High HDAC I/IIb selective inhibitor purinostat mesylate in relapsed and refractory peripheral T-cell lymphoma: A single-agent phase IIa study

Abstract Background Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas associated with poor survival outcomes. Relapsed or refractory (R/R) PTCLs have an even worse prognosis, with historically reported median overall survival (mOS) of less than 6 months. Current monotherapies yield only modest overall response rates (ORR) ranging from 22% to 38%, except for brentuximab vedotin in CD30-positive anaplastic large cell lymphoma (ALCL). Purinostat Mesylate (PM) is a highly selective HDAC I/IIb inhibitor. In a phase I dose-escalation study, PM achieved an encouraging ORR of 61.1% in R/R lymphomas with manageable toxicities. A phase IIa was conducted to further evaluate the efficacy and safety of PM in R/R PTCL (NCT06485219). Methods Eligible patients were adults with pathologically confirmed R/R PTCL who had received 1 to 5 prior lines of therapy, including anthracycline-based chemotherapy for PTCL and asparaginase-based therapy for NK/T-cell lymphoma (NKTCL), ECOG≤2. Patients were randomized 1:1 to receive PM at doses of 11.2 or 15.0 mg/m² on Days 1, 4, 8, and 11 of a 21-day cycle. 10-15 patients were planned to be enrolled at each group. Patients continued treatment until disease progression or unacceptable toxicity. The primary endpoint was ORR; secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. Results As of July 23, 2025, 24 patients with R/R PTCL were enrolled. Baseline characteristics included a median age of 58.0 years (range: 36–76), 19 males (79.2%), and a median of 2 prior lines of therapy. Twenty patients had at least one response evaluation. After a median follow-up of 5.39 months, the ORR was 55.0% (11/20), comprising 4 complete responses (CR) and 7 partial responses (PR). Four patients at 11.2 mg/m2 (4/8) achieved an ORR of 50.0% with 1 CR and 3 PR. Seven patients at 15.0 mg/m2 (7/12) achieved ORR of 58.3% with 3 CR and 4 PR. ORRs by histology were 20% (1/5) for PTCL-NOS (CR), 100% (1/1) for NKTCL, 50.0% (5/10) for AITL, and 100% (4/4) for ALCL. Most patients can benefit from the treatment at an earlier time with a median time to response (TTR) of 2.76 months (1.28, NR), and the median duration of response (mDOR) was 6.01 months (0.66, NR). Among responders, 5 patients remain on treatment, with the longest ongoing treatment lasting 16 cycles. Median PFS was 4.24 months (2.56, 7.29) and median OS was 7.59 months (6.18, NR). The most common grade ≥3 treatment-related adverse events included neutropenia (83.3%), thrombocytopenia (75.0%), leukocytopenia (50.0%), lymphocytopenia (41.7%), anemia (20.8%), infectious pneumonia (16.7%), bacterial pneumonia (12.5%), and hypokalemia (12.5%). There was one treatment-related death due to infection. Conclusion Preliminary results from this phase IIa study indicate that PM administered in 21-day cycles demonstrates promising efficacy compared with currently available single agents, with a manageable safety profile in patients with R/R PTCL.