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Abstract Introduction Peripheral T-cell lymphoma (PTCL) is a rare, aggressive group of non-Hodgkin lymphomas (NHL), including PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). For patients who achieve remission, autologous stem cell transplant (ASCT) is the standard consolidative approach. However, relapse remains common, and no post-ASCT maintenance therapies are currently approved. In the NLG-T-01 study, the 5-year progression-free survival (PFS) following upfront ASCT was 44%, and overall survival (OS) was 51%, underscoring the need for strategies to prolong remission in this high-risk population. Duvelisib, an oral dual PI3K-δ/γ inhibitor, has demonstrated clinical activity in relapsed/refractory PTCL. In the PRIMO study, duvelisib achieved an overall response rate (ORR) of 48% and complete response rate (CRR) of 33%, with a manageable safety profile using a dose-optimized approach. Given its clinical activity across PTCL subtypes and manageable toxicity, we hypothesized that maintenance therapy with low-dose duvelisib following ASCT could improve PFS. We conducted a study to evaluate the safety and efficacy of post-transplant duvelisib maintenance in patients with PTCL. Methods This single-center, phase II trial enrolled duvelisib-naive patients with TCL or B-NHL who underwent consolidative ASCT. Following a safety lead-in, enrollment was limited to TCL. Duvelisib maintenance began after hematologic recovery (day +30) and continued for up to 11 cycles. Due to tolerability, the initial dosing (25 mg BID, days 1–28) was amended after 7 patients with a modified schedule (25 mg BID, days 1–14 of a 28-day cycle). Response assessment scans occurred at the end of cycle 2 and subsequently every 3 cycles. Those with stable (SD) or progressive disease (PD) were taken off study. All patients received PJP and herpesvirus prophylaxis. Results Seventeen patients were enrolled from July 2020 to July 2024. Histologic subtypes included PTCL-NOS (n = 6), ALCL (n = 4), AITL (n = 2), and transformed follicular lymphoma (tFL, n = 5). Ten patients were male; the median age at ASCT was 59 years (range, 24–69). Twelve patients had stage III/IV disease at diagnosis. Pre-transplant responses included 16 in complete remission (CR) and 1 in partial remission (PR). Among the 12 patients with TCL, 11 (92%) were in first CR/PR and 1 was in CR2 at the time of transplant. The median treatment durations for Schedules 1 and 2 were 5.4 months (Interquartile Range [IQR], 2.8–11.1) and 11.3 months (IQR, 7.5–11.8), respectively, with median follow-up of 17.2 (IQR, 14.6–22.5) and 19.0 months (IQR, 8.7–23.3), respectively. All twelve patients with TCL were included in the efficacy analysis. Median progression-free survival (PFS) was not reached (NR) (95% CI, 5.9–NR), and median overall survival (OS) was 35.6 months (95% CI, NR–NR). At 12 months, PFS and OS were 83.3% (95% CI, 48.2–95.6%) and 91.7% (95% CI, 53.9–98.8%), respectively. All 17 patients were included in the safety analysis. Three of 7 patients treated on Schedule 1 discontinued duvelisib due to toxicity: one grade 3 elevated liver enzymes, one grade 3 diarrhea, and one muscle weakness (unlikely related to duvelisib nor disease progression). This prompted a protocol amendment to Schedule 2, with subsequent improvement in tolerability. The most common adverse events (AEs) were hematologic, gastrointestinal, and hepatic. Grade 3 treatment-related AEs were observed in 9 patients, including febrile neutropenia (n = 1), lymphopenia (n = 3), diarrhea (n = 1), pneumonia (n = 1), and elevated liver enzymes (n = 3). There was one Grade 4 AE, lymphopenia, and no treatment-related deaths. Infectious events occurred in 7 patients, including thrush (n = 2), upper respiratory tract infections (n = 3), sinusitis (n = 1), and pneumonia (n = 1); none of these infections led to treatment holds or dose reductions. Four patients have relapsed (TCL, n = 2; tFL, n = 2), and 15 of 17 remain alive to date. Conclusion Duvelisib maintenance for up to one-year post-ASCT was safe and generally well tolerated, especially with the modified intermittent dosing schedule (25 mg BID, days 1–14 of a 28-day cycle). In patients with TCL, duvelisib maintenance yielded promising disease control and compares favorably to historical outcomes in this high-risk population. Given the promising results, a larger multicenter phase 3 trial is warranted.