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Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity

Bone Marrow Transplantation (2024)Cite this article

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Abstract

Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

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Fig. 1: Proposed workflow for automated grading of complex patterns of early ICAHT.
Fig. 2: Examples for automated grading of early ICAHT using occurrence and duration of periods of neutropenia as detected by {heatwaveR}.
Fig. 3: Examples for automated grading of late ICAHT.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) National Heart, Lung, and Blood Institute (ECL: 5T32HL007093), NIH Cancer Institute (KR and RS: P30 CA008748; JJH: 5T32CA951539; RS: K08CA282987; JG: P30 CA15704), Swim Across America (JG, Seattle Chapter; RS: Long Island Sound Chapter), School of Oncology of the German Cancer Consortium (KR), Else Kröner Forschungskolleg within the Munich Clinician Scientist Program (KR), the Bruno and Helene Jöster Foundation (KR, MS), and the Bavarian Center for Cancer Research (BZKF) (KR, MS).

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Author notes

  1. These authors contributed equally: Emily C. Liang, Kai Rejeski, Roni Shouval, Jordan Gauthier.

Authors and Affiliations

  1. Fred Hutchinson Cancer Center, Seattle, WA, USA

    Emily C. Liang, Aya Albittar, Jennifer J. Huang, Andrew J. Portuguese, Qian Wu & Jordan Gauthier

  2. University of Washington, Seattle, WA, USA

    Emily C. Liang, Jennifer J. Huang, Andrew J. Portuguese & Jordan Gauthier

  3. Adult Bone Marrow Transplantation and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Kai Rejeski, Sandeep Raj & Roni Shouval

  4. Department of Medicine III – Hematology/Oncology, LMU University Hospital, LMU Munich, Munich, Germany

    Kai Rejeski & Marion Subklewe

  5. Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Teng Fei

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Contributions

Conception and design: ECL, KR, JG, and RS. Collection and assembly of data: All authors. Data analysis and interpretation: ECL, KR, TF, RS, and JG. Manuscript writing: ECL, KR, JG, and RS. Critical review and approval of manuscript: All authors.

Corresponding author

Correspondence to Emily C. Liang.

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Competing interests

ECL: Glass Health: consultancy. KR: BMS/Celgene: consultancy, honoraria; Novartis: honoraria; Kite/Gilead: research funding, travel support; Pierre-Fabre: travel support. MS: Amgen: research funding, speakers’ bureau; BMS/Celgene: research funding, speakers’ bureau; Gilead: research funding, speakers’ bureau; Janssen: research funding, consultancy, speakers’ bureau; Miltenyi Biotec; research funding, consultancy; Novartis: research funding, consultancy, speakers’ bureau; Roche: research funding, speakers’ bureau; Seattle Genetics: research funding; Takeda: research funding, consultancy, speakers’ bureau; AvenCell: consultancy; CDR-Life: consultancy; Ichnos Sciences: consultancy; Incyte Biosciences: consultancy; Molecular Partners: consultancy; Pfizer: consultancy, speakers’ bureau; AztraZeneca: speakers’ bureau; GSK: speakers’ bureau. JG: Kite Pharma: consultancy, honoraria; MorphoSys: consultancy, research funding; Angiocrine Bioscience: research funding; Century Therapeutics: independent data review committee; Celgene (a Bristol Myers Squibb company): research funding; Legend Biotech: consultancy, honoraria; Janssen: consultancy, honoraria; Juno Therapeutics (a Bristol Myers Squibb company): research funding; Sobi: consultancy, honoraria, research funding. The remaining authors have nothing to declare. None of the mentioned conflicts of interest were related to financing of the content of this manuscript.

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Liang, E.C., Rejeski, K., Fei, T. et al. Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity. Bone Marrow Transplant (2024). https://doi.org/10.1038/s41409-024-02278-3

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  • DOI: https://doi.org/10.1038/s41409-024-02278-3

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