The 5th Tianjin International Lymphoma Academic Conference, as an academic platform to promote international academic exchange and cooperation, has actively played its role as a bridge, facilitating in-depth exchange and cooperation in the field of international lymphoma. During the conference, "Hematology Frontier" specially invited Professor Owen O’Connor, President of the Lymphoma Alliance and from the University of Virginia Cancer Center, and Professor Zhengzi Qian from the Tianjin Medical University Cancer Hospital to engage in a dialogue between China and the rest of the world, reviewing the current status and latest advances in the treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL).

Hematology Frontier：What are the key challenges in developing new treatments for R/R PTCL, and how do you think these can be effectively addressed in both your regions?

Professor Owen O’Connor: So the PTCL had many challenges。Probably the one that is the most significant at the moment relates to the heterogeneity or diversity of the disease。We now have two different classifications schemes，the ICC and the WHO which recognize let’s call it 35 different types of T cell lymphoma。As a group，there are awfully rare diseases may be in the United States 10,000 cases per year。And even with the most common sub types，maybe a couple of thousand patients per year。So this makes it very hard because those35 different subtypes are all biologically very different。And as we’re seeing in lots of new data sets with new drugs，some sub types respond amazingly well to one class of drugs while other sub types don’t and how these relative proportions of patients with these different sub types can then influence the outcome of these trials becomes pretty significant。And it has an impact on how we develop these drugs for those diseases。So I think the notion that there’s incredible heterogeneity that heterogeneity is reflected in differences in biologic behavior，differences in genetics and ultimately differences in vulnerability to different drugs。Makes it very difficult to develop a singular unifying platform of care for all types of T cell lymphoma。And it presents a challenge as to how we go about getting drugs approved for the disease。

Professor Zhengzi Qian: PTCL represents a category of highly aggressive and heterogeneous non-Hodgkin lymphomas, characterized by a myriad of subtypes, each regarded as a distinct disease entity. These subtypes exhibit significant differences in clinical manifestations, pathogenesis, molecular genetic profiles, and prognosis, posing considerable challenges for therapeutic interventions. In general, the majority of T-cell lymphomas lack standardized treatment protocols and have poor survival outcomes. Except for early-stage NK/T-cell lymphoma and ALK-positive anaplastic large cell lymphoma, the five-year overall survival rates for other subtypes are generally low, often not exceeding 30%. Notably, there are notable geographical variations in the incidence of peripheral T-cell lymphoma subtypes. In China, NK/T-cell lymphoma, peripheral T-cell lymphoma-not otherwise specified, and angioimmunoblastic T-cell lymphoma are the primary subtypes, whereas in European and American countries, ALCL and cutaneous T-cell lymphoma are more prevalent.

In response to the severe challenges posed by PTCL, the medical community in China has conducted extensive research on various types of peripheral T-cell lymphomas. Professor Zhang Huilai’s team at the Lymphoma Department of Tianjin Medical University Affiliated Cancer Hospital has achieved certain results using azacitidine combined with chidamide, a dual epigenetic therapy, for the treatment of relapsed/refractory PTCL. Based on this, they initiated a prospective, multicenter, randomized controlled Phase III clinical study comparing dual epigenetic therapy combined with CHOP versus CHOP alone in the treatment of naive follicular helper T-cell phenotype peripheral T-cell lymphoma. Professor Zhao Weili’s team at Ruijin Hospital, has made significant achievements in the field of NK/T-cell lymphoma. They conducted subtype exploration and identified three subtypes: TSIM, MB, and HEA, which differ in their sensitivity to drugs. Meanwhile, Professors Huang Huiqiang and Cai Qingqing at Sun Yat-sen University Cancer Center have also made crucial breakthroughs in clinical research on NK/T-cell lymphoma. Their proposed immune epigenetic therapy has demonstrated remarkable efficacy for patients with relapsed/refractory NK/T-cell lymphoma and further explored first-line and combination treatment strategies.

In summary, China has achieved in-depth research results in the types of peripheral T-cell lymphomas with high incidence rates and holds promise for providing more effective treatment concepts and strategies for patients worldwide.

Hematology Frontier：What are the key factors that influence the selection of treatment options for R/R PTCL, and how do you balance these factors in clinical decision-making?

