Page 98 - Haematologica Vol. 107 - September 2022

ARTICLE - Body composition impacts CRS after CAR-T therapy D.M. Cordas dos Santos et al.
facilitate CRS development. These include high tumor burden, concomitant and previous infections, increased C- reactive protein (CRP) or ferritin, and thrombocytopenia.7-11 While CRS represents a prevalent CAR-T-associated toxic- ity, the wide-spread adoption of risk-adapted supportive measures has reduced the frequency of its high-grade presentation. Still, the systemic hyperinflammation found in CRS can predispose for the neurological side effects of CAR-T, which remain a major clinical challenge. Immune effector cell-associated neurotoxicity syndrome (ICANS) is found in approximately 20-60% of CAR-T-treated pa- tients and presents with symptoms ranging from mild confusion to aphasia, seizures, cerebral edema, and po- tentially death.12-14 Patient-associated and dynamic risk factors that predispose for ICANS include prior neurologic diseases and structural impairments, organ dysfunction, older age and severe CRS.15-17 High-grade ICANS has also been linked to higher peak levels of systemic cytokines and inflammatory mediatiors (e.g., CRP, ferritin and IL-6),8 and a lower median peak absolute monocyte count.18
In other hyperinflammatory states including COVID-19 or influenza infections, as well as sepsis, obesity has been demonstrated to be a risk factor for disease severity.19-21 Amongst the underlying mechanisms, obesity-associated chronic systemic inflammation, termed metaflammation, has been proposed to enhance an hyperinflammatory im- mune response, which precedes organ dysfunction.22 Mechanistically, macrophages and CD8+ T cells can infil- trate fat deposits turning adipose tissue into an inflam- matory endocrine organ secreting pro-inflammatory cytokines such as IL-6, TNF-a and IL-1b.23 Various adipose tissue sites differentially contribute to metaflammation: visceral adipose tissue (VAT) in particular plays an impor- tant role in metaflammation and obesity-associated pa- thologies such as type II diabetes and cardiovascular diseases.24,25 Epicardial adipose tissue (EAT) has been de- scribed as a surrogate marker of VAT and, in turn, as a marker for cardiovascular and metabolic morbidity.26,27 In contrast, subcutaneous adipose tissue (SAT) displays a more heterogeneous effect on systemic inflammatory processes.28,29
More recently, skeletal muscle has also been recognized as a regulator of immune responses.30,31 Skeletal muscle cells modulate immune function by signaling through muscle cell-derived cytokines, termed myokines, cell sur- face molecules and cell-to-cell interactions. Myokines such as IL-6, IL-7 and IL-15 can modulate CD8+ T-cell ho- meostasis and promote survival and proliferation of naïve T and B cells.32-35 Sarcopenia, which describes the loss of skeletal muscle as a consequence of old age and cancer, is often found in cancer patients and has been linked to immune senescence.30
Despite rapidly growing evidence that adipose and muscle tissue play an important role in shaping immune re-
sponses, the influence of body composition in the context of CAR-T therapy remains poorly understood. Therefore, we aimed to investigate the impact of body composition on severity and dynamics of CRS and ICANS, as well as serum cytokine levels.
Methods
Patient cohort
We performed a retrospective chart review of R/R large B-cell lymphoma (LBCL), B-cell precursor acute lympho- blastic leukemia (BCP-ALL) and mantle cell lymphoma (MCL) patients who underwent CAR-T at the University Hospital of the LMU Munich between 01/2019 until 08/2021. Patients received the commercial CAR-T prod- ucts Axicabtagene ciloleucel (Axi-cel), Tisagenlecleucel (Tisa-cel), or received KTE-X19 in the compassionate use program for MCL. Patients received lymphodepleting chemotherapy (LDC) with fludarabine and cyclophospha- mide according to the manufacturers’ instructions.2,3 CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) consen- sus criteria.6 All patients were closely monitored prospec- tively for CRS and ICANS from the day of CAR-T transfusion until at least day 21, or until symptoms re- solved. Swimmers plots were generated via day-by-day recording of ASTCT grade according to the treating phys- icians’ discretion (Online Supplementary Figures S1 and S2). Heat maps were generated by cross-sectional analy- sis of the mean CRS/ICANS grade between days 0-21. Toxicity management followed institutional guidelines. Pa- tients with CRS grade ≥2 and persistent CRS grade 1 (>24 hours) were treated with the anti-IL-6 receptor antagonist tocilizumab. In the absence of concurrent CRS or if ICANS was refractory to anti-cytokine therapy, corticosteroids were initiated for grade ≥2 ICANS. Clinical metadata was obtained with Institutional Review Board approval and in- cluded a waiver of informed consent.
Measurements of body composition
Body composition (BC) analyses were performed using clinical records (weight, height) and computerized tomog- raphy (CT) scans (waist, adipose/muscle tissue distribu- tion) obtained prior to CAR-T transfusion. The majority of patients received CT imaging on the day before LDC initi- ation (median imaging to LDC time -1 day, interquartile range [IQR] -4 to 0 days). Three anthropometric measures were included: body mass index (BMI), waist circumfer- ence (waist) and waist-to-height ratio (WtHR). Waist was derived from single CT slices.36 WtHR was calculated by dividing waist by height. For quantification of SAT, VAT and muscle tissue distribution (psoas muscle index [PMI] and skeletal muscle index [SMI]), segmentation analyses of
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