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

Literature Information ​

DOI10.1056/NEJMoa1709866
PMID29385370
JournalThe New England journal of medicine
Impact Factor78.5
JCR QuartileQ1
Publication Year2018
Times Cited2743
KeywordsCAR T-cell therapy, B-cell acute lymphoblastic leukemia, complete remission rate
Literature TypeClinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't
ISSN0028-4793
Pages439-448
Issue378(5)
AuthorsShannon 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

TL;DR ​

This global phase 2 study demonstrated that a single infusion of the anti-CD19 CAR T-cell therapy tisagenlecleucel achieved an 81% overall remission rate in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia, with long-term persistence of the treatment observed for up to 20 months. While most patients experienced serious but manageable toxic effects, the findings underscore the potential of tisagenlecleucel as an effective therapeutic option for this challenging patient population.

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CAR T-cell therapy · B-cell acute lymphoblastic leukemia · complete remission rate

Abstract ​

BACKGROUND 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).

METHODS We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months.

RESULTS For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported.

CONCLUSIONS In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).

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Primary Questions Addressed ​

  1. What are the long-term effects of tisagenlecleucel on pediatric patients beyond the 12-month follow-up?
  2. How does the efficacy of tisagenlecleucel compare to traditional chemotherapy treatments for B-cell ALL in children and young adults?
  3. What specific factors contribute to the high rate of adverse events observed in patients receiving tisagenlecleucel?
  4. How does the persistence of tisagenlecleucel in the blood correlate with overall survival rates in these patients?
  5. What are the implications of the high rate of cytokine release syndrome for the management of patients undergoing CAR T-cell therapy?

Key Findings ​

Background and Objectives ​

The study investigates the efficacy and safety of tisagenlecleucel, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). The objective was to evaluate the overall remission rate within three months post-infusion.

Main Methods/Materials/Experimental Design ​

The research was a phase 2, single-cohort, multicenter global study involving 25 centers across 11 countries. Key eligibility criteria included patients aged 3 to 21 years with CD19+ relapsed or refractory B-cell ALL, with at least 5% lymphoblasts in bone marrow. Patients with prior anti-CD19 therapy were excluded.

The process for administering tisagenlecleucel involved:

  1. Lymphodepleting chemotherapy: Patients received fludarabine and cyclophosphamide prior to T-cell infusion.
  2. T-cell collection and transduction: Autologous T cells were collected, transduced with a lentiviral vector to express the CAR, and then expanded.
  3. Infusion: Patients received a single infusion of the CAR T cells.

The primary endpoint was the overall remission rate, defined as complete remission or complete remission with incomplete hematologic recovery, assessed within three months.

Mermaid diagram

Key Results and Findings ​

  • Patient Demographics: 75 patients received tisagenlecleucel infusion, with a median age of 11 years and a median of 3 prior therapies.
  • Overall Remission Rate: 81% (95% CI, 71 to 89) achieved remission within three months.
  • Complete Remission: 60% achieved complete remission, with 95% of these patients negative for minimal residual disease by day 28.
  • Event-Free Survival: 73% at 6 months and 50% at 12 months.
  • Overall Survival: 90% at 6 months and 76% at 12 months.
  • Adverse Events: 73% experienced grade 3 or 4 adverse events, including cytokine release syndrome (77%) and neurological events (40%).

Main Conclusions/Significance/Innovation ​

The study demonstrates that a single infusion of tisagenlecleucel can achieve high rates of durable remission in pediatric and young adult patients with relapsed or refractory B-cell ALL. The persistence of CAR T cells and associated B-cell aplasia suggest a robust treatment effect, although significant adverse effects require careful management.

Limitations and Future Directions ​

  • Limitations: The study was non-randomized and lacked a control group, which may affect the generalizability of results. The high incidence of severe adverse events also raises concerns regarding the safety profile of the therapy.
  • Future Directions: Further studies are needed to explore long-term outcomes, the optimal management of adverse events, and the potential combination of tisagenlecleucel with other therapeutic agents to enhance efficacy and safety. Additionally, the exploration of the CAR design variations and their impact on patient outcomes could provide insights for future therapies.

