CD19-directed chimeric antigen receptor (CAR) T cells have evolved as new standard-of-care (SOC) treatment in patients with relapsed/refractory large B-cell lymphoma (LBCL). Here, we report the first German real-world data on SOC CAR-T cell therapies with the aim to explore risk factors associated with outcome. Patients who received SOC axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for LBCL and were registered with the German Registry for Stem Cell Transplantation (DRST) were eligible. Main outcomes analyzed were toxicities, response, overall survival (OS), and progression-free survival (PFS). We report 356 patients who received axi-cel (n=173) or tisa-cel (n=183) between November 2018 and April 2021 at 21 German centers. Whereas the axi-cel and tisa-cel cohorts were comparable for age, sex, LDH, IPI, and pretreatment, the tisa-cel group comprised significantly more patients with poor performance status, ineligibility for ZUMA-1, and need for bridging, respectively. With a median follow-up alive of 11 months, Kaplan-Meier estimates of OS, PFS, and non-relapse mortality (NRM) 12 months after dosing were 52%, 30%, and 6%, respectively. While NRM was largely driven by infections subsequent to prolonged neutropenia and/or severe neurotoxicity and significantly higher with axi-cel, significant risk factors for PFS on multivariate analysis included bridging failure, elevated LDH, age, and tisa-cel use. In conclusion, this study suggests that important outcome determinants of CD19-directed CAR-T cell treatment of LBCL in the real-world setting are bridging success, CAR-T product selection, LDH, and the absence of prolonged neutropenia and/or severe neurotoxicity. These findings may have implications for designing risk-adapted CAR-T cell therapy strategies.

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We investigated whether outcome prediction of aggressive B-cell lymphoma patients can be improved by combining clinical, molecular genotype and radiomics features. MYC, BCL2 and BCL6 rearrangements were assessed using fluorescence in situ hybridization. Seventeen radiomics features were extracted from the baseline PET/CT of 323 patients: maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume (MTV), total lesion glycolysis and 12 dissemination features pertaining to distance, differences in uptake and volume between lesions, respectively. Logistic regression with backward feature selection was used to predict progression after 2 years. The predictive value of 1) international prognostic index (IPI), 2) IPI+MYC (wild type, single hit or double/triple hit), 3) IPI, MYC and MTV, 4) radiomics and 5) MYC+radiomics models was tested using the cross-validated area under the curve (CV-AUC) and positive predictive values (PPV). IPI yielded a CV-AUC of 0.65±0.07 with a PPV of 29.6%. The IPI+MYC model yielded a CV-AUC of 0.68±0.08. IPI, MYC and MTV yielded a CV-AUC of 0.74±0.08. The highest model performance of the radiomics model was observed for MTV combined with the maximum distance between the largest lesion and another lesion, the maximum difference in SUVpeak between 2 lesions and the sum of distances between all lesions, yielding an improved CV-AUC of 0.77±0.07. The same radiomics features were retained when adding MYC (CV-AUC:0.77±0.07). PPV was highest for the MYC+radiomics model (50.0%) and increased with 20% compared to the IPI (29.6%). Adding radiomics features improved model performance and PPV and can therefore aid in identifying poor prognosis patients.

Introduction Patients with hematologic disease are at high risk of morbidity and mortality from COVID‐19 due to disease‐inherent and therapy‐related immunodeficiency. Whether infection with the SARS‐CoV2 omicron variant leads to attenuated disease severity in these patients is currently unknown. Methods We assessed clinical and laboratory parameters in 61 patients with underlying hematologic conditions with a SARS‐CoV2 omicron variant infection confirmed by nucleic acid amplification testing. Results Fifty patients reported symptoms of COVID‐19, most commonly fatigue (37 patients, 60.66%) and cough (32 patients, 52.46%). 39.34% of patients reported fever. Dyspnea was reported by 10 patients and 7 patients (11.48%) required oxygen therapy. Anosmia and ageusia were relatively rare, occurring in less than 10% of patients. Severity of SARS‐CoV2 infection could be assessed in 60 patients. Five cases of critical illness leading to ICU admission occurred during the observation period. Overall mortality was 9.84% in this patient cohort, with heterogeneous causes of death. The majority of omicron‐infected hematologic patients experienced mild symptoms or remained asymptomatic. Discussion In this study, symptoms of COVID‐19 tended to be milder than described for previous SARS‐CoV2 variants. However, the extent to which attenuated severity of omicron‐variant SARS‐CoV2 infection is caused by altered viral pathogenicity or pre‐existing host immunity cannot be inferred from our data and should be investigated in larger prospective studies.

The objective of this study was to externally validate the clinicalPET model developed in the HOVON-84 trial and to compare the model performance of our clinicalPET model to the international prognostic index (IPI). In total, 1195 Diffuse large B-cell lymphoma patients were included. 887 patients from 6 studies were used as external validation datasets. Primary outcomes were 2-year progression free survival (PFS) and 2-year time to progression (TTP). Metabolic tumor volume (MTV), the maximum distance between the largest lesion and another lesion (Dmaxbulk) and the peak standardized uptake value (SUVpeak) were extracted. The predictive value of the IPI and the HOVON-84 clinicalPET model (MTV, Dmaxbulk, SUVpeak, performance status and age) were tested. Model performance was assessed using the area under the curve (AUC), and diagnostic performance with the positive predictive value (PPV). Using 2-year PFS as outcome, the IPI yielded an AUC of 0.62 (range:0.51-0.65). The clinicalPET model yielded a significantly higher AUC of 0.71 (range:0.59-0.75, p<0.001). Comparable results were found using 2-year TTP. High-risk IPI patients had a 2-year PFS of 61.4%, versus 51.9% for the high-risk clinicalPET patients, with an increase in PPV from 35.5% to 49.1%, respectively. 66.4% of high-risk IPI patients were free from progression or relapse versus 55.5% for high-risk clinicalPET patients, with an increased PPV from 33.7% to 44.6%, respectively. The clinicalPET model that was developed in the HOVON-84 dataset remained predictive of outcome in 6 independent first-line DLBCL studies, and had higher model performance than the currently used IPI in all studies.