From September 13 to 17, the 2024 European Society for Medical Oncology (ESMO) Annual Meeting was held in Barcelona, Spain. As one of the world's leading oncology events, experts and scholars from across the globe gathered to share cutting-edge research results and explore future development directions. In the Mini Oral session on hematologic malignancies, Dr. Zhiming Li from the Sun Yat-sen University Cancer Center presented the results of a phase I/II study on the combination of chidamide and mitoxantrone hydrochloride liposome in the treatment of relapsed or refractory peripheral T-cell lymphoma (R/R PTCL). This study offers new options to improve the prognosis of R/R PTCL patients and contributes a promising Chinese strategy to the global development of hematologic oncology. Hematology Frontier invited Professor Li to provide an in-depth analysis of the study and share his expectations for future research on this combination therapy.

Hematology Frontier: At this year’s ESMO conference, you presented the phase I/II study results on the combination of chidamide and mitoxantrone hydrochloride liposome in treating relapsed or refractory peripheral T-cell lymphoma (R/R PTCL). Could you briefly explain the background for conducting this study?

Dr. Zhiming Li: PTCL is a malignancy of mature T lymphocytes, characterized by high heterogeneity and aggressiveness. Despite receiving anthracycline-based chemotherapy, the majority of patients experience relapse or refractory disease. With no standard treatment available, the prognosis of R/R PTCL is poor, with a median overall survival (mOS) of less than six months, highlighting the urgent need for more effective salvage therapies.

Although some new drugs have been approved for R/R PTCL in recent years, the efficacy of most monotherapies remains limited, necessitating exploration of novel combination strategies. Chidamide, a subtype-selective histone deacetylase inhibitor (HDACi) developed in China, is a well-established drug for treating R/R PTCL and is recommended as a second-line treatment option in the CSCO lymphoma guidelines. Chidamide has shown good efficacy and safety in both monotherapy and in combination with chemotherapy. Mitoxantrone hydrochloride liposome is a new anthracycline liposomal formulation that has been approved by the National Medical Products Administration (NMPA) as a treatment option for R/R PTCL, showing promising efficacy as a monotherapy.

For R/R PTCL patients, the remission rates and durability of response to traditional salvage chemotherapy are often limited. Combining chidamide with an anthracycline-based chemotherapy could be a novel strategy to improve prognosis. Preclinical studies have shown that combining low-dose chidamide with doxorubicin synergistically inhibits PTCL cells and enhances chemotherapy-induced apoptosis. Moreover, a phase I study in the U.S. combining the HDACi romidepsin with liposomal doxorubicin in R/R cutaneous T-cell lymphoma reported acceptable safety and promising efficacy (objective response rate [ORR] of 70% and complete response [CR] rate of 10%).

Thus, we conducted this study to explore the safety and efficacy of combining chidamide with mitoxantrone hydrochloride liposome (PLM60) in patients with R/R PTCL.

Hematology Frontier: In this study, the maximum tolerated dose (MTD) of mitoxantrone hydrochloride liposome was determined to be 20 mg/m² in combination with chidamide. Can you explain the main challenges encountered during the MTD determination process, and what significance this dosage choice holds for patient safety and efficacy?

Dr. Zhiming Li: The primary endpoint of the phase I study was to determine the recommended phase II dose (RP2D) of mitoxantrone hydrochloride liposome in combination therapy. Both mitoxantrone hydrochloride liposome and chidamide as monotherapies are associated with hematologic toxicities, so determining the MTD was essential to avoid overlapping toxicities in the combination therapy.

Previous studies on chidamide-based combination therapies have shown tha  t a dosage of 20 mg twice a week (biw) is well-tolerated and effective. Therefore, we used a fixed dose of chidamide at 20 mg biw in this study. In a phase II study on mitoxantrone hydrochloride liposome monotherapy for R/R PTCL, a dose of 20 mg/m² every four weeks was associated with hematologic toxicities, with the most common grade ≥3 toxicities being leukopenia (50%) and neutropenia (45.4%). Based on previous reports of mitoxantrone hydrochloride liposome combined therapy, we set three dose levels at 14, 17, and 20 mg/m².

