The efficacy and safety of a Histone deacetylase inhibitor: chidamide as a maintenance therapy for peripheral T-cell lymphoma

The efficacy and safety of a Histone deacetylase inhibitor: chidamide as a maintenance therapy for peripheral T-cell lymphoma | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The efficacy and safety of a Histone deacetylase inhibitor: chidamide as a maintenance therapy for peripheral T-cell lymphoma Hao-Rui Shen, Jia-Zhu Wu, Jin-Hua Liang, Yue Li, Xin-Yu Zhang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3804699/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose This study aimed to assess the efficacy and safety of chidamide as a maintenance therapy in peripheral T-cell lymphoma. Methods Chidamide was given orally as a maintenance therapy after first-line or salvage treatment. Progression-free survival (PFS), overall survival (OS), and safety were analyzed. Results Fifty-eight patients were enrolled between January 2015 and July 2022. Among 39 patients underwent first-line maintenance, 11 (28.2%) patients experienced disease progression. A total of 19 patients received maintenance treatment after salvage therapy, 9(47.4%) had disease progression and median duration of remission was 16 (2‒25) months. For all patients, the median maintenance time was 16 (1–72) months, the median PFS was 33 months, and the median OS had not been reached. The median PFS and OS of the patients received first-line maintenance were not reached, significantly better than patients received salvage maintenance (median PFS and OS were 7 and 67 months, P < 0.001, P = 0.009, respectively). The most common toxicities were hematologic toxicities. Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment. Conclusion The study showed that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy. Registration number: ClinicalTrials.gov (NCT05967949), retrospectively registered on July 23, 2023. peripheral T-cell lymphoma chidamide maintenance Figures Figure 1 Figure 2 Figure 3 1. Introduction Peripheral T-cell lymphomad (PTCL) is a set of rare and highly heterogeneous tumors of non-Hodgkin’s lymphoma (NHL) with inferior outcomes [ 1 ] [ 2 ]. The incidence of PTCL is much higher in China compared to western countries [ 3 ]. The most common types of PTCLs include PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) [ 4 ]. There is no standard treatment for PTCL patients, although conventional chemotherapy includes cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen is widely applied, it is usually associated with a poor response and high disease relapse rates [ 5 – 8 ]. Histone deacetylase (HDAC) have traditionally been described as belonging to one of the 4 classes: I, IIa, IIb, and IV, and plays important roles in oncogenesis. It triggers chromatin remodeling by inhibiting HDACs to increase the acetylation level of chromatin histones, resulting in changes in gene expression targeting multiple signaling pathways (i.e. epigenetic changes), thereby inhibiting tumor cell cycle, inducing tumor cell apoptosis, and regulating immune activity, inducing and enhancing natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL) mediated tumor killing effects [ 9 – 11 ]. Chidamide also plays a potential role in restoring drug sensitivity of tumor cells and inhibiting tumor metastasis and recurrence by inducing tumor stem cell differentiation and reversing epithelial mesenchymal phenotype transformation (EMT) through epigenetic regulatory [ 12 ]. HDAC inhibitors, including romidepsin and belinostat, have shown efficacy in the treatment of relapse/refractory (R/R) PTCL, and they were approved by the US Food and Drug Administration (FDA) for the treatment of R/R PTCL [ 13 – 14 ]. Chidamide is a novel benzamide class of HDAC inhibitor (HDACi), that was approved by the Chinese Food and Drug Administration (CFDA) for the treatment of R/R PTCL patients [ 15 ]. However, the role of chidamide in PTCL maintenance therapy is still uncertain, this study aimed to assess the efficacy and safety of chidamide as a maintenance therapy after induction or salvage treatment in patients with PTCLs. 