Page 104 - Haematologica Vol. 107 - September 2022

ARTICLE - Body composition impacts CRS after CAR-T therapy D.M. Cordas dos Santos et al..
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Figure 4. Adipose tissue correlates with peak interleukin 6 and interleukin 6 dynamics. (A) Peak interleukin 6 (IL-6) by body mass index (BMI), waist circumference (Waist), waist-to-height ratio (WtHR), and visceral adipose tissue (VAT) (from left to right). The previously established discriminatory values were used to distinguish high vs. low groups. (B) Aggregated median IL-6 values over time comparing BMI/Waist/WtHR/VAThigh vs. BMI/Waist/WtHR/VATlow patients. The dotted vertical line indicates the median day of the peak for each group. Significance values were determined by two-way ANOVA considering both time and effect size.
verse events occurred.42 However, the impact of over- weight and obesity on survival and toxicity has been more mixed in the context of BCL in the pre-CAR-T era. For example, improved outcomes were noted for overweight patients in first-line rituximab-containing chemotherapy regimens, though the opposite was observed in obese pa- tients receiving autologous stem cell transplantation.43,44 One study analyzing the impact of body weight on clinical outcomes in R/R LBCL patients receiving CAR-T was negative, though detailed body composition analyses were not performed and only Axi-cel patients were included.45 In our study, BC parameters negatively correlated with CRS onset, suggesting that overweight patients harbor a pro-inflammatory environment that predisposes them for earlier and more severe systemic inflammation. This would be consistent with prior studies establishing the role of adipose tissue as an endocrine organ with the po- tential of amplifying immune responses.22 Consistent with this hypothesis, the anthropometric body fat indices and VAT were all associated with elevated peak IL-6 serum
levels. VAThigh patients exhibited not only markedly in- creased peak IL-6 levels, but also a shorter time to peak IL-6, mirroring the clinical observation of an earlier CRS onset in VAThigh patients. While we did not observe a link between body composition and CRS duration, this may re- flect early tocilizumab administration in this patient co- hort, which may have blunted the natural CRS time course. Notably, IL-6 analyses revealed a second peak around day 19-21 for patients with excess body fat. Wei and colleagues propose a conceptual framework wherein a minimal IL-6 peak in week 3 coincides with the redis- tribution of CAR T-cells into the periphery in the absence of target cells.46 Such redistribution results in the activa- tion of tissue-resident immune cells such as macro- phages or neutrophils, and may be potentiated by metaflammation-inherent feedback loops. The second peak also temporally coincides with the burgeoning hematopoetic recovery observed in the third week after CAR-T transfusion.47 As diet can impact remodeling of the bone marrow niche and skew hematopoietic stem and
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