CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma

Rejeski K, Perez A, Sesques P, Hoster E, Berger C, Jentzsch L, Mougiakakos D, Frölich L, Ackermann J, Bücklein V, Blumenberg V, Schmidt C, Jallades L, Fehse B, Faul C, Karschnia P, Weigert O, Dreyling M, Locke FL, von Bergwelt-Baildon M, Mackensen A, Bethge W, Ayuk F, Bachy E, Salles G, Jain MD, Subklewe M (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Blood American Society of Hematology

Book Volume: 138

Pages Range: 2499-2513

Journal Issue: 24

DOI: 10.1182/blood.2020010543

Abstract

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell–related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (absolute neutrophil count [ANC] <100 cells per µL) neutropenia in 72% of patients and prolonged (21 days or longer) neutropenia in 64% of patients. The median duration of severe neutropenia (ANC < 500 cells per µL) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary end point. In the training cohort (n = 58), we observed a significant correlation with baseline thrombocytopenia (r = −0.43; P = .001) and hyperferritinemia (r = 0.54; P < .0001) on univariate and multivariate analysis. Incidence and severity of cytokine-release syndrome, immune effector cell–associated neurotoxicity syndrome, and peak cytokine levels were not associated with the primary end point. We created the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (eg, platelet count, hemoglobin, and ANC) and baseline inflammation (eg, C-reactive protein and ferritin). This model was validated in independent cohorts, one from Europe (n = 91) and one from the United States (n = 109) and discriminated patients with severe neutropenia ≥14 days to <14 days (pooled validation: area under the curve, 0.89; sensitivity, 89%; specificity, 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs 5.5 days; P < .001) and a higher incidence of severe thrombocytopenia (87% vs 34%; P < .001) and anemia (96% vs 40%; P < .001). The score implicates bone marrow reserve and inflammation prior to CAR T-cell therapy as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.

Authors with CRIS profile

Dimitrios Mougiakakos Medizinische Fakultät Andreas Mackensen Lehrstuhl für Innere Medizin V

Involved external institutions

Klinikum der Universität München DE Germany (DE) H. Lee Moffitt Cancer Center & Research Institute US United States (USA) (US) Université Claude Bernard Lyon 1 (UCB) FR France (FR) Universitätsklinikum Hamburg-Eppendorf (UKE) DE Germany (DE) Universitätsklinikum Tübingen DE Germany (DE) Deutsches Krebsforschungszentrum (DKFZ) DE Germany (DE)

How to cite

APA:

Rejeski, K., Perez, A., Sesques, P., Hoster, E., Berger, C., Jentzsch, L.,... Subklewe, M. (2021). CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma. Blood, 138(24), 2499-2513. https://doi.org/10.1182/blood.2020010543

MLA:

Rejeski, Kai, et al. "CAR-HEMATOTOX: a model for CAR T-cell–related hematologic toxicity in relapsed/refractory large B-cell lymphoma." Blood 138.24 (2021): 2499-2513.

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