2. Methods 2.1 Study design and procedure This was a retrospective, single center, single-arm study (NCT05967949). All patients were diagnosed according to WHO 2016 tumor and hematopoietic lymphoid tissue classification for pathology [ 1 ], including AITL, PTCL-NOS, ALCL, ENKTL and MEITL. All patients were required to have achieved a complete response (CR) or partial response (PR) after induction or salvage treatment. Patients with the following conditions were excluded: (1) who were pregnant or breastfeeding; (2) who had class III or IV cardiac failure according to New York Heart Association, or had a history of acute coronary syndrome, acute heart failure, or severe ventricular arrhythmia in the previous six months; (3) positive for HIV, syphilis, HCV, or with an HBV viral load (HBV DNA) > 1×10 5 copies/ml; (4) with poor hepatic function defined as total bilirubin > 1.5 times the upper-normal level, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 times the upper-normal level or > 5 times the upper-normal level with hepatic involvement; (5) with poor renal function defined as serum creatinine > 1.5 times the upper-normal level. All aspects of this study were performed in accordance with the principles of the Declaration of Helsinki (2013 No. 64). The research was approved by the Centralized Ethics Committee of The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital (the clinical registration number was 2023-SR-297). All patients provided written informed consent, and this study was registered at ClinicalTrials.gov (NCT05967949). 2.2 Treatment and Procedures The first-line induction therapy for PTCL (except for ENKTL) patients was anthracycline based combination chemotherapy, like CHOP, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and CPCT (chidamide, prednisone, cyclophosphamide, thalidomide) regimen was for patients who cannot tolerate chemotherapy; The first-line induction therapy for ENKTL patients was asparaginase based combination chemotherapy. After reaching CR or PR after treatment, all patients are evaluated for the feasibility of autologous hematopoietic stem cell transplantation (ASCT). Patients received chidamide 20 mg alone twice a week as consolidation therapy after CR or PR after first-line or salvage treatment. Response assessments were performed by clinical examination and positron emission tomography (PET) / computer tomography (CT) or CT. During maintenance therapy, every 3 months in the first year, and every 6 months after 1 year. All responses were determined using the clinical and radiologic criteria of the international National Cancer Institute (NCI)-Sponsored International Working Group that focused on the use of enhanced CT scans [ 16 ] and the Lugano 2014 criteria that focused on the use of positron emission tomography (PET)/CT [ 10 ].. Patients received chidamide treatment until disease progression or unacceptable toxicity. The main purpose of this study is to evaluate the progression-free survival (PFS), overall survival (OS) and safety of chidamide in maintenance treatment. PFS was defined as the time from the date of diagnosis to the date of recurrence or progression. OS referred to the interval between diagnosis and death due to any cause or the end of follow-up. Safety assessments included physical examinations, laboratory parameters, and adverse events (AEs), which were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events scale, version 4.0. 2.3 Statistical analysis Statistical analysis was performed using SPSS statistical software (version26.0), MedCalc statistical software (version 20.1.0) and GraphPad Prism (version 9.0). Categorical variables were expressed as percentage (%). Continuous variables were expressed as mean ± standard deviation or median (interquartile range). Differences in continuous variables between two groups were assessed by two-tailed Student’s t-test while for differences between more groups one-way ANOVA followed by a post hoc test was used. Survival curves were drawn using the Kaplan-Meier method, and differences in survival were compared using the log-rank test. A two-sided P value of < 0.05 was considered statistically significant. 3. Results 3.1 Baseline characteristics Fifty-eight patients were enrolled in our study between January 2015 and July 2022, the baseline characteristics of evaluable patients are presented in Table 1 . The median age was 66 (29‒83) years old. Patients with AITL represented the largest subgroup (34, 58.6%), followed by PTCL-NOS (10, 17.2%), ALCL (8, 13.8%), ENKTL (5, 8.6%) and MEITL (1, 1.7). Thirty-four (58.6%) patients were stage III‒IV, 28 (48.3%) patients were 3‒5 of International Prognostic Index (IPI) and 38 (65.5%) were 2‒4 of Prognostic Index for T-cell lymphoma (PIT). Forty-nine patients received anthracycline based combination chemotherapy and 4 patients received CPCT as first-line therapy. All the 5 ENKTL patients received asparaginase based combination chemotherapy as first-line therapy. Tirty-nine patients received chidamide as a maintenance therapy after first-line treatment and 19 patients after salvage treatment. The median