Aggressive Lymphoma after CD19 CAR T-Cell Therapy

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

doi:10.1056/NEJMoa2402730

Aggressive Lymphoma after CD19 CAR T-Cell Therapy

N Engl J Med. 2024 Oct 3;391(13):1217-1226. doi: 10.1056/NEJMoa2402730.

Authors

Guido Kobbe¹, Monika Brüggemann¹, Ben-Niklas Baermann¹, Laura Wiegand¹, Heiko Trautmann¹, Schayan Yousefian¹, Silvana Libertini¹, Hans D Menssen¹, Harald J Maier¹, Peter Ulrich¹, Jingbo Gao¹, Peter-Martin Bruch¹, Nora Liebers¹, Aleksandar Radujkovic¹, Marc Seifert¹, Christina Schniederjohann¹, Nagarajan Paramasivam¹, Donnacha Fitzgerald¹, Maximilian Seidel¹, Irene Esposito¹, Ulrich Germing¹, Ron-Patrick Cadeddu¹, Kathrin Nachtkamp¹, Paul Jäger¹, Thomas Ulrych¹, Johannes C Fischer¹, Jutta M Rox¹, Frederik Giesel¹, Raphael Koch¹, Gerald Antoch¹, Jörg H W Distler¹, Sven G Meuth¹, Malte Jacobsen¹, Daniel Hübschmann¹, Junyan Lu¹, Ingram Iaccarino¹, Simon Haas¹, Frederik Damm¹, Sascha Dietrich¹

Affiliation

¹ 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.

PMID: 39589371
DOI: 10.1056/NEJMoa2402730

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 DNMT3A and TET2 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 TET2 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.

Publication types

Case Reports

MeSH terms

Antineoplastic Agents, Immunological* / administration & dosage
Antineoplastic Agents, Immunological* / adverse effects
Carcinogenesis / drug effects
Carcinogenesis / genetics
Carcinogenesis / immunology
Central Nervous System Neoplasms* / drug therapy
Central Nervous System Neoplasms* / immunology
Clonal Hematopoiesis / drug effects
Clonal Hematopoiesis / immunology
DNA Methyltransferase 3A / genetics
DNA-Binding Proteins / genetics
Dioxygenases / genetics
Fatal Outcome
Gene Rearrangement, T-Lymphocyte / genetics
Gene Rearrangement, T-Lymphocyte / immunology
Humans
Immunotherapy, Adoptive* / adverse effects
Lymphoma, T-Cell, Peripheral* / blood
Lymphoma, T-Cell, Peripheral* / diagnosis
Lymphoma, T-Cell, Peripheral* / genetics
Lymphoma, T-Cell, Peripheral* / immunology
Male
Middle Aged
Mutation
Receptors, Antigen, T-Cell* / administration & dosage
Receptors, Antigen, T-Cell* / agonists
Receptors, Chimeric Antigen / analysis
Receptors, Chimeric Antigen / immunology
Receptors, Chimeric Antigen / metabolism

Substances

Receptors, Antigen, T-Cell
Receptors, Chimeric Antigen
tisagenlecleucel
Antineoplastic Agents, Immunological
DNMT3A protein, human
DNA Methyltransferase 3A
TET2 protein, human
DNA-Binding Proteins
Dioxygenases

Abstract

Publication types

MeSH terms

Substances

Grants and funding