A Comprehensive Review of T-Cell Lymphoma Following CAR T-Cell Immunotherapy.

While chimeric antigen receptor (CAR) T-cell therapy provides potential cure for patients with non-Hodgkin B-cell lymphomas/leukemias and plasma cell myelomas, rare reports of development of T-cell lymphomas(TCLs) in these patients have raised serious safety concerns with regard to whether CAR T-cell therapy could directly contribute to the development of TCLs in a specific patient or in those with certain types of underlying hematologic malignancy. This review aims to comprehensively evaluate the clinicodemographic features, types of TCLs, immunophenotypic characteristics, mutational profiles, and CAR-T 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 the pre-existing clonal hematopoiesis, immune dysregulation, and reported genomic alterations that may predispose to and/or drive T-cell lymphomagenesis. Among the total 18 reported cases, they developed in all types of underlying hematologic malignancies, and they occurred in all types of widely used commercial CAR T-cell products. The majority of the TCLs showed aberrant T-cell phenotypes according to CD4 and/or CD8 expression. The infused CAR-T transgene from lymphoma cells was detected in 63%(10/16) cases, and 73%(8/11) cases showed 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 pre-existing clonal hematopoiesis of indeterminate potential genes, malignant transformation of CAR T-cells, and lymphodepletion chemotherapy.