Aggressive Lymphoma after CD19 CAR T-Cell Therapy.

Christina Schniederjohann, Marc Seifert, Ben-Niklas Baermann, Heiko Trautmann, Schayan Yousefian, Silvana Libertini, Harald J Maier, Peter Ulrich, Jingbo Gao, Aleksandar Radujkovic, Sven G Meuth, Maximilian Seidel, Ron-Patrick Cadeddu, Paul Jäger, Thomas Ulrych, Johannes C Fischer, Jutta M Rox, Malte Jacobsen, Ingram Iaccarino, Frederik Damm, Simon Haas, Raphael Koch, Irene Esposito, Laura Wiegand, Donnacha Fitzgerald, Hans D Menssen, Nagarajan Paramasivam, Monika Brüggemann, Gerald Antoch, Guido Kobbe, Frederik Giesel, Kathrin Nachtkamp, Ulrich Germing, Nora Liebers, Peter-Martin Bruch, Junyan Lu, Sascha Dietrich, Jörg H W Distler, Daniel Hübschmann

Journal: The New England journal of medicine 2024;391(13):1217-1226

PMID: 39589371

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Abstract

The development of a fatal, clonal, autonomously proliferating CD4-CD8- chimeric antigen receptor (CAR)+ peripheral T-cell lymphoma (PTCL) occurred 1 month after a patient received treatment with tisagenlecleucel for relapsed primary central nervous system lymphoma. The PTCL had a clonal T-cell receptor rearrangement, which was already detectable in the apheresis product for CAR T-cell manufacturing and 7 months earlier for autologous transplantation. Somatic and mutations in CD34+ stem cells and their progeny were detected in the PTCL, in the apheresis specimen that was obtained for CAR T-cell production, and in the autotransplant. The PTCL harbored an additional somatic mutation, which was already detectable in the CAR T-cell apheresis product and the final CAR T-cell product at very low frequencies, providing evidence that clonal hematopoiesis had contributed to lymphomagenesis.

Address: From the Department of Hematology, Oncology and Clinical Immunology (G.K., B.-N.B., P.-M.B., N.L., A.R., M. Seifert, C.S., U.G., R.-P.C., K.N., P.J., T.U., S.D.), the Institute of Pathology (M. Seidel, I.E.), the Institute for Transplantation Diagnostics and Cellular Therapy (J.C.F., J.M.R.), the Departments of Nuclear Medicine (F.G.), Rheumatology (J.H.W.D.), and Neurology (S.G.M.), and the Hiller Research Center (J.H.W.D.), University Hospital Düsseldorf, the Center for Integrated Oncology, Aachen-Bonn-Cologne-Düsseldorf (G.K., B.-N.B., P.-M.B., N.L., A.R., M. Seifert, C.S., U.G., R.-P.C., K.N., P.J., T.U., S.D.), and the Department of Diagnostic and Interventional Radiology, University Düsseldorf (G.A.), Düsseldorf, Medical Department II, Hematology and Oncology (M.B., H.T.), and the Department of Pathology (I.I.), University Medical Center Schleswig-Holstein, Kiel, the Department of Hematology, Oncology and Cancer Immunology, Campus Virchow, Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin (L.W., F.D.), Berlin Institute of Health, Charité Universitätsmedizin Berlin (S.Y., S.H.), and Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (S.Y., S.H.), Berlin, the Computational Oncology Group, Molecular Precision Oncology Program, National Center for Tumor Diseases Heidelberg (N.P.), the Innovation and Service Unit for Bioinformatics and Precision Medicine (D.H.), German Cancer Research Center, the European Molecular Biology Laboratory, Molecular Medicine Partnership Unit (D.F.), German Cancer Consortium (D.H., S.H., F.D.), the Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine (D.H.), the Medical Faculty of Heidelberg (J.L.) and the Department of Medicine V (S.D.), Heidelberg University, German Cancer Consortium, partner site Berlin, and German Cancer Research Center (S.H., F.D.), Heidelberg, the Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen (R.K.), and the Department of Internal Medicine I, University Hospital Aachen, RWTH Aachen University, Aachen (M.J.) - all in Germany; and Biomedical Research, Novartis (S.L., P.U.), and Novartis Pharma (H.D.M., H.J.M., J.G.) - both in Basel, Switzerland.

DOI: 10.1056/NEJMoa2402730

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MeSH Terms: Humans, Male, Middle Aged, Central Nervous System Neoplasms, Clonal Hematopoiesis, Immunotherapy, Adoptive, Lymphoma, T-Cell, Peripheral, Mutation, Receptors, Antigen, T-Cell, Receptors, Chimeric Antigen, Antineoplastic Agents, Immunological, DNA Methyltransferase 3A, DNA-Binding Proteins, Dioxygenases, Gene Rearrangement, T-Lymphocyte, Carcinogenesis, Fatal Outcome