Ergebnisse der CAR-T-Zelltherapie am Zentrum für zelluläre Therapie des Universitätsklinikums Tübingen: Eine retrospektive Analyse

Diese Arbeit stellt erste klinische Ergebnisse der CAR-T-Zelltherapie am Zentrum für zelluläre Therapie des Universitätsklinikums Tübingen in Form einer retrospektiven Analyse dar. Dafür wurden die ersten Patienten, die am UKT mit CAR-T-Zellen behandelt wurden, bezüglich ihres Ansprechens, der Nebenwirkungen und Toxizitäten der CAR-T-Zelltherapie sowie des Gesamt- und progressionsfreien Überlebens beobachtet und statistisch ausgewertet. Die CAR-T-Zelltherapie ist eine Therapie, bei der körpereigene T-Zellen mittels eines Vektors in vitro mit einem chimärischen Antigen-Rezeptor ausgestattet werden und nach Rückgabe diese T-Zellen in vivo die Tumorzellen angreifen und bekämpfen sollen. Die Patienten dieser Arbeit, die mit CAR-T-Zellen behandelt wurden, litten unter einer malignen lymphatischen Neoplasie und zeigten eine wiederholte refraktäre Erkrankung nach den bisherigen Standardtherapien. Die Ergebnisse dieser Arbeit zeigen, dass die CAR-T-Zelltherapie bei Patienten mit lymphatischen Neoplasien der B-Zell-Reihe eine hohe Ansprechrate und ein verlängertes progressionsfreies Überleben und Gesamtüberleben erzielt. Gleichzeitig zeigt diese Arbeit das hohe Auftreten ausgeprägter Toxizitätssyndrome und Nebenwirkungen der CAR-T-Zelltherapie. Die hohen Ansprechraten bei Patienten, die nach den bisherigen Standardtherapien therapierefraktär sind und eine sehr schlechte Prognose haben, illustriert das große Potential der CAR-T-Zelltherapie und sollte somit einen hohen Stellenwert in den zukünftigen Therapieentwicklungen haben

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL

Hematologic neoplasms; Receptors; Chimeric antigenNeoplasias hematológicas; Receptores; Antígeno quiméricoNeoplàsies hematològiques; Receptors; Antigen quimèricBackground CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score—composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)—enables risk stratification of hematological toxicity. Methods In this multicenter retrospective analysis, we characterized early infection events (days 0–90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates. Results In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HThigh patients more frequently developed severe infections (40% vs 8%, p<0.0001)—particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HThigh (16% vs 46%, p<0.001), but not HTlow patients (0% vs 2%, p=n.s.). Collectively, HThigh patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HThigh patients was observed (8.0% vs 3.7%, p=0.09). Conclusions These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse.This work was supported by a Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) research grant provided within the Sonderforschungbereich SFB-TRR 388/1 2021-452881907, and DFG research grant 451580403 (to MS). The work was further supported by the Bavarian Elite Graduate Training Network (to MS), the Wilhelm-Sander Stiftung (to MS, project no. 20180871), the Else-Kröner-Fresenius Stiftung (to MS), and the Bavarian Center for Cancer Research (BZKF)

The CAR-HEMATOTOX risk-stratifies patients for severe infections and disease progression after CD19 CAR-T in R/R LBCL

BACKGROUND: CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) represents a promising treatment modality for an increasing number of B-cell malignancies. However, prolonged cytopenias and infections substantially contribute to the toxicity burden of CAR-T. The recently developed CAR-HEMATOTOX (HT) score-composed of five pre-lymphodepletion variables (eg, absolute neutrophil count, platelet count, hemoglobin, C-reactive protein, ferritin)-enables risk stratification of hematological toxicity. METHODS: In this multicenter retrospective analysis, we characterized early infection events (days 0-90) and clinical outcomes in 248 patients receiving standard-of-care CD19 CAR-T for relapsed/refractory large B-cell lymphoma. This included a derivation cohort (cohort A, 179 patients) and a second independent validation cohort (cohort B, 69 patients). Cumulative incidence curves were calculated for all-grade, grade ≥3, and specific infection subtypes. Clinical outcomes were studied via Kaplan-Meier estimates. RESULTS: In a multivariate analysis adjusted for other baseline features, the HT score identified patients at high risk for severe infections (adjusted HR 6.4, 95% CI 3.1 to 13.1). HT(high) patients more frequently developed severe infections (40% vs 8%, p<0.0001)-particularly severe bacterial infections (27% vs 0.9%, p<0.0001). Additionally, multivariate analysis of post-CAR-T factors revealed that infection risk was increased by prolonged neutropenia (≥14 days) and corticosteroid use (≥9 days), and decreased with fluoroquinolone prophylaxis. Antibacterial prophylaxis significantly reduced the likelihood of severe bacterial infections in HT(high) (16% vs 46%, p<0.001), but not HT(low) patients (0% vs 2%, p=n.s.). Collectively, HT(high) patients experienced worse median progression-free (3.4 vs 12.6 months) and overall survival (9.1 months vs not-reached), and were hospitalized longer (median 20 vs 16 days). Severe infections represented the most common cause of non-relapse mortality after CAR-T and were associated with poor survival outcomes. A trend toward increased non-relapse mortality in HT(high) patients was observed (8.0% vs 3.7%, p=0.09). CONCLUSIONS: These data demonstrate the utility of the HT score to risk-stratify patients for infectious complications and poor survival outcomes prior to CD19 CAR-T. High-risk patients likely benefit from anti-infective prophylaxis and should be closely monitored for potential infections and relapse