From molecular pathogenesis to novel Therapeutic approaches - a review of recent advances in the treatment of peripheral T cell Lymphomas.

Peripheral T-cell lymphomas (PTCLs) comprise approximately 30 distinct subtypes, collectively accounting for around 10-20% of all non-Hodgkin lymphomas, with a geographic distribution that is more predominant in East Asia and South America. They differ significantly in tumor biology, microenvironmental composition, and chemosensitivity. Standard frontline therapy remains anthracycline-based regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone). With the exception of ALK+ anaplastic large cell lymphoma (ALCL), such treatments typically yield poor clinical outcomes in most histological subtypes. Oncogenesis in PTCL is driven by a convergence of genetic and epigenetic aberrations, T-cell receptor (TCR) signaling dysregulation and microenvironmental remodeling. Together, they disrupt the balance between cell survival and apoptosis, leading to malignant transformation. Advances in molecular characterization have started to shed light on subtype-specific oncogenic targets, thus allowing for rational development of targeted therapies. A major recent breakthrough was the landmark ECHELON-2 trial, which has led to the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, which in combination with CHP (cyclophosphamide, doxorubicin and prednisolone) has become the standard of care for CD30-positive PTCLs. Beyond brentuximab, novel therapeutic agents targeting various aspects of PTCL lymphomagenesis are under active investigation, with some already entering routine clinical practice. Epigenetic modifiers including HDAC inhibitors, hypomethylating agents, and EZH2 inhibitors exploit the epigenetic dysregulation characteristic of T-follicular helper cell-derived lymphomas. In addition, small molecule inhibitors targeting JAK-STAT, PI3K, and ALK pathways, as well as immunotherapy strategies such as monoclonal antibodies, bispecific antibodies, checkpoint inhibitors, and CAR-T cell therapy, are also in varying stages of clinical development. An area of unmet clinical need is the increasing prevalence of PTCL in older patients, where treatment toxicity is a major consideration, and where such tailored treatment might yield the greatest benefit.