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Publications

Journal Article Review Ahead of print

PubMed: 41932580 DOI: 10.1016/j.annonc.2026.03.006

Cytokine Release Symptoms rather than Syndromes: A call for Granular Reporting of Cytokine Related Adverse Events in Clinical Trials.

Ann Oncol

Authors: J-D Fumet, M Roulleaux Dugage, F-X Danlos, T Hueso, D J Pinato, J Luke, I Melero Bermejo, P Lorusso, J Brody, K Harrington, N H Segal, A Diab, E Gerralda Cabanas, T Marron, R Houot, S Champiat, A Marabelle

Affiliations

  • Université Bourgogne Europe, Centre Georges-François Leclerc, Unicancer, Cancer Biology Transfer Platform, UMR INSERM 1231, TIRECs team, 21000 Dijon, France; Université Paris Saclay, Gustave Roussy, INSERM U1356 & CIC1428, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif, France.
  • Université Paris Saclay, Gustave Roussy, INSERM U1363 (Biothérapie Innovante), Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif, France; Université Paris Saclay, Gustave Roussy, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif, France.
  • Université Paris Saclay, Gustave Roussy, INSERM U1356 & CIC1428, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif, France; Université Paris Saclay, Gustave Roussy, Département d'Innovation Thérapeutique et des Essais Précoces (DITEP), Villejuif, France.
  • Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.
  • Chief Medical Officer - Strand Therapeutics.
  • Clinica Universidad de Navarra, CIMA and CIBERONC, Pamplona, Spain; Nuffield Department of Medicine. University of Oxford. Oxford. UK.
  • Yale Cancer Center, Yale University, New Haven, CT 06517.
  • Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Marc and Jennifer Lipschultz Precision Immunology Institute.
  • Institute of Cancer Research London United Kingdom.
  • Memorial Sloan Kettering Cancer Center, New York, NY, United States.
  • Department of Cancer Science, Center for Immunotherapy and Precision Immuno-Oncology, Cleveland Clinic, Cleveland, OH, USA; The Cancer Institute, Cleveland Clinic Abu Dhabi, United Arab Emirates.
  • Medical Oncology Department. Vall d'Hebron University Hospital (HUVH). Barcelona, Spain; Research Unit for Molecular Therapy of Cancer (UITM) -"CaixaResearch". Vall d' Hebron Institute of Oncology (VHIO). Barcelona, Spain.
  • Icahn school of medicine at Mount Sinai.
  • Department of Hematology, University Hospital of Rennes, UMR U1236, INSERM, University of Rennes, Rennes, France.
  • Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

BACKGROUND

T-cell redirecting therapies, notably CAR T-cells and bispecific antibodies, have revolutionized the treatment of hematologic malignancies. Their rapid expansion into solid tumors, alongside the emergence of next-generation agents, such as immunocytokines and CD28-costimulatory bispecifics, has brought Cytokine Release Syndrome (CRS) to the forefront of clinical oncology. However, the absence of a unified grading system for these novel constructs remains a critical barrier to drug development and patient safety. Current toxicity management relies on disparate grading scales leading to inconsistent reporting and hindering cross-trial comparisons. A fundamental challenge lies in the diagnostic ambiguity created by the significant clinical and temporal overlap between CRS, infusion-related reactions (IRRs), and other diagnosis. While fever, hypotension, and hypoxia are common denominators, their distinct pathophysiological drivers necessitate divergent therapeutic interventions.

PROPOSAL

We advocate for a paradigm shift from aggregate syndromic grading toward a granular, longitudinal reporting framework. This approach prioritizes the precise documentation of symptom kinetics, specific interventions (e.g., exact vasopressor requirements, oxygen flow rates), and real-time biomarker integration By capturing high-fidelity data, researchers can retrospectively apply evolving criteria and develop more tailored, evidence-based management algorithms.

CONCLUSION

Transitioning to a standardized, symptom-driven reporting model is essential to navigate the complexities of "Immuno-oncology 2.0." Such a framework will harmonize safety assessments across global trials and ultimately optimize the therapeutic index of next-generation immunotherapies.

MeSH

Cytokines, Cells, Safety, Neoplasms, Signs And Symptoms, Drug-Related Side Effects And Adverse Reactions, Therapeutics