Professor Owen O’Connor: the current standards of care typically involve some form of chemotherapy。And the type of chemotherapy folks pick is usually modeled after how they treat B cell lymphoma a radically different disease。And so when it comes to combination chemotherapy，we really don’t have that much great data to say what combination chemotherapy works best in the relapsed or refractory setting，I think is a general statement that’s true。Most chemotherapy in the relapse to refractory setting is not effective。I believe if you look at the data and most of it is retrospective，we don’t have prospective randomized studies。It would suggest that new drugs using them earlier will work better。And there’s data that we’ve published with pralatrexate。There’s lots of data with histone deacetylase inhibitors and other drugs。It’s my very strong opinion。We wait too long to start these new drugs。here in China，you’re extraordinarily fortunate。You have a lot of new drugs that we don’t have in the United States。You’ve got two new ones potentially pending，including the PI3K inhibitor, the EZH2 inhibitor。And you already have other approved agents。And I would suggest because I do it in my own practice that we use those novel drugs as early as possible because what the data suggests is they can have a big impact。And in the case of pralatrexateusing the drug earlier has been shown to have impacts on overall survival in very strong robust case match control analyses。I think that paradigm is going to hold true as we begin to develop these other drugs。And secondarily I think clinical trials I think we need to start studying these drugs in combination new drugs。We need to prioritize studying those new drugs in combination with each other over chemotherapy and really try to get patients into those clinical trials as efficiently and fast rapidly as possible。So we can better understand how to develop what the next relapse refractory setting therapies might be。

Professor Zhengzi Qian: In the treatment of relapsed/refractory peripheral T-cell lymphoma (R/R PTCL), the therapeutic considerations for Chinese patients are particularly complex. Firstly, a detailed analysis of the patient’s specific pathological type is required, as different pathological types exhibit unique pathogenesis and molecular genetic characteristics, which provide critical evidence for doctors to develop more targeted therapeutic strategies.

Furthermore, when devising treatment plans for Chinese patients, it is necessary to comprehensively consider their physical constitution, functional status, economic capacity, and personal treatment preferences. It is noteworthy that patients with relapsed/refractory disease have often undergone multiple treatment regimens and drug therapies. Therefore, when formulating subsequent treatment plans, it is crucial to thoroughly review their past treatment regimens, assess treatment efficacy, and consider side effects.

Hence, when customizing treatment plans for individual patients, multiple factors must be comprehensively weighed to strive for an optimal balance between efficacy and toxicity. As Professor Owen has pointed out, there are numerous clinical trial projects currently ongoing in China, providing diverse treatment options for patients with relapsed/refractory disease. For those patients who have undergone multiple lines of treatment with suboptimal efficacy or significant economic burdens, participating in clinical trials may be a worthwhile consideration.

Hematology Frontier：What are the most significant clinical trial results for new treatments of R/R PTCL that have emerged recently, and how do these results impact clinical practice?

Professor Owen O’Connor: the most impactfull clinical trials are those that are zeroing in mechanisms that seem to be recurring and important in treating T cell lymphoma。Those mechanisms include drugs targeting PI3K mechanisms targeting JAK1 mechanisms targeting the epigenetic biology， Pralatrexate which globally affects DNA synthesis。And so what I believe is important of late has been two things。One is combination studies of those novel drugs。And in our hands，at least for my group，the combinations of histone de acetylase inhibitors and hypomethylating agents。Romidepsin and azacitidine have to date produced the most compelling maybe the best outcomes for patients with relapse disease of any drug combination that’s been studied so far。I think it’s a testament to the benefit of these novel scientifically driven combinations。And I think we gotta do much more of that。the other in compelling data that’s coming from clinical trials pertains to the emergence of all these promising new drugs like we talked about earlier with the PI3K inhibitor Linperlisib，the EZH2 inhibitor SHR2554, another EZH1/2 inhibitor valemetostat，I think and the recent approval of gold to sit nib the JAK1 inhibitor，and the recent approval of Golidocitinib the JAK1 inhibitor.I think those clinical trials there’s no doubt are changing practice today。I think we are only scratching the surface and the potential of those drugs to change practice because they are being used as single agents。We’re not really optimizing their full capability by exploring and understanding the right combination。So I think that combinations early combination studies of novel drugs are the most compelling and the vast recurring array of smaller single agent studies like the PI3K, EZH2, JAK1 are all going to change practice and they’re going to continue to change practice as we move away from these paradigms of chemotherapy combinations and move towards more of a chemotherapy free idea about treating these diseases。

