A comprehensive review of T-cell lymphoma following CAR T-cell immunotherapy.

abstractAlthough chimeric antigen receptor (CAR) T-cell therapy provides a potential cure for patients with non-Hodgkin B-cell lymphomas/leukemias and plasma cell myelomas, rare reports of the development of T-cell lymphomas (TCLs) in these patients have raised serious safety concerns regarding whether CAR T-cell therapy could directly contribute to the development of TCLs in a specific patient or in patients with certain types of underlying hematologic malignancies. This review aims to comprehensively evaluate the clinicodemographic features, types of TCLs, immunophenotypic characteristics, mutational profiles, and CAR T-cell transgene expression status within the lymphoma cells, as well as explore the underlying mechanisms of lymphomagenesis. A special focus is placed on the interplay between preexisting clonal hematopoiesis, immune dysregulation, and reported genomic alterations that may predispose to and/or drive T-cell lymphomagenesis. Among the total 18 reported cases, TCLs developed in patients with all types of underlying hematologic malignancies and occurred after treatment with all types of widely used commercial CAR T-cell products. Most TCLs showed aberrant T-cell phenotypes according to CD4 and/or CD8 expression. The infused CAR T-cell transgene in lymphoma cells was detected in 63% (10/16) of cases, and 73% (8/11) of cases showed the integration of the CAR transgene into a known tumor suppressor gene or oncogene. At the molecular genomic level, mutations involved in epigenetic regulators (TET2 and DNMT3A) and JAK-STAT signaling pathway, especially JAK3 mutation, were often detected. The potential mechanisms of T-cell lymphomagenesis were complex and multifactorial, including but not limited to preexisting clonal hematopoiesis of indeterminate potential, malignant transformation of CAR T cells, and lymphodepletion chemotherapy.