Page 105 - Haematologica Vol. 107 - September 2022

ARTICLE - Body composition impacts CRS after CAR-T therapy D.M. Cordas dos Santos et al.
Figure 5. Proposed model of meta-inflammation as potentiating factor in cytokine release syndrome pathogenesis.
progenitor cell function,48 this may indirectly affect in- flammation cascades facilitated by mobilized immune cells – though this remains to be systematically studied in the context of CAR T-cell therapy.
Based on our results, we postulate that elevated visceral adipose tissue mass in overweight or obese CAR-T pa- tients predisposes to more severe and earlier CRS. Fur- thermore, obesity-associated metaflammation with subsequent elevation of serum IL-6 levels may represent the potential link for the adipose tissue-induced effects (Figure 5). The relationship between obesity and IL-6 in the context of metaflammation has been extensively de- scribed, and is predominantly driven via IL-6 secretion by adipocytes and adipose-tissue macrophages.49-51 Surpris- ingly, we found an association between adipose tissue and CRS in a patient cohort with very few obese patients as defined by World Health Organization criteria (BMI >30 kg/m2, n=4). However, this may be explained by the long- lasting effect of metaflammation that can be preserved even after weight loss.52 Unfortunately, we did not have BMI data at the time of initial diagnosis for all patients to test this hypothesis. However, we expect that most pa- tients were subject to weight loss due to their disease and treatment. Alternatively, even low amounts of adipose tis-
sue may be sufficient to facilitate a pro-immunogenic ef- fect. Nevertheless, further prospective studies, preferably in patient cohorts with a higher percentage of obese pa- tients, are needed to validate the role of overweight and obesity as a risk factor for severe CRS. If validated, an- thropometric data like BMI and waist circumference may serve as an attractive auxiliary component in the risk- stratification tool box of the CAR-T treating physician due to the easy-to-measure nature of these parameters. For example, acquiring BC data requires only a tape measure and a scale, underlining clinical ease-of-use. This may be especially pertinent for patients who are fit enough to re- ceive CAR-T in an outpatient setting.53
In contrast to the interactions between adipose tissue and CRS, we did not find that skeletal muscle mass im- pacts CRS or ICANS. Although nearly half of our patients were defined as sarcopenic according to the published sarcopenia classifications,54 CRS and ICANS severity was equally distributed between sarcopenic and non-sarco- penic patients. There are several potential explanations for this observation. First, patient numbers may have been too small to discern interactions between skeletal muscle and systemic inflammation. Second, previously described interactions between muscle mass and the immune sys-
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