The classification of peripheral T-cell lymphomas (PTCL) is constantly changing and contains multiple subtypes. Here, we focus on Tfh-like PTCL, to which angioimmunoblastic T-cell lymphoma (AITL) belongs, according to the last WHO classification. The first-line treatment of these malignancies still relies on chemotherapy but gives very unsatisfying results for these patients. Enormous progress in the last decade in terms of understanding the implicated genetic mutations leading to signaling and epigenetic pathway deregulation in Tfh PTCL allowed the research community to propose new therapeutic approaches. These findings point towards new biomarkers and new therapies, including hypomethylating agents, such as azacytidine, and inhibitors of the TCR-hyperactivating molecules in Tfh PTCL. Additionally, metabolic interference, inhibitors of the NF-κB and PI3K-mTOR pathways and possibly novel immunotherapies, such as antibodies and chimeric antigen receptors (CAR) directed against Tfh malignant T-cell surface markers, are discussed in this review among other new treatment options.

Purpose of reviewAngioimmunoblastic T-cell lymphoma (AITL) is a frequent peripheral T-cell lymphoma affecting elderly patients with a poor outcome when treated with conventional chemotherapy. Molecular studies revealed a homogenous mutational landscape gathering anomalies in genes regulating the DNA methylation and hydroxymethylation and anomalies in T-cell signalling. Recent findingsRecent studies indicate that AITL emerges from a TET2 and/or DNMT3A mutated clonal haematopoiesis. This clonal haematopoiesis bearing mutations altering DNA hydroxymethylation can explain the observed coexistence of AITL with myeloid neoplasms. In addition, AITL development requires AITL-specific mutations, such as the RHOA G17V mutations. Combination of TET2 and RHOA G17V alterations results in the development of AITL-like disease in mouse models. The impact of the presence of these mutations on patient outcome seems limited and new biological factor predicting treatment response and survival remains to be determined. At the therapeutic level, therapies targeting epigenetic changes, such as histone deacetylase inhibitors and the hypomethylating 5-azacytidine agent, could have efficacy in this disease and gave promising results. Recent progress in mouse model development should allow development of new treatments. SummaryEpigenetic changes are frequent in AITL and could be a promising target.

Background:TFH lymphomas (TFH PTCL) constitute the most frequent non-cutaneous PTCL entity and are characterized by chemoresistance and a poor prognosis. The main obstacles in therapeutic innovations are the rarity of the disease, the difficulty of diagnosis, and the lack of relevant in vitro/in vivo models which make preclinical studies laborious to perform. 5-azacytidine is a hypomethylating agent associated with prolonged survival (Dupuis et al. ASH2022) in relapsed or refractory TFH PTCL patients, but biomarkers of response and synergistic therapeutic combinations are unknown. Patient-Derived Xenograft (PDX) mouse model allow performing preclinical studies in various cancers, but data on TFH PTCL PDX, and how they recapitulate the patient sensitivity to the drug are limited.