Page 97 - Haematologica Vol. 107 - September 2022

ARTICLE - Cell Therapy & Immunotherapy
Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies
David M. Cordas dos Santos,1-3* Kai Rejeski,1,3-4* Michael Winkelmann,5 Lian Liu,6 Paul Trinkner,1,2 Sophie Günther,1,2 Veit L. Bücklein,1,4 Viktoria Blumenberg,1,3-4 Christian Schmidt,1 Wolfgang G. Kunz,5 Michael von Bergwelt-Baildon,1,3,6 Sebastian Theurich1-3# and Marion Subklewe1,3-4#
1Department of Medicine III, University Hospital, LMU Munich, Munich; 2Cancer- and Immunometabolism Research Group, LMU Gene Center, Munich; 3German Cancer Consortium (DKTK), Munich Site, and German Cancer Research Center, Heidelberg; 4Laboratory for Translational Cancer Immunology, LMU Gene Center, Munich; 5Department of Radiology, University Hospital, LMU Munich and 6Comprehensive Cancer Center Munich, LMU Munich, Munich, Germany
*DMCDS and KR contributed equally as co-first authors. #ST and MS contributed equally as co-senior authors.
Abstract
Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is characterized by the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory B- cell malignancies. Patients with grade ≥2 CRS presented with a significantly higher median body mass index (BMI), waist circumference, waist-to-height ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with grade 0-1 CRS versus grade ≥2 CRS. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥2 CRS. Receiver operating characteristic analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.
Correspondence: M. Subklewe marion.subklewe@med.uni-muenchen.de
S. Theurich
sebastian.theurich@med.uni-muenchen.de
Received: Accepted: Prepublished:
October 13, 2021. February 9, 2022. February 17, 2022.
https://doi.org/10.3324/haematol.2021.280189
©2022 Ferrata Storti Foundation Published under a CC BY-NC license
Introduction
The advent of chimeric antigen receptor T-cell (CAR-T) therapy as a powerful new class of immunotherapeutic agents has improved outcomes for multiple B-cell malig- nancies in the relapsed/refractory (R/R) setting.1-4 As these therapies move to the clinical mainstream, understanding the mechanisms that drive the unique spectrum of CAR- T-related immunotoxicity becomes paramount.
Cytokine release syndrome (CRS) represents the most commonly observed adverse event and is characterized by an increase of pro-inflammatory cytokines such as in- terleukin-6 (IL-6), resulting in endothelial activation and diffuse capillary leakage.5 The clinical management of CRS follows a risk-adapted strategy for monitoring and ther- apy, and the anti-IL-6 receptor antagonist tocilizumab is commercially available to ameliorate symptoms.6 Several patient-associated risk factors have been identified that
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