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Acute Lymphoblastic Leukemia

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study

Leukemia volume 36, pages 1525–1532 (2022)Cite this article

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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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Fig. 1: Toxicity of CAR T-cells for patients with CNS involvement.
Fig. 2: Outcome following CD19-CAR T-cells for CNS leukemia.
Fig. 3: Outcome following tisagenlecleucel for CNS leukemia.

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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

  1. The Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Israel

    Elad Jacoby, Bella Bielorai & Amos Toren

  2. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Elad Jacoby, Asaf D Yanir, Ronit Elhasid, Bella Bielorai & Amos Toren

  3. Developmental Biology and Cancer, UCL Great Ormond Street Institute of Child Health, London, ENG, UK

    Sara Ghorashian & Srdan Rogosic

  4. Princess Maxima Center for Paediatric Oncology, Utrecht, Netherlands

    Britta Vormoor

  5. Dept of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium

    Barbara De Moerloose

  6. University Children’s Hospital Zürich, Zürich, Switzerland

    Nicole Bodmer & Jean Pierre Bourquin

  7. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation

    Olga Molostova & Michael Maschan

  8. Schneider Children’s Medical Center, Petah Tikvah, Israel

    Asaf D Yanir

  9. Department of Pediatric Hematology and Oncology, Oslo University Hospital, Oslo, Norway

    Jochen Buechner

  10. Department of Pediatric Hemato-Oncology, Tel Aviv Medical Center, Tel Aviv, Israel

    Ronit Elhasid

  11. Department of Pediatric Hematology and Immunology, University Hospital Robert Debré (APHP) and Université de Paris, Paris, France

    Marie-Emilie Dourthe & Andre Baruchel

  12. Pediatric Hematology and Oncology, University Children’s Hospital Muenster, Muenster, Germany

    Claudia Rossig

  13. Department of Pediatric Oncology/Hematology, Charite Medical Center, Berlin, Germany

    Arend von Stackelberg

  14. 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

  15. Division for Stem Cell Transplantation and Immunology, Department for Children and Adolescents, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany

    Peter Bader

  16. Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    Martin Zimmermann

Authors
  1. Elad Jacoby
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  2. Sara Ghorashian
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  3. Britta Vormoor
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  20. Jean Pierre Bourquin
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  21. Andre Baruchel
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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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