Emerging Targeted Therapies for Peripheral T-Cell Lymphoma
At the 2025 Lymphoma, Leukemia & Myeloma (LL&M) Congress in New York, New York, Jia Ruan, MD, Weill Cornell Medicine, New York, New York, discussed emerging therapies, including valemetostat and duvelisib, for patients with peripheral T-cell lymphoma (PTCL), highlighting progress toward more targeted and individualized treatment strategies.
Transcript:
My name's Dr Jia Ruan. I'm a lymphoma doctor at Weill Cornell Medicine, New York Presbyterian Hospital. I see patients with lymphoma, and I also do clinical research for patients with lymphoma. I'm very pleased to be participating in the LL&M 2025 conference.
This is a lymphoma session today and I have a talk which is focusing on what's next as a novel emergent therapy for peripheral T-cell lymphoma. I'm very excited to share the progress on T-cell lymphoma with our colleagues and also the patients alike.
Peripheral T-cell lymphoma—it's a group of heterogeneous diseases and I think the treatment outcome has been proven, but I think there's significant unmet needs both for initial treatment ,as well as for patients who may have recurrent disease. One of the themes is that we're trying to develop more individualized and precision medicine therapy so that it's actually targeted for biological pathways. For example, in specific T-cell lymphoma subtypes, so that we can improve effectiveness but also reduce side effects like toxicity. I'll give you some examples.
Historically, we use a backbone of chemotherapy called CHOP, initially for pretty much everybody who has peripheral T-cell lymphoma. But we have learned that for those patients who have CD30-positive peripheral T-cell subtypes, such as anaplastic large cell or a small group of other types of T-cell lymphoma, if we use a target which is known as brentuximab vedotin, it's an antibody drug conjugate targeting CD30, to combine that with CHOP-based treatment in the form of brentuximab, vedotin and CHP, the outcome for those patient treated with this combination is significantly better. This has been demonstrated in a phase 3 randomized global study called ECHELON-2.
Since 2018, adding brentuximab vedotin to CHOP-based backbone is now the standard of care for CD30-positive PTCL. We want to learn from that lesson, and expanding as a subtype of peripheral T-cell lymphoma, including PTCLNOS or follicular helper T-cell type of PTCL. How are we doing in that respect? I think there are a number of agents that have very promising activity for other subtype of PTCL, they tend to run in 2 different categories. One is an epigenetic-modifying agent and then the other is small molecule that target intracellular pathway such as PI3 kinase inhibitor or JAK inhibitor.
Examples of epigenetic agents include HDAC inhibitors such as romidepsin, belinostat, and as well as a hypomethylation agent such as azacitidine. In the last few years, we also now have data on something called EZH1/2 inhibitor, which is a histone demethylation agent. One of such agents is known as valemetostat. Valemetostat has been studied in both phase 1 and phase 2 trial globally and the data looks very promising. They bring an overall response rate of about 50%, maybe 15 to 20% CR rate, and it's very well tolerated. We look forward to having more experience with this agent either alone or in combination.
As far as the PI3 kinase inhibitor, we have something called duvelisib. Duvelisib has been studied in a phase 2 study called PRIMO with over 100 patients and it actually has very promising activity and a response rate over 50%. Some of the response has been very long lasting and quite durable. We do have to monitor side effects, which sometimes can be related to inflammatory side effects such as elevated liver function tests, pneumonitis and colitis. More recently there are a bunch of combinations with duvelisib, either in combination of HDAC inhibitors such as romidepsin ,or in JAK inhibitors such as ruxolitinib.
Duvelisib plus romidepsin has been studied in a phase 1 [trial] with dose expansion and the duvelisib with JAK inhibitor, ruxolitinib, has also been studied in a phase 1 [trial] with dose expansion. Both those combination looks very promising, especially for patients with follicular helper T peripheral T-cell lymphoma subtypes. In addition, they also seem to reduce the inflammatory side effects which are typically associated with duvelisib. In fact, those combinations make the medication even better tolerated with more promising results.
The outlook looks certainly very promising, and we're hoping to generate more long-term data and also advocate for our patient to have access to those combinations, so that they could have a better response rate and hopefully durability of response as well.
Lastly, I want to bring up a very important point in terms of T-cell lymphoma management, which is to promote clinical trial participation. It's a very rare disease and it's important that we come together to support clinical trials. They are 2 national trials ongoing in initial treatment setting. One of them is a randomized phase 2 study, which is to compare the standard of care, CHOP or CHOIP [CHOP + ibrutinib], with 2 experimental arms. One of them is CHOP, CHOIP plus azacitidine, which is a hypomethylating agent, and the third arm is CHOP, CHOIP plus duvelisib. So to add a PI3 kinase inhibitor, the purpose of that is to introduce a biological target for treatment of T-cell lymphoma subtypes, to allow us to understand if adding that targeted agent [to that regimen] would improve response rates and outcomes.
The second national study that's just beginning is to evaluate whether consolidative autologous stem cell transplant after initial induction indeed improves the outcome. It's comparing patients getting induction treatment, subsequently to be observed without further maintenance or consolidation, to the experiment arm, which is induction and then followed by consolidative stem cell transplant. It's going to be the very first randomized study that's evaluating transplant in the context of initial therapy for peripheral T-cell lymphoma.
It's very exciting and we hope that collectively for providers and patients we can all contribute to T-cell lymphoma treatment and research. Thank you very much.
Source:
Ruan J. What’s New in T cell Lymphomas? Presented at Lymphoma, Leukemia & Myeloma Congress; October 14-17, 2025. New York, NY.
