CMOP Regimen and Chidamide in the Treatment of Newly Diagnosed Peripheral T-cell Lymphoma

Overview

Peripheral T-cell lymphoma (PTCL) is a highly heterogeneous and aggressive non-Hodgkin's lymphoma. The incidence rate of PTCL in China is much higher than the global average, and there is no unified standard treatment for initial PTCL. Currently, the CHOP regimen is widely used as first-line treatment. However, the overall response rate is still low, and effective therapies need to be explored. Epigenetics and genetics jointly determine critical features of tumors, and exploring new treatment strategies and developing targeted drugs based on deep understanding of the pathogenesis is of significant importance. The combined application of DNMT inhibitors and HDAC inhibitors has strong scientific support. The Phase II clinical study of Mitoxantrone Hydrochloride Liposome in treating relapsed or refractory PTCL achieved positive results and regulatory approval. The CMOP regimen combining Mitoxantrone Hydrochloride Liposome with Chidamide is worth exploring for initial PTCL treatment.

Peripheral T-cell lymphoma (PTCL) originates from mature thymic T-cells and is a highly heterogeneous and aggressive non-Hodgkin's lymphoma (NHL). The 2016 revised WHO classification divides PTCL into 4 major categories with over 30 subtypes, including common subtypes such as anaplastic large-cell lymphoma (ALCL), ALK-positive/+ and ALK-negative/-, angioimmunoblastic T-cell lymphoma (AITL), and PTCL, not otherwise specified (PTCL-NOS) . In 2020, the estimated global incidence of new NHL patients was over 540,000, with over 90,000 cases in China. Compared with B-cell lymphomas, PTCL has a lower incidence rate, but PTCL patients' proportion in China is significantly higher than in Western countries at approximately 21% . The incidence rate of PTCL in China accounts for nearly 21% of NHL, much higher than the global average . Currently, there is no unified standard treatment for initial PTCL. The National Comprehensive Cancer Network (NCCN) guidelines in the US and the Chinese Society of Clinical Oncology (CSCO) recommend using the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) as first-line treatment . However, the CHOP regimen is mainly based on treatment experience with B-cell lymphomas, and more effective therapies need to be explored. Over the past few decades, research progress in both basic and clinical aspects of PTCL has been slow, with poor treatment outcomes. The overall response rate of first-line treatment is 50%-70%. Except for ALCL, ALK(+), PTCL patients receiving induction therapy are suggested to undergo autologous hematopoietic stem cell transplantation (ASCT) treatment, yet even so, the overall response rate is still low, with a poor prognosis. Except for ALCL, ALK+ patients, the five-year overall survival (OS) rate of other subtypes is less than 50% , and PTCL patients are prone to relapse , with a three-year OS probability of about 20% . The overall treatment effect for PTCL patients is still not ideal, and their prognosis has not improved over the past few decades. Patients often relapse early, with a shorter progression-free survival (PFS) and OS. Genetic mutations, variations, and tumor occurrence and development are closely related, and the same is true for epigenetic regulation. Epigenetics and genetics jointly determine critical features of a tumor: heterogeneity, plasticity, stem cell-like properties, and immune escape. As lymphomas often have epigenetic mutations, exploring new treatment strategies and developing targeted drugs based on a deep understanding of the pathogenesis is of significant importance in improving the efficacy of PTCL treatment. Since both highly methylated DNA and low acetylated histones can lead to a closed chromatin state by independent mechanisms, resulting in the silencing of tumor suppressor genes , the combined application of DNMT inhibitors and HDAC inhibitors has strong scientific support. Both DNMT inhibitors and HDAC inhibitors have a chemosensitizing effect. Acetylation changes the chromatin structure, plays a role in regulating epigenetics as well as in chemotherapy sensitization, while DNMT inhibitors can enhance the sensitivity of lymphoma resistant to chemotherapy. Currently, the combination of AZA+HDACi in epigenetic treatments has been explored for lymphoma treatment. In the Phase II clinical study of Mitoxantrone Hydrochloride Liposome, 108 patients with relapsed or refractory PTCL were treated with Mitoxantrone Hydrochloride Liposome alone, achieving an objective response rate (ORR) of 41.7% (32.3%, 51.5%) and a complete response rate (CRR) of 23.1% (25/108). The median PFS was 8.5 months, and the median OS was 22.8 months. The treatment was well-tolerated and efficacious, resulting in regulatory approval for Mitoxantrone Hydrochloride Liposome in treating relapsed or refractory PTCL adult patients . Based on this, the CMOP regimen, which is based on Mitoxantrone Hydrochloride Liposome combined with Chidamide, is worth exploring for initial PTCL treatment.