SOHO State of the Art Updates and Next Questions | Beyond Romidepsin: Novel Therapeutic Targets and Emerging...

Peripheral T-cell lymphomas (PTCLs) represent heterogeneous aggressive non-Hodgkin lymphomas with dismal outcomes in the relapsed/refractory (R/R) setting. Following romidepsin's withdrawal from the R/R PTCL indication in 2021, the only FDA-approved agents are belinostat and pralatrexate, and Brentuximab Vedotin. Median overall survival following relapse is approximately 5.8 months, highlighting the urgent need for effective therapies. Novel agents targeting distinct molecular pathways demonstrate promising activity. PI3K inhibitors, particularly duvelisib, achieved an ORR of 48% (complete response [CR] 33%) in the PRIMO trial. EZH2 inhibitors represent a mechanistically novel class: valemetostat produced an ORR of 43.7% with a median duration of response of 11.9 months. JAK/STAT inhibitors, including golidocitinib (ORR 44.3%) and cerdulatinib (ORR 51.9% in AITL/TFH), show subtype-selective activity. Rational combinations yield superior efficacy: duvelisib plus romidepsin achieved ORR of 56% (CR 44%), while azacitidine combined with romidepsin produced ORR of 61% (CR 48%), particularly in TFH-phenotype disease (ORR 80%). DR-01, an anti-CD94 monoclonal antibody, represents a novel approach for cytotoxic T-cell lymphomas. A consistent pattern emerges: agents targeting epigenetic mechanisms demonstrate pronounced activity in nodal TFH lymphoma subtypes characterized by TET2, DNMT3A, and RHOA mutations. The Ro-CHOP trial's failure in unselected populations, contrasted with efficacy signals in nTFHL subsets, underscores a critical lesson: PTCL is not one disease, and future trial designs must incorporate biomarker-driven enrichment strategies to advance precision therapeutics. Improved outcomes can be expected as we decipher more of the targetable dysfunctional molecular pathways in this group of lymphomas.