - The New England journal of medicine (2017)
  2. Adverse reactions during stem cell infusion in children treated with autologous and allogeneic stem cell transplantation. - T H Truong;R Moorjani;D Dewey;G M T Guilcher;N L Prokopishyn;V A Lewis - Bone marrow transplantation (2016)
  3. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. - Shannon L Maude;Theodore W Laetsch;Jochen Buechner;Susana Rives;Michael Boyer;Henrique Bittencourt;Peter Bader;Michael R Verneris;Heather E Stefanski;Gary D Myers;Muna Qayed;Barbara De Moerloose;Hidefumi Hiramatsu;Krysta Schlis;Kara L Davis;Paul L Martin;Eneida R Nemecek;Gregory A Yanik;Christina Peters;Andre Baruchel;Nicolas Boissel;Francoise Mechinaud;Adriana Balduzzi;Joerg Krueger;Carl H June;Bruce L Levine;Patricia Wood;Tetiana Taran;Mimi Leung;Karen T Mueller;Yiyun Zhang;Kapildeb Sen;David Lebwohl;Michael A Pulsipher;Stephan A Grupp - The New England journal of medicine (2018)
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  6. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. - James N Kochenderfer;Mark E Dudley;Robert O Carpenter;Sadik H Kassim;Jeremy J Rose;William G Telford;Frances T Hakim;David C Halverson;Daniel H Fowler;Nancy M Hardy;Anthony R Mato;Dennis D Hickstein;Juan C Gea-Banacloche;Steven Z Pavletic;Claude Sportes;Irina Maric;Steven A Feldman;Brenna G Hansen;Jennifer S Wilder;Bazetta Blacklock-Schuver;Bipulendu Jena;Michael R Bishop;Ronald E Gress;Steven A Rosenberg - Blood (2013)
  7. Symptomatic pseudo-progression followed by significant treatment response in two lung cancer patients treated with immunotherapy. - Maximilian J Hochmair;Sophia Schwab;Otto C Burghuber;Dagmar Krenbek;Helmut Prosch - Lung cancer (Amsterdam, Netherlands) (2017)
  8. High-Frequency Oscillatory Ventilation Use and Severe Pediatric ARDS in the Pediatric Hematopoietic Cell Transplant Recipient. - Courtney M Rowan;Ashley Loomis;Jennifer McArthur;Lincoln S Smith;Shira J Gertz;Julie C Fitzgerald;Mara E Nitu;Elizabeth As Moser;Deyin D Hsing;Christine N Duncan;Kris M Mahadeo;Jerelyn Moffet;Mark W Hall;Emily L Pinos;Robert F Tamburro;Ira M Cheifetz; - Respiratory care (2018)
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Literatures Citing This Work ​

  1. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. - Daniel W Lee;Bianca D Santomasso;Frederick L Locke;Armin Ghobadi;Cameron J Turtle;Jennifer N Brudno;Marcela V Maus;Jae H Park;Elena Mead;Steven Pavletic;William Y Go;Lamis Eldjerou;Rebecca A Gardner;Noelle Frey;Kevin J Curran;Karl Peggs;Marcelo Pasquini;John F DiPersio;Marcel R M van den Brink;Krishna V Komanduri;Stephan A Grupp;Sattva S Neelapu - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2019)
  2. Safety and Tolerability of Adoptive Cell Therapy in Cancer. - Benita Wolf;Stefan Zimmermann;Caroline Arber;Melita Irving;Lionel Trueb;George Coukos - Drug safety (2019)
  3. Modelling CAR-T therapy in humanized mice. - Yongxia Wu;Xue-Zhong Yu - EBioMedicine (2019)
  4. The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. - George Hucks;Susan R Rheingold - Blood cancer journal (2019)
  5. Mechanisms of resistance to CAR T cell therapy. - Nirali N Shah;Terry J Fry - Nature reviews. Clinical oncology (2019)
  6. Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy. - Juliane Gust;Olivia C Finney;Daniel Li;Hannah M Brakke;Roxana M Hicks;Robert B Futrell;Danielle N Gamble;Stephanie D Rawlings-Rhea;Hedieh K Khalatbari;Gisele E Ishak;Virginia E Duncan;Robert F Hevner;Michael C Jensen;Julie R Park;Rebecca A Gardner - Annals of neurology (2019)
  7. Pediatric Cardio-Oncology: Development of Cancer Treatment-Related Cardiotoxicity and the Therapeutic Approach to Affected Patients. - Thomas D Ryan;Rajaram Nagarajan;Justin Godown - Current treatment options in oncology (2019)
  8. Immunotherapeutic options for management of relapsed or refractory B-cell acute lymphoblastic leukemia: how to select newly approved agents? - Prajwal Dhakal;Jasleen Kaur;Krishna Gundabolu;Vijaya Raj Bhatt - Leukemia & lymphoma (2020)
  9. Cellular therapy: Immune-related complications. - Joseph H Oved;David M Barrett;David T Teachey - Immunological reviews (2019)
  10. CAR-T - and a side order of IgG, to go? - Immunoglobulin replacement in patients receiving CAR-T cell therapy. - Joshua A Hill;Sergio Giralt;Troy R Torgerson;Hillard M Lazarus - Blood reviews (2019)

... (99 more literatures)

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