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Less frequent complications following CAR T-cell therapies: hemophagocytic lymphohistiocytosis, graft-versus-host disease, thrombotic microangiopathy, coagulation disorders and secondary malignancies: best practice recommendations from the EBMT Practice Harmonization and Guidelines Committee

Bone Marrow Transplantation volume 60, pages 751–758 (2025)Cite this article

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Abstract

CAR T-cell therapies have revolutionized the treatment of hematologic malignancies; however, alongside the well-known complications of cytokine release syndrome (CRS), neurotoxicity, immune effector cell–associated hematotoxicity (ICAHT), and infections, other non-classical toxicities are emerging. This review, developed by the EBMT Practice Harmonization and Guidelines Committee, addresses the management of other critical post-CAR T-cell complications including hemophagocytic lymphohistiocytosis (HLH), graft-versus-host disease (GvHD), thrombotic microangiopathy (TMA), coagulation disorders and secondary malignancies. These complications, though less frequent, present a significant challenge, often contributing to morbidity and mortality with no standardized management protocols. This review provides best practice recommendations for early identification, risk mitigation, and therapeutic interventions, supported by limited but emerging clinical evidence. Comprehensive expert guidance is essential for optimal management of these under-explored toxicities following CAR T-cell therapies.

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Fig. 1: Management of CAR-HLH. Adapted from Hayden et al. [2].

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Author information

Author notes

  1. These authors contributed equally: Guillermo Ortí, Guillaume Dachy.

  2. These authors jointly supervised this work: Ibrahim Yakoub-Agha, Olaf Penack.

Authors and Affiliations

  1. Vall d´Hebron University Hospital, Vall d´Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Guillermo Ortí

  2. Hematology Department, Cliniques Universitaires Saint-Luc, Brussels, Belgium

    Guillaume Dachy

  3. School of Cancer and Pharmaceutical Sciences, King’s College London, London, UK

    Charlotte E. Graham

  4. Department of Haematology, King’s College Hospital NHS Foundation Trust, London, UK

    Charlotte E. Graham & Orla Stewart

  5. University Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia

    Zinaida Peric

  6. Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain

    Ana Alarcon

  7. Department of Hematology, Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy

    Francesca del Bufalo

  8. Co-Lead of the Immunology Subcommittee ADWP of the EBMT, Milan, Italy

    Matteo Doglio

  9. Experimental Hematology Unit, Vita-Salute University. Pediatric Immuno-Hematology Unit, IRCCS San Raffaele Hospital, Milan, Italy

    Matteo Doglio

  10. Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden

    Jan-Inge Henter

  11. Pediatric Oncology, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

    Jan-Inge Henter

  12. University College London Hospital NHS Foundation Trust, London, UK

    Claire Roddie

  13. Amsterdam UMC, Vrije Universiteit Amsterdam, Department of Hematology, Cancer Center Amsterdam, Amsterdam, The Netherlands

    W.C.J. Van de Donk

  14. Department of Neurology, Neuro-oncology Unit & Lymphoma Unit, Institut Català d´Oncologia—Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain

    Roser Velasco

  15. King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia

    Mahmoud Aljurf

  16. Vice-Chair of the Practice Harmonisation and Guidelines Committee of EBMT and Chair of the CTIWP of the EBMT, Milano, Italy

    Annalisa Ruggeri

  17. Hematology and BMT Unit, Cellular Therapy and Immunobiology Working Party of the EBMT, San Raffaele Scientific Institute, Milano, Italy

    Annalisa Ruggeri

  18. VIce-Chair of the Practice Harmonisation and Guidelines Committee of the EBMT, 19- Hematology and BMT Unit, ASST Fatebenefratelli-Sacco, Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy

    Francesco Onida

  19. Secretary of the Practice Harmonisation and Guidelines Committee of EBMT, Milan, Italy

    Francesco Onida

  20. EBMT Medical Officer, Executive Office, Barcelona, Spain

    Isabel Sánchez-Ortega

  21. Chair of the EBMT Practice Harmonisation and Guidelines Committee, Milano, Italy

    Ibrahim Yakoub-Agha

  22. CHU de Lille, Univ Lille, INSERM U1286, Infinite, Lille, France

    Ibrahim Yakoub-Agha

  23. Department of Hematology, Oncology and Tumorimmunology, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany

    Olaf Penack

Authors
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  2. Guillaume Dachy
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Contributions

GO: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. GD: participated in the meeting, wrote the original draft, revised the manuscript and approved the final version. CG: conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. ZP: conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. AA: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. FB: participated in the meeting, wrote the original draft, revised the manuscript and approved the final version. MD: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. JH: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. CR: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. OS: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. WVJ: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. RV: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. MA: participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. AR: developed the methodology, conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. FO: developed the methodology, conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. ISO: developed the methodology, conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. IYA: developed the methodology, conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version. OP: conceptualized the subject for this workshop, participated in the meeting, wrote the original draft, revised the manuscript, and approved the final version.

Corresponding author

Correspondence to Guillermo Ortí.

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Competing interests

GO has received consulting fees from BMS, Incyte, Norvartis, Pfizer, and Sanofi; travel support from BMS, Incyte, Norvartis, and Sanofi; institutional research grant from Incyte; and honoraria from BMS, Incyte, Jazz, Norvartis, Pfizer, and Sanofi. GD received honoraria from Kite/Gilead, BMS. JIH: consultant for Sobi. FdB received support from the Italian Ministry of Health (project code: GR-2021-12372614). N.W.C.J.v.d.D. has received research support from Janssen Pharmaceuticals, AMGEN, Celgene, Novartis, Cellectis, and BMS, and serves in advisory boards for Janssen Pharmaceuticals, AMGEN, Celgene, BMS, Sanofi, Takeda, Roche, Novartis, Bayer, Adaptive, Merck, Kite Pharma, Pfizer, AbbVie, and Servier, all paid to institution. RV: has received consulting fees from Takeda, Novartis, Kite/ Gilead, and Seagen; received honoraria from Takeda, Janseen, and Kite/Gilead, and travel grants from Takeda and Kite/Gilead. IYA received honoraria from Kite/Gilead, BMS, Novartis, Janssen. OP has received honoraria or travel support from Alexion, Gilead, Jazz, MSD, Neovii, Novartis, Pfizer, and Therakos. He has received research support from Incyte and Priothera. He is member of advisory boards to Apogepha, Alexion, Equillium Bio, Jazz, Gilead, Novartis, MSD, Omeros, Orca Bio, Priothera, Sanofi, Shionogi, and SOBI.

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Ortí, G., Dachy, G., Graham, C.E. et al. Less frequent complications following CAR T-cell therapies: hemophagocytic lymphohistiocytosis, graft-versus-host disease, thrombotic microangiopathy, coagulation disorders and secondary malignancies: best practice recommendations from the EBMT Practice Harmonization and Guidelines Committee. Bone Marrow Transplant 60, 751–758 (2025). https://doi.org/10.1038/s41409-025-02567-5

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