number of prior systemic therapies was 2 (2‒4). A total of 6 patients received ASCT, with 3 patients were after first-line treatment, 3 were after salvage treatment. Five of them received maintenance of chidamide after ASCT. Table 1 Baseline of 58 PTCLs patients. Total (%) First-line (%) Salvage (%) Gender Male 43 (74.1) 29 (67.4) 12 (32.6) Female 15 (25.9) 9 (60.0) 6 (40.0) Age ≤ 60 19 (32.8) 10 (52.6) 9 (47.4) > 60 39 (67.2) 29 (74.4) 10 (25.6) Ann Arbor stage I‒II 24 (41.4) 14 (58.3) 10 (41.7) III‒IV 34 (58.6) 25 (73.5) 9 (26.5) ECOG PS 0‒1 52 (90.0) 30 (57.7) 22 (42.3) 2‒4 6 (10.0) 5 (83.3) 1 (16.7) ALB <LLN 11 (19.0) 9 (81.8) 2 (18.2) ≥LLN 47 (81.0) 30 (63.8) 17 (36.2) IPI 0‒2 30 (51.7) 23 (76.7) 7 (23.3) 3‒5 28 (48.3) 16 (57.1) 12 (42.9) PIT 0‒1 20 (34.5) 15 (75.0) 5 (25.0) 2‒4 38 (65.5) 24 (63.2) 14 (36.8) Pathologic subtypes AITL 34 (58.6) 21 (61.8) 13 (38.2) PTCL-NOS 10 (17.2) 4 (40.0) 6 (60.0) ALK + ALCL 1 (1.7) 1 (100.0) 0 (0.0) ALK-ALCL 7 (12.1) 3 (42.9) 4 (57.1) ENKTL 5 (8.6) 1 (20.0) 4 (80.0) MEITL 1 (1.7) 1 (100.0) 0 (0.0) Abbreviations: ALB, albumin; ECOG PS, Eastern Cooperative Oncology Group performance status; LLN, lower limit of normal; IPI, International Prognostic Index; PIT, Prognostic Index for T-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; ENKTL, extranodal NK/T-cell lymphoma; ALCL, anaplastic large cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma 3.2 Survival and efficacy The median follow-up time was 39 (2–79) months, the median PFS was 33 months, and the median OS had not been reached (Fig. 1 A and 1 B) for all patients. The one-year PFS and OS rates were 64.1% (95% CI, 23.3%‒71.6%) and 91.16% (95% CI, 53.2%‒96.5%), respectively; the two-year PFS and OS rates were 57.82% (95% CI, 25.3%‒74.9%) and 82.92% (95% CI, 51.4%‒92.1%), respectively; and the five-year PFS and OS rates were 36.92% (95% CI, 22.7%‒49.1%) and 77.39% (95% CI, 50.2%‒89.1%), respectively. The median PFS and OS of the patients who received first-line maintenance therapy were not reached, which were significantly better compared to patients who received chidamide as salvage treatment maintenance (the median PFS and OS were 7 and 67 months, P < 0.001 and P = 0.009, respectively) (Fig. 1 C and 1 D). The five-year PFS and OS rates of patients who received chidamide as first-line maintenance (56.52% and 91.0%, respectively) were significantly better compared to patients who received chidamide as salvage treatment maintenance (8.3% and 58.80%, respectively) ( P < 0.001 and P < 0.001, respectively). The median PFS of AITL was not reached, and the median PFS of PTCL-NOS, ENKTL, ALCL and EMITL were 16.5, 41, 19 and 7 months, respectively. The median OS of AITL, PTCL-NOS, ENKTL were not reached, and the median OS of ALCL and EMITL were 68 and 12 months, respectively. There was no statistical difference in PFS and OS among the different pathological subtypes, but AITL seemed to achieve a better PFS (Fig. 1 E and 1 F). PFS and OS were not differed significantly between patients with CR and PR after first-line treatment (the 2-year PFS was 69.0% and 64.3%, respectively, P = 0.778; the 2-year OS was 92.1% and 83.3%, respectively, P = 0.512). Among the 39 patients who underwent chidamide maintenance after first-line treatment, 30/39 (76.9%) patients began maintenance after reaching CR and 9/39 (23.1%) after achieving PR. Notably, 8 of 9 (88.9%) patients who were PR after first-line treatment achieved CR from PR during maintenance treatment, with a median time of 6 (3–12) months. A total of 11/39 (28.2%) patients experienced disease progression during the maintenance treatment, and their median duration of remission was 6 (3‒13) months. Among them, 2 patients experienced disease progression 2 to 3 months after drug withdrawal due to COVID-19 infection. Three patients received ASCT after first-line treatment, and 2 of them received chidamide maintenance treatment after ASCT, 1 patient sustained CR during maintenance treatment and is still being followed up. One patient stopped maintenance treatment due to personal reason after 1 year, and the disease progressed 2 months later. One patient did not receive chidamide maintenance treatment after ASCT, and the disease progressed 2 years later. A total of 19 patients who received maintenance treatment after salvage therapy, 9 (47.4%) received maintenance therapy after CR and 10 (52.6%) received maintenance therapy after PR. Among them, 9/19 (47.4%) had disease progression and their median duration of remission was 16 (2‒25) months. The remaining 10 patients (8 CR and 2 PR) were still undergoing maintenance treatment and