Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use
Veit Bücklein,
Ariel Perez,
Kai Rejeski,
Gloria Iacoboni,
Vindi Jurinovic,
Udo Holtick,
Olaf Penack,
Soraya Kharboutli,
Viktoria Blumenberg,
Josephine Ackermann,
Lisa Frölich,
Grace Johnson,
Kedar Patel,
Brian Arciola,
Rahul Mhaskar,
Anthony Wood,
Christian Schmidt,
Omar Albanyan,
Philipp Gödel,
Eva Hoster,
Lars Bullinger,
Andreas Mackensen,
Frederick Locke,
Michael von Bergwelt,
Pere Barba,
Marion Subklewe,
Michael D. Jain
Affiliations
Veit Bücklein
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Ariel Perez
3 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
Kai Rejeski
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Gloria Iacoboni
6 Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Department of Medicine, Universitat Autònoma of Barcelona (UAB), Spain
Vindi Jurinovic
7 Institute for Medical Information Processing, Biometry, and Epidemiology, LMU Munich, Germany
Udo Holtick
8 Department I of Internal Medicine, Medical Faculty and University Hospital, Cologne, University of Cologne, Germany
Olaf Penack
9 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
Soraya Kharboutli
10 Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany
Viktoria Blumenberg
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Josephine Ackermann
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Lisa Frölich
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Grace Johnson
11 USF Health Morsani College of Medicine, Tampa, FL, USA
Kedar Patel
11 USF Health Morsani College of Medicine, Tampa, FL, USA
Brian Arciola
11 USF Health Morsani College of Medicine, Tampa, FL, USA
Rahul Mhaskar
11 USF Health Morsani College of Medicine, Tampa, FL, USA
Anthony Wood
3 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
Christian Schmidt
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Omar Albanyan
3 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
Philipp Gödel
8 Department I of Internal Medicine, Medical Faculty and University Hospital, Cologne, University of Cologne, Germany
Eva Hoster
7 Institute for Medical Information Processing, Biometry, and Epidemiology, LMU Munich, Germany
Lars Bullinger
9 Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
Andreas Mackensen
10 Department of Internal Medicine 5, Hematology and Oncology, University of Erlangen-Nuremberg, Germany
Frederick Locke
3 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
Michael von Bergwelt
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Pere Barba
6 Department of Hematology, Vall d’Hebron Institute of Oncology (VHIO), University Hospital Vall d’Hebron, Department of Medicine, Universitat Autònoma of Barcelona (UAB), Spain
Marion Subklewe
1 Department of Medicine III, University Hospital, LMU Munich, Germany
Michael D. Jain
3 Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, FL, USA
Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.