References ​

  1. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. - Adrienne H Long;Waleed M Haso;Jack F Shern;Kelsey M Wanhainen;Meera Murgai;Maria Ingaramo;Jillian P Smith;Alec J Walker;M Eric Kohler;Vikas R Venkateshwara;Rosandra N Kaplan;George H Patterson;Terry J Fry;Rimas J Orentas;Crystal L Mackall - Nature medicine (2015)
  2. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. - Daniel W Lee;James N Kochenderfer;Maryalice Stetler-Stevenson;Yongzhi K Cui;Cindy Delbrook;Steven A Feldman;Terry J Fry;Rimas Orentas;Marianna Sabatino;Nirali N Shah;Seth M Steinberg;Dave Stroncek;Nick Tschernia;Constance Yuan;Hua Zhang;Ling Zhang;Steven A Rosenberg;Alan S Wayne;Crystal L Mackall - Lancet (London, England) (2015)
  3. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. - Stephan A Grupp;Michael Kalos;David Barrett;Richard Aplenc;David L Porter;Susan R Rheingold;David T Teachey;Anne Chew;Bernd Hauck;J Fraser Wright;Michael C Milone;Bruce L Levine;Carl H June - The New England journal of medicine (2013)
  4. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. - Renier J Brentjens;Marco L Davila;Isabelle Riviere;Jae Park;Xiuyan Wang;Lindsay G Cowell;Shirley Bartido;Jolanta Stefanski;Clare Taylor;Malgorzata Olszewska;Oriana Borquez-Ojeda;Jinrong Qu;Teresa Wasielewska;Qing He;Yvette Bernal;Ivelise V Rijo;Cyrus Hedvat;Rachel Kobos;Kevin Curran;Peter Steinherz;Joseph Jurcic;Todd Rosenblat;Peter Maslak;Mark Frattini;Michel Sadelain - Science translational medicine (2013)
  5. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. - Sima Jeha;Paul S Gaynon;Bassem I Razzouk;Janet Franklin;Richard Kadota;Violet Shen;Lori Luchtman-Jones;Michael Rytting;Lisa R Bomgaars;Susan Rheingold;Kim Ritchey;Edythe Albano;Robert J Arceci;Stewart Goldman;Timothy Griffin;Arnold Altman;Bruce Gordon;Laurel Steinherz;Steven Weitman;Peter Steinherz - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2006)
  6. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. - David L Porter;Wei-Ting Hwang;Noelle V Frey;Simon F Lacey;Pamela A Shaw;Alison W Loren;Adam Bagg;Katherine T Marcucci;Angela Shen;Vanessa Gonzalez;David Ambrose;Stephan A Grupp;Anne Chew;Zhaohui Zheng;Michael C Milone;Bruce L Levine;Jan J Melenhorst;Carl H June - Science translational medicine (2015)
  7. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. - Arend von Stackelberg;Franco Locatelli;Gerhard Zugmaier;Rupert Handgretinger;Tanya M Trippett;Carmelo Rizzari;Peter Bader;Maureen M O'Brien;Benoît Brethon;Deepa Bhojwani;Paul Gerhardt Schlegel;Arndt Borkhardt;Susan R Rheingold;Todd Michael Cooper;Christian M Zwaan;Phillip Barnette;Chiara Messina;Gérard Michel;Steven G DuBois;Kuolung Hu;Min Zhu;James A Whitlock;Lia Gore - Journal of clinical oncology : official journal of the American Society of Clinical Oncology (2016)
  8. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. - Michael C Milone;Jonathan D Fish;Carmine Carpenito;Richard G Carroll;Gwendolyn K Binder;David Teachey;Minu Samanta;Mehdi Lakhal;Brian Gloss;Gwenn Danet-Desnoyers;Dario Campana;James L Riley;Stephan A Grupp;Carl H June - Molecular therapy : the journal of the American Society of Gene Therapy (2009)
  9. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. - Rebecca A Gardner;Olivia Finney;Colleen Annesley;Hannah Brakke;Corinne Summers;Kasey Leger;Marie Bleakley;Christopher Brown;Stephanie Mgebroff;Karen S Kelly-Spratt;Virginia Hoglund;Catherine Lindgren;Assaf P Oron;Daniel Li;Stanley R Riddell;Julie R Park;Michael C Jensen - Blood (2017)
  10. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. - Cameron J Turtle;Laïla-Aïcha Hanafi;Carolina Berger;Theodore A Gooley;Sindhu Cherian;Michael Hudecek;Daniel Sommermeyer;Katherine Melville;Barbara Pender;Tanya M Budiarto;Emily Robinson;Natalia N Steevens;Colette Chaney;Lorinda Soma;Xueyan Chen;Cecilia Yeung;Brent Wood;Daniel Li;Jianhong Cao;Shelly Heimfeld;Michael C Jensen;Stanley R Riddell;David G Maloney - The Journal of clinical investigation (2016)

Literatures Citing This Work ​

  1. Immunotherapy: CAR T cell therapy efficacious against B-ALL across age groups. - Peter Sidaway - Nature reviews. Clinical oncology (2018)
  2. Building a CAR Garage: Preparing for the Delivery of Commercial CAR T Cell Products at Memorial Sloan Kettering Cancer Center. - Karlo Perica;Kevin J Curran;Renier J Brentjens;Sergio A Giralt - Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation (2018)
  3. CD19 CAR-T cell therapy for relapsed/refractory acute lymphoblastic leukemia: factors affecting toxicities and long-term efficacies. - Li-Na Zhang;Yongping Song;Delong Liu - Journal of hematology & oncology (2018)
  4. Current Strategies to Enhance Anti-Tumour Immunity. - Katherine W Cook;Lindy G Durrant;Victoria A Brentville - Biomedicines (2018)
  5. Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR-T cell therapy. - Jordan Gauthier;Cameron J Turtle - Current research in translational medicine (2018)
  6. Tapping the RNA world for therapeutics. - Judy Lieberman - Nature structural & molecular biology (2018)
  7. Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector. - Eric L Smith;Mette Staehr;Reed Masakayan;Ishan J Tatake;Terence J Purdon;Xiuyan Wang;Pei Wang;Hong Liu;Yiyang Xu;Sarah C Garrett-Thomson;Steven C Almo;Isabelle Riviere;Cheng Liu;Renier J Brentjens - Molecular therapy : the journal of the American Society of Gene Therapy (2018)
  8. Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis. - Leslie S Kean - Blood (2018)
  9. Chimeric antigen receptor-modified T cells: CD19 and the road beyond. - Alexander I Salter;Margot J Pont;Stanley R Riddell - Blood (2018)
  10. Introduction to a review series on emerging immunotherapies for hematologic diseases. - Sophie Paczesny;Steven Z Pavletic;Catherine M Bollard - Blood (2018)

... (2733 more literatures)

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