follow-up. Three patients received ASCT after salvage treatment, and all of them received maintenance of chidamide after ASCT. All the 3 patient sustained CR during maintenance treatment and is still being followed up. The median duration of response (DOR) of them was 48 months (24‒60 months). Up to the last follow-up date there were 29 patients who manifested a DOR more than 24 months and 8 patients with a DOR more than 60 months (Table 2 ). We did not observe any meaningful differences in PFS and OS regarding any of the other clinical characteristics of age, gender, IPI, PIT, albumin (ALB), ferritin, β2-microglobulin (β2-MG) or the pathologic subtypes (Figs. 2 and 3 ). Table 2 Clinical characteristics and outcomes of individual cases with long-term DOR (> 60 months) No. Subtype Age Sex Maintenance Disease staging at enrollment IPI PIT Evaluation after induction therapy ASCT OS (months) Alive (0) /Dead (1) 01 AITL 76 Female First-line III 3 3 CR N 69 0 02 AITL 68 Male First-line IV 4 3 CR N 63 0 03 AITL 56 Male First-line III 2 2 CR N 62 0 04 ALK + ALCL 29 Male First-line IV 2 3 CR N 65 0 05 AITL 65 Female First-line IV 3 3 CR N 74 0 06 AITL 63 Male First-line III 2 2 CR Y 62 0 07 PTCL-NOS 59 Male Salvage III 2 2 PD N 66 0 08 AITL 61 Female Salvage III 2 2 PD Y 65 0 PTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; ALCL, anaplastic large-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; PIT, Prognostic Index for T-cell lymphoma; DOR, duration of response; CR, complete response; PD, progressive disease; N, no; Y, yes; Auto-HSCT, autologous hematopoietic stem cell transplantation; OS, overall survival. 3.3 Safety The median maintenance treatment time for all patients was 16 (1–72) months, and the median maintenance dose was 20 (15–30) mg twice weekly. Eighteen patients took chidamide as maintenance treatment for more than 24 months, and 2 patients took chidamide for more than 60 months. The most common toxicities were hematologic toxicities, including neutropenia (42, 72.4%), anemia (23, 39.7%), and thrombocytopenia (29, 50.0%), followed by fatigue (35, 60.3%), anorexia (31, 53.4%), liver dysfunction (10, 17.2%), and pneumonia (4, 6.9%). Most adverse events were grade 1 or 2, and the grade 3‒4 adverse events were neutropenia (15/42), thrombocytopenia (7/29), fatigue (1/35), and pneumonia (2/4). Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment (two patients with severe pulmonary infections, and one patient had intolerable fatigue) due to adverse events (Table 3 ). One patient stopped maintenance treatment after taking chidamide for 10 months for financial reasons and he is still in follow-up. Table 3 Adverse events of PTCL patients with chidamide maintenance treatment Event Any grade Grade ≥ 3 n % n % Hematologic adverse events Thrombocytopenia 29 50.0 7 12.1 Neutropenia 42 72.4 15 25.9 Anemia 23 39.7 0 0.0 Non-hematologic adverse events Fatigue 35 60.3 1 1.7 Anorexia 31 53.4 0 0.0 Lung infection 4 6.9 2 3.4 Increase in aminotransferase 10 17.2 0 0.0 4. Discussion PTCL is a type of NHLs with strong heterogeneity and poor prognosis. Although brentuximab vedotin has been approved for the treatment of CD30 positive PTCLs, the ECHELON-2 study results showed significant benefits for ALCL patients in subgroup analysis, but not significant improvements in PFS and OS for other pathological types of patients [ 18 ]. At present, it is widely believed that ASCT can improve the prognosis of PTCL patients, but PTCL patients often occur in the elderly with poor physical condition and are often unable to tolerate ASCT. A a prospective, multicenter cohort study showed the estimated 2-year OS and PFS rates for patients with AITL in the ASCT group were 93.3% and 68.8% ,and 52.9% and 41.2% in the non-ASCT group, but the median OS and PFS were not significantly different between the ASCT and non-ASCT groups for patients with PTCL NOS [ 19 ]. And the role of ASCT in relapsed PTCL remains unproven [ 20 ]. Therefore, exploring effective maintenance treatment is imminent. HDAC inhibitors have been approved to have significant anticancer potential for R/R PTCL. Chidamide is a novel member of the oral benzamide class of HDAC inhibitors. The pivotal phase II study of chidamide showed the ORR was 66.2%, and it was approved in 2014 by the CFDA for the treatment of R/R PTCL [ 15 ]. Previous studies showed that chidamide could inhibit proliferation and induce apoptosis via cell cycle arrest and the regulation of apoptotic proteins, and it could also activate NK-cell and antigen-specific CD8 + cytotoxic T-lymphocyte-mediated cellular antitumor immunity [ 9 , 10 ]. Our previous study