Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included (n = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade ≥ 2 (both p = 0.04), and the EASIX approached statistical significance at infusion (p = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61–0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade ≥ 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade ≥ 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade ≥ 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment.

Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (< 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients (p < 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP (p = 0.041) and OS (p = 0.015), compared to patients with a high pre-LD MATV (> 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens.

Normal tissue complication probability (NTCP) models can be used to guide radiation therapy (RT) decisions by estimating side-effect risks pretreatment to minimize (late) side-effects. Recently, a comprehensive individual toxicity risk (CITOR) profile of NTCP models addressing common side-effects in head and neck cancer (HNC) patients was developed. This study investigates the generalizability of these models in an international setting, with different treatment approaches and side-effect assessments, promoting their integration into more widespread clinical practice. From a prospective registry study, 407 HNC patients were included who were treated with definitive RT with or without systemic therapy between 2015 and 2022. NTCP models predicting dysphagia, aspiration, xerostomia, sticky saliva, taste loss, speech problems, oral pain, and fatigue at 6 and 12 months after RT were evaluated. All side-effects were patient-rated using the MDASI-HN, except dysphagia which was reported by clinicians using the PSS-HN diet normalcy score. Model performance was appraised by discrimination (area under the curve [AUC]) and calibration. CITOR models showed moderate-to-high performance in this cohort (mean AUC = 0.67[range = 0.55-0.80], moderate-to-good calibration). NTCP models for dysphagia, xerostomia, sticky saliva, and fatigue were the top performing models. Models for aspiration, taste loss and speech problems performed moderately well, which was partly explained by lower incidences. Despite differences between the CITOR development and this evaluation cohort, including use of different side-effect scoring systems, most models exhibited moderate-to-high performance. This demonstrated that the dose-effect relations were generalizable. Therefore, this study supports further integration of these NTCP models in clinical practice.

Early identification of patients at risk of immune effector cell–associated hematotoxicity (ICAHT) is essential to minimize nonrelapse mortality. The CAR-HEMATOTOX (HT) score is an implemented risk-stratification tool for ICAHT, infections, and survival in patients with relapsed/refractory large B-cell lymphoma (R/R LBCL) receiving chimeric antigen receptor T-cell therapy (CART). Although validated in its defining study, the HT score was developed in a small cohort, necessitating independent external validation. This study externally validates the HT score in a real-world population-based cohort of adults with R/R LBCL receiving CART. The HT score, based on absolute neutrophil count (ANC), hemoglobin, platelets, C-reactive protein, and ferritin, was calculated before lymphodepleting chemotherapy. Of 245 consecutive patients, 171 (70%) had an HT score of ≥2 (HThigh). The initial end point, clinically significant neutropenia (ANC of <500/μL for ≥14 days), occurred in 21% of patients. The binary HT score was associated with clinically significant neutropenia (odds ratio [OR], 2.94; 95% confidence interval [CI], 1.27-6.80; P = .012) with a good predictive performance (area under the curve = 0.73). Similar results were achieved for early and late ICAHT grade ≥3 (OR, 2.92; 95% CI, 1.19-7.14; P = .019; and OR, 2.42; 95% CI, 1.31-4.47; P = .005). A trend toward an association with severe infections was observed (OR, 2.02; 95% CI, 0.91-4.48; P = .085). HThigh patients had a lower progression-free and overall survival (hazard ratio [HR], 1.84; 95% CI, 1.15-2.93; P = .011; and HR, 2.83; 95% CI, 1.64-4.87; P < .001, respectively). The HT score identified CART-treated patients with R/R LBCL at risk of clinically significant neutropenia, poor survival outcomes, and potentially severe infections.

Chimeric antigen receptor T-cell therapy (CART) has revolutionized the treatment of patients with refractory/relapsed large B-cell lymphoma (R/R LBCL). Limited biopsy data indicate that a higher activated CD8⁺ T-cell density is associated with tumor response. However, tumor biopsies fail to capture the systemic kinetics of CD8⁺ T-cells. Therefore, we conducted an exploratory phase 2 single-arm trial utilizing a zirconium-89-labeled one-armed anti-CD8α antibody (⁸⁹ZED88082A) to enable whole-body imaging of CD8⁺ T-cells through positron emission tomography (PET) (NL9034; EUCTR2020-004749-35-NL). Imaging analysis was performed in 23 patients with R/R LBCL, encompassing 251 lesions before (pre-CART) and after infusion (post-CART). Primary endpoint was to determine the whole-body distribution of the tracer in normal and tumor tissues before and after CART. ⁸⁹ZED88082A uptake in normal tissues varied over time. Tumor uptake was heterogeneous between and within patients. At the lesion level, higher pre-CART ⁸⁹ZED88082A tumor uptake was associated with higher post-CART tumor uptake at day +2. As secondary endpoints, no tracer-related side effects occurred and above median pre-CART ⁸⁹ZED88082A tumor uptake was associated with a longer time to progression, while lesions that relapsed exhibited consistently low uptake. Exploratory analysis showed a 42% tumor volume reduction from pre-CART to post-CART day +7. In conclusion, ⁸⁹ZED88082A has the potential to detect lesions at risk for progression and worse patient outcome, emphasizing the critical role of a CD8-permissive tumor microenvironment.