Professor Zhengzi Qian:The latest research on relapsed/refractory primary cutaneous T-cell lymphoma has primarily focused on the development of novel small-molecule targeted therapies and innovations in immune checkpoint inhibitors. In recent years, we have witnessed significant improvements in efficacy in the fields of PI3K inhibitors, EZH1/2 inhibitors,JAK1 inhibitors, immune checkpoint inhibitors, and Histone Deacetylase Inhibitors. However, it is noteworthy that despite demonstrating certain therapeutic potential, the overall response rates of these small-molecule targeted therapies as monotherapy are generally limited to between 30% and 60%, posing significant constraints on treatment options for patients. Consequently, the strategy of multidrug combination therapy has become a key area of exploration both currently and in the future.

When formulating combination therapy regimens, it is essential to comprehensively consider the efficacy, side effects of the drugs, and whether there is a synergistic effect between them. Additionally, some emerging therapeutic regimens have demonstrated remarkable efficacy. For instance, the regimen combining brentuximab vedotin with bendamustine has achieved an objective response rate of up to 71% and a complete response rate close to 50%. This outcome not only provides us with a new treatment option but also indicates that immune-targeted therapy may increasingly play a prominent role in the treatment of relapsed/refractory diseases, especially when the effectiveness of chemotherapy gradually diminishes in later stages of the disease. Meanwhile, oral-only regimens such as chidamide in combination with prednisone, cyclophosphamide, and thalidomide (CPCT regimen) have also shown good efficacy and exhibited excellent safety and tolerability profiles. These results further confirm the significant role of new drugs in the treatment of R/R PTCL and suggest that multidrug combination therapy regimens will become a mainstream trend in the future.

However, while pursuing efficacy, we must also pay close attention to the potential adverse reactions associated with combination therapy. Therefore, when devising treatment plans, it is crucial to fully consider individual patient differences, drug-drug interactions, and potential risks of adverse reactions to ensure the safety and effectiveness of treatment.

In summary, with the continuous emergence of new drugs and the ongoing optimization of combination therapy regimens, the treatment prospects for R/R PTCL patients are becoming broader. In the future, we will continue to explore more effective, safe, and well-tolerated treatment regimens, aiming to provide patients with better therapeutic outcomes and quality of life.

Professor Owen O’Connor

Chairman of the Columbia University Medical Center

President of the Lymphoma Alliance

Co-Director of the Lymphoma Development and Malignant Neoplasms Program at the Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center

Director of the Center for Lymphoid Malignancies

An international authority in managing Hodgkin’s lymphoma and non-Hodgkin’s lymphoma, as well as in developing new drugs for these diseases

Focused on discovering and developing new drugs for the treatment of lymphoma, having pioneered the development of three new drugs approved for the treatment of lymphoma, and having published over 200 articles, book chapters, and reviews on lymphoma therapy.

Professor Zhengzi Qian

Tianjin Medical University Cancer Hospital, Lymphoma Department

Doctor of Oncology

Vice Chairman of the Lymphoma Professional Committee, Tianjin Integrated Medical Society Standing Committee Member of the Lymphoma Professional Committee, Tianjin Anti-Cancer Association

Member of the Clinical Chemotherapy Professional Committee, Tianjin Anti-Cancer Association

Member of the Adverse Reactions Treatment Professional Committee, Tianjin Anti-Cancer Association

Member of the Chinese Society of Clinical Oncology (CSCO) Autologous Hematopoietic Stem Cell Transplantation Working Group

Member of the Head and Neck Tumor Professional Committee, CSCO

Editorial Board Member of “Leukemia-Lymphoma” Journal

In 2008, studied at the University of Texas M.D. Anderson Cancer Center in the United States Published several papers in domestic and international journals Undertook and participated in multiple national-level research projects.