Peripheral T-cell lymphoma (PTCL) is a rare and heterogeneous group of clinically aggressive mature T- and natural killer (NK)-cell neoplasms associated with poor prognosis. Twenty-seven different types of PTCL are described in the 2016 revision of the World Health Organization classification of lymphoid neoplasms. PTCL represents 10–15% of non‐Hodgkin lymphomas (NHLs) in Western countries and accounts for about 25–30% of NHLs in China (1, 2). Moreover, the subtype distribution of PTCL is different between China and Western countries. The most common subtype of PTCL in China is extranodal NK/T-cell lymphoma (NKTCL), nasal type, followed by PTCL-not otherwise specified (PTCL-NOS), anaplastic large-cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL) (2, 3).

For relapsed or refractory PTCL, conventional chemotherapy without intensification is usually associated with high treatment failure and disease relapse rates (3–5). Novel agents that target various pathways, such as histone deacetylase (HDAC) inhibitors, have been intensively studied and developed. Epigenetic therapies is also supported by identifying mutations of epigenetic genes in different PTCL subtypes, including TET2, IDH2, RHOA, DNMT3A, CD28, and FYN (6–10). Chidamide, a novel benzamide class of HDAC inhibitors, has been demonstrated to block the catalytic pocket of class I HDACs and selectively inhibit the activity of HDAC1, 2, 3, and 10 (11–17). For relapsed/refractory (R/R) PTCL, chidamide led to an overall response rate (ORR) of 28% in a phase II study (18) and an ORR of 39% in a real-world study (19). This study was a single arm, open-label, retrospective, post-marketing observational study of chidamide. The primary objective was to evaluate the safety, efficacy, and survival benefit of chidamide-containing therapy for relapsed or refractory (R/R) PTCL.

The current large-scale, real-world study explored the safety, efficacy, and survival benefit of chidamide for R/R PTCL. Chidamide-containing therapy led to a satisfactory efficacy with a ORR of 73.2% and good tolerance without unanticipated AEs. Moreover, chidamide-containing therapy brought a survival advantage with a 2-year OS rate of 35.8%. Especially for those patients achieving CR, both chidamide monotherapy and combination therapy resulted in improved survival outcome with the 2-year OS of more than 60%.

Previous studies have shown that HDAC inhibitors have significant anticancer potential for R/R PTCL. In a phase II study involving 131 patients, romidepsin led to rapid response with a median time to objective response of 1.8 months, and resulted in an ORR of 25% and a CR rate of 15% (21). During the long-term follow-up period, the median DOR for all responders was 28 months, and 32% of patients achieving CR had a DOR of more than 24 months (22). In a real-world study, romidepsin resulted in an ORR of 33%, a CR rate of 12.5%, and a median DOR of 13.4 months (23). Similarly, a pivotal phase II study showed the ORR of belinostat led to an ORR of 25.8% with a CR rate of 10.8% (24). In the current study, the ORR of chidamide-containing therapy was 66.2% for the entire cohort. Notably, a relatively higher response rate was observed in AITL with an ORR of 75.1% and a CR rate of 29.9%. AITL is characterized by high frequencies of mutations in epigenetic modifiers in neoplastic T cells (9), which can partly explain the significant clinical benefits of chidamide. In addition, the efficacy of chidamide seemed to be higher than that of pralatrexate which led to an ORR of 29% with a CR rate of 11% for relapsed or refractory PTCL (25), but it was lower than that of Brentuximab vedotin which led to an ORR of 86% with a CR rate of 57% for ALCL (26).Therefore, future studies focusing on the impact of HDAC inhibitors on the survival benefit of specific subtypes are needed.

Survival expectations for patients with R/R PTCL treated with salvage chemotherapy is very poor. A retrospective study demonstrated that patients with first-time relapsed PTCL treated with chemotherapy only had a median OS of 6.5 months (27). In contrast, HDAC inhibitors showed a better survival advantage. Romidepsin resulted in a median DOR of 28 months and a median PFS of 29 months, of which a better survival benefit was observed in those who achieved CR for ≥ 12 months (22). In the current study, the overall median OS for all patients was 15.1 months, and the 2-year OS rate was 69.4% for patients achieving CR, suggesting a significantly improved long-term survival benefit of chidamide to patients with R/R PTCL.

Chidamide was generally well-tolerated in the current study. Most of the AEs were hematological toxicities of grades 1–2, including thrombocytopenia, neutropenia, and anemia. The incidence of AEs slightly increased in patients receiving chidamide-containing combination treatments, but all AEs were manageable. Transient prolongation of QT interval corrected by heart rate (QTc) period was observed, which was not associated with concurrent cardiac symptoms. Therefore, this study further confirmed the safety of chidamide both in monotherapy and along with other chemotherapies.

There was several limitations in the current study. First, the time to response was taken into account when the inclusion criteria was developed. The median time to objective response for romidepsin was 1.8 months (21), while chidamide led to a rapid response with 74% of all responses occurring within the first 6 weeks after treatment (18). Based on these reports, patients who received therapy with a duration more than six weeks were enrolled to explore the long-term survival benefit of chidamide in the current study. However, it resulted in a significant selection bias for the evaluation of efficacy, which led to a higher ORR (58.6%) than that reported in a previous real-world study (ORR was 51.2%) (19). Second, the optimal combined cytotoxic drugs were not determined due to the heterogeneous regimens during combined therapy, and data of salvage therapy after disease progression was not collected. Third, many baseline characteristics data including central pathology review, clinical manifestation, imaging examination methods for staging and response, and prognosis except international prognostic index was missing due to multicenter nature and enrollment, which made it difficult to select particular patient population who potentially benefitted from chidamide therapy.

In conclusion, the current large-scale study demonstrated that chidamide had a favorable efficacy and a tolerable safety profile for patients with R/R PTCL. In addition, the current study demonstrated the potential survival benefit of chidamide for patients with R/R PTCL when combined with chemotherapy.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional Review Board of all of the participating centers. The ethics committee waived the requirement of written informed consent for participation.

WpL conceived and designed the study, analyzed the data, and drafted and revised the paper. DLZ prepared and analyzed the data. JuZ, JM, and ZS conceptualized and designed the study. All authors provided critical comments to the manuscript. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The reviewer JH declared a shared affiliation, with WZ and a past co-authorship with JJ, TL, LQ, WC, JH, and PL to the handling editor at the time of the review.

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