showed that chidamide could upregulate adaptive immune-associated genes in PD‐1 + cells of PTCL patients, which means it may reverse the drug resistance of tumor cells [ 21 ]. Based on the good efficacy of chidamide in the treatment of R/R PTCL, many researchers have further explored the efficacy and safety of chidamide in newly diagnosed PTCL patients. Yawen Wang et al. explored the efficacy and safety of chidamide plus prednisone, etoposide, and thalidomide (CPET) for untreated angioimmunoblastic T-cell lymphoma in a Chinese population, the results showed that the ORR and CRR of the 51 patients were 90.2 and 54.9%, respectively, and the median PFS was 42.6 months, and the median OS was not reached [ 22 ]. Qingqing Cai et al. compared the efficacy and safety of chemotherapy combined with chidamide (ChT + C) versus chemotherapy (ChT) in newly diagnosed PTCLs, they found that patients in ChT + C group had superior PFS compared with patients in ChT group, and the benefits of ChT + C are higher for patients with high IPI scores, there was no significantly statistical difference observed between the two groups in OS. It is worth noting that, the median duration of response in ChT group and ChT + C group were 10.0 months and 14.0 months, with no significant difference ( P = 0.135) [ 23 ]. The above research indicates that chidamide combined with chemotherapy has achieved good efficacy in first-line treatment of PTCL, but how to further prolong the duration of response, improve PFS and OS is still a problem worth exploration. Wei Guo et al. reported the potential benefit of chidamide maintenance therapy after first-line therapy. The median follow-up period was 12.8 months (3.0–66.6), 14 patients developed PD (29.2%), 10 of them died of lymphoma (20.8%). No patients discontinued chidamide because of AEs. The most common toxicities were neutropenia, anemia, thrombocytopenia, anorexia, and fatigue [ 24 ]. In this study, we explored the efficacy and safety of chidamide as maintenance therapy either after first-line treatment or salvage treatment. During a follow-up period of 39 (2‒79) months, median PFS was 33 months and the OS median was not reached for the whole cohort, and the five-year PFS and OS rates were 36.92% and 77.39%, respectively. Further analysis showed that patients who received first-line maintenance therapy had better PFS and OS than patients who received chidamide as salvage treatment maintenance, indicating that early maintenance treatment of chidamide after reaching PR or CR in first-line treatment can help reduce recurrence rate, prolong PFS and OS with tolerable AEs. Notably, 8 of 9 (88.9%) patients who were PR after first-line treatment achieved CR from PR during maintenance treatment, with a median time of 6 (3–12) months, indicating that chidamide can also improve the efficacy in maintenance phase and finally get long-term remission. Among these 8 patients, 5 were diagnosed with AITL. Although there was no statistical difference in PFS and OS among the different pathological subtypes, AITL seemed to have a better PFS and OS. Meanwhile, among the 8 patients with a DOR greater than 60 months, 6 (75.0%) patients were AITL, further confirming that continuous maintenance treatment with chidamide can improve the PFS and OS for PTCLs, especially for the AITL due to its high mutations of epigenetic genes like TET2, RhoA, IDH2 [ 25 – 27 ]. It is worth noting that a total of 6 patients received ASCT after first-line or salvage treatment, 5 of them received chidamide maintenance treatment after ASCT, and 1 patient had disease progressed after suspending maintenance treatment, while the remaining 4 patients were still remission. One patient did not receive chidamide maintenance treatment after ASCT, and the disease progressed 2 years later. The results suggested that chidamide maintenance treatment is still necessary for patients after ASCT, but due to the small number of cases, this conclusion is needed for further validation. There were several limitations to the present study. This study is a retrospective analysis, lacking contemporaneous control data, and the number of patients is small. At the same time, there is still no consensus on how long maintenance treatment should last and when maintenance medication can be discontinued, these issues are needed further exploration. In conclusion, our study indicated that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy. And we also found that it is necessary to take chidamide as maintenance therapy after ASCT to prolong the remission time. We conclude that chidamide can be used as a maintenance treatment to improