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Acute Lymphoblastic Leukemia
- Elad Jacoby ORCID: orcid.org/0000-0003-1411-89421,2,
- Sara Ghorashian3,
- Britta Vormoor4,
- Barbara De Moerloose5,
- Nicole Bodmer6,
- Olga Molostova7,
- Asaf D Yanir2,8,
- Jochen Buechner ORCID: orcid.org/0000-0001-5848-45019,
- Ronit Elhasid ORCID: orcid.org/0000-0002-5663-69192,10,
- Bella Bielorai1,2,
- Srdan Rogosic3,
- Marie-Emilie Dourthe11,
- Michael Maschan ORCID: orcid.org/0000-0003-1735-00937,
- Claudia Rossig12,
- Amos Toren1,2,
- Arend von Stackelberg13,
- Franco Locatelli14,
- Peter Bader ORCID: orcid.org/0000-0003-4554-026515,
- Martin Zimmermann16,
- Jean Pierre Bourquin6 &
- …
- Andre Baruchel ORCID: orcid.org/0000-0003-0120-608911
Leukemia volume36,pages 1525–1532 (2022)Cite this article
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Subjects
- Acute lymphocytic leukaemia
- Risk factors
Abstract
Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach.
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Funding
This work was done on behalf of the international BFM Resistant Disease study group. This study was funded by the Dotan research center in hemato-oncology and by the Israel Cancer Association.
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Authors and Affiliations
The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel
Elad Jacoby,Bella Bielorai&Amos Toren
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
Elad Jacoby,Asaf D Yanir,Ronit Elhasid,Bella Bielorai&Amos Toren
Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, ENG, UK
Sara Ghorashian&Srdan Rogosic
Princess Maxima Center for Paediatric Oncology, Utrecht, Netherlands
Britta Vormoor
Dept of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
Barbara De Moerloose
University Children’s Hospital Zürich, Zürich, Switzerland
Nicole Bodmer&Jean Pierre Bourquin
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
Olga Molostova&Michael Maschan
Schneider Children’s Medical Center, Petah Tikvah, Israel
Asaf D Yanir
Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway
Jochen Buechner
Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel
Ronit Elhasid
Department of Pediatric Hematology and Immunology, University Hospital Robert Debré (APHP) and Université de Paris, Paris, France
Marie-Emilie Dourthe&Andre Baruchel
Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany
Claudia Rossig
Department of Pediatric Oncology/Hematology, Charite Medical Center, Berlin, Germany
Arend von Stackelberg
Department of Hematology and Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Sapienza, University of Rome, Rome, Italy
Franco Locatelli
Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany
Peter Bader
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
Martin Zimmermann
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- Elad Jacoby
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- Sara Ghorashian
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- Barbara De Moerloose
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Contributions
EJ, JPB and AB conceived the study and oversaw the project; EJ, SG, BV, BDM, NB, OM, AY, JB, RE, BB, SR, ED, MM, CR, AT, AVS, FL, PB, JPB and AB collected patient data. EJ and MZ performed statistical analysis, EJ, MZ and AB analyzed and interpreted data; EJ, AB, SG, BV and BDM wrote and significantly revised the manuscript. All authors approved the manuscript.
Corresponding authors
Correspondence to Elad Jacoby or Andre Baruchel.
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Competing interests
This study was not supported by phama but by a NPO grant (ICA to Dr. Jacoby). EJ reports participation of advisory boards for Novartis and Lonza and speaker’s fee from Novartis. SG reports honoraria and conference support from Novartis. BDM reports participation of advisory boards for Novartis, NB reports speaker’s fee from Novartis. JB has received personal fees, advisory board/steering committee honoraria, and nonfinancial support from Novartis; and advisory board honoraria from Pfizer, Kite, and Janssen. MM reports speaker’s fee from Miltenyi. CR reports participation in advisory boards by Amgen, BMS, Celgene, Novartis and Pfizer. AB reports participation on advisory boards and travel from Servier, Celgene, Novartis, Jazz, AstraZeneca, and being an investigator on trials from Novartis, Kite, Celgene and Cellectis. BV, OM, AY, RE, BB, SR, ED, AT, AVS, FL, PB, and JPB report no conflict of interests.
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Jacoby, E., Ghorashian, S., Vormoor, B. et al. CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study. Leukemia 36, 1525–1532 (2022). https://doi.org/10.1038/s41375-022-01546-9
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DOI: https://doi.org/10.1038/s41375-022-01546-9
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