In the phase I study, no dose-limiting toxicities (DLT) were observed, and the RP2D was determined to be 20 mg/m². The most common grade 3/4 treatment-related adverse events (TRAEs, ≥10%) were hematologic toxicities, including neutropenia (66.7%), leukopenia (52.4%), lymphopenia (42.9%), thrombocytopenia (23.8%), and anemia (23.8%). Importantly, there was no significant overlap in hematologic toxicities between the two drugs at their monotherapy-effective doses, and no new safety signals were identified. Therefore, the combination therapy demonstrated a favorable balance between efficacy and toxicity for patients.

Hematology Frontier: In this phase I/II study, how effective was the combination of chidamide and mitoxantrone hydrochloride liposome, and could it potentially become a new standard treatment for this disease in the future?

Dr. Zhiming Li: As of the data cutoff (March 10, 2024), a total of 21 patients with R/R PTCL were enrolled (9 in phase I and 12 in phase II), most of whom had advanced disease (stage III-IV, 76%) and were refractory (62%) or high-risk (IPI score 2-5, 71%). Among the 16 evaluable patients in both phases, the ORR was 56.3% (9/16), with a CR rate of 31.3% (5/16). After a median follow-up of 3.8 months, the median PFS and OS were not reached.

Phase II of the study is still ongoing. In the 8 evaluable patients from phase II, the ORR was 75% (6/8), and the CR rate was 37.5% (3/8). The combination of chidamide and mitoxantrone hydrochloride liposome achieved encouraging ORR and CR rates in these mostly high-risk and refractory PTCL patients, which were higher than previously reported with monotherapy. With further enrollment in the phase II study, we expect to see enhanced efficacy and hope to provide a new treatment option to improve the prognosis of R/R PTCL patients.

Hematology Frontier: What future results do you anticipate from the continued research on the combination of chidamide and mitoxantrone hydrochloride liposome in R/R PTCL? Will you and your team also explore its efficacy in different subtypes and molecular characteristics?

Dr. Zhiming Li: Previous phase II studies in China, Japan, and South Korea have shown that chidamide monotherapy achieved a median overall survival (mOS) of over 20 months in R/R PTCL patients. Recent phase IIb studies in Japan and South Korea have also reported that long-term monotherapy with chidamide is safe, deepens the response, and brings clinically meaningful improvements in OS (mOS of 33.6 months). Additionally, several studies have shown that maintenance therapy with chidamide after first-line induction can significantly reduce the risk of disease progression.

In this study, after completing six cycles of combination therapy, patients will continue on maintenance therapy with chidamide (20 mg biw) for up to one year. With longer follow-up, we hope to observe a reduction in the risk of disease progression and an improvement in survival in R/R PTCL patients.

Furthermore, epigenetic dysregulation is a prominent feature in the pathogenesis of PTCL, particularly in angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T-cell lymphoma (TFH), suggesting that these subtypes may be more sensitive to epigenetic therapy. In previous studies, chidamide monotherapy or combination therapy has shown superior responses in the AITL subtype. Therefore, we hold positive expectations for the efficacy of combination therapy in this subtype in future studies.

Dr. Zhiming Li Chief Physician, PhD Supervisor Department of Medical Oncology, Sun Yat-sen University Cancer Center Chairman, Lymphoma Professional Committee, Guangdong Anti-Cancer Association Chairman, Comprehensive Head and Neck Oncology Treatment Professional Committee, Guangdong Clinical Medicine Association Chairman-Elect, Hematologic Oncology Professional Committee, Guangdong Anti-Cancer Association Deputy Secretary-General and Standing Committee Member, Anti-Lymphoma Alliance, CSCO Standing Committee Member, Lymphoma Professional Committee, Chinese Anti-Cancer Association Secretary-General and Standing Committee Member, Lymphoma Professional Committee, China Geriatric Healthcare Association Standing Committee Member, Head and Neck Tumor Expert Committee, CSCO Executive Director, Youth Council, Chinese Anti-Cancer Association