Page 103 - Haematologica Vol. 107 - September 2022

ARTICLE - Body composition impacts CRS after CAR-T therapy D.M. Cordas dos Santos et al.
cordingly, BMIhigh (≥ 27.05 kg/m2) patients exhibited an ear- lier median CRS onset compared to their BMIlow counter- parts (day 1 vs. day 3, P=0.05, Online Supplementary Figure S5). Earlier CRS onset was also noted for WtHR and VAT (Online Supplementary Figure S5). On the other hand, an- thropometric and BC parameters did not significantly cor- relate with CRS duration (Online Supplementary Table S4). These data may reflect the aggressive and early CRS man- agement in this patient cohort, as 91.5% (54/59) of pa- tients with CRS received tocilizumab after a median of 4 days. In summary, adipose tissue parameters were associ- ated with an earlier CRS onset but not duration.
Sarcopenia and body composition are neither associated with immune effector cell-associated neurotoxicity syndrome severity nor dynamics
In addition to adipose tissue distribution analyses, whole skeletal muscle mass and psoas muscle mass with re- spective indices (SMI, PMI) were measured for all patients. Twenty-four patients were classified as sarcopenic cor- rected for sex and BMI. Distribution of sarcopenia and muscle masses (SMI, PMI) did not differ between grade ≥2 CRS and grade 0-1 CRS patients (Online Supplementary Table S2). Moreover, muscle parameters did not affect CRS onset or CRS duration. Since CRS represents a risk factor for ICANS,16,17 we also investigated the influence of BC parameters on severity and dynamics of ICANS. How- ever, none of the measured BC parameters differed be- tween patients with grade 0-1 ICANS versus grade ≥2 ICANS nor did they correlate with either ICANS onset or ICANS duration (Online Supplementary Tables S2 and S5).
Adipose tissue correlates with peak IL-6 levels and IL-6 dynamics
In order to better understand the potential pathomechan-
Table 3. Body mass index, waist, waist-to-height ratio and visceral adipose tissue represent independent risk factors for grade ≥2 cytokine release syndrome in a multivariate logistic regression analyses including previously described risk factors.
Odds ratios were calculated based on four separate multivariate lo- gistic regressions for each of the body composition parameters. Com- plete model parameters and estimates are shown in the Online Supplementary Table S6. 95% CI: 95% confidence interval; AUC: area under curve; BMI: body mass index; CRS: cytokine release syndrome; OR: odds ratio; VAT: visceral adipose tissue; WtHR: waist-to-height ratio.
isms that may underlie earlier and more severe CRS in pa- tients with increased adipose tissue, we analyzed serum levels of pro-inflammatory markers and their distribution according to the BC groups.
First, we correlated BC parameters with baseline and peak serum levels of ferritin, CRP and IL-6–revealing an effect for IL-6 in particular (Online Supplementary Figure S6). In- terestingly, peak IL-6 levels were significantly increased in patients with elevated waist circumference (3.442 vs. 1.019 pg/mL, P=0.008), WtHR (3.768 pg/ml vs. 1.385 pg/mL, P=0.03), and VAT (6.530 pg/ml vs. 1.143 pg/ml, P= 0.01) (Fig- ure 4A). A comparison of aggregated median IL-6 courses over time (baseline until day 21) further demonstrated that the median time-to-peak IL-6 was earlier in patients with an increased amount of adipose tissue (Figure 4B). In a comparison of curves accounting for both time and effect size, BMIhigh patients developed an earlier IL-6 peak (5 days vs. 7 days) and the peak was approximately 5-fold higher than in BMIlow patients (top left panel, Figure 4B). The ob- served differences in IL-6 dynamics were especially prominent in patients with excess visceral adipose tissue (peak 11-fold higher, day 4 vs. day 8, P<0.0001, lower right panel, Figure 4B). Notably, patients rich in adipose tissue developed a second IL-6 peak, which occurred between days 19-21 in the WtHRhigh and VAThigh patients (Figure 4B). These results demonstrate that pro-inflammatory cyto- kines such as IL-6 are elevated in patients with abundant visceral fat.
Discussion
The CAR-T-related side effects CRS and ICANS represent a novel toxicity category in the 21st century armentarium of cancer therapy. However, their underlying pathome- chanisms remain incompletely understood. Here, we present the first comprehensive analysis of immunometa- bolically relevant tissues and their impact on CRS and ICANS in patients with advanced B-cell malignancies re- ceiving CAR-T. Our data indicate that increased visceral adipose tissue is associated with CRS severity and early CRS onset. On the other hand, skeletal muscle mass measures did not impact CRS or ICANS occurrence.
The finding that visceral adipose tissue deposits drive dif- ferences in CRS severity is in line with previous reports demonstrating a strong association of VAT with obesity- associated metaflammation and the development of car- diovascular diseases and diabetes.24,25 The ‘obesity paradox’, meaning the unexpected inverse relationship be- tween excess adipose tissue and immunotherapy efficacy, has been established for immune checkpoint blockade both in preclinical models and in cancer patients.40 41 The observed therapeutic benefit in the excess weight popu- lation was further enhanced when immune-related ad-
Body composition parameter
OR
95% CI
P-Value
BMI, kg/m2
1.37
1.02-1.83
0.04
Waist, cm
1.16
1.04-1.29
0.009
WtHR, cm/m2
1.24
1.05-1.46
0.01
VAT, cm2
1.15
1.02-1.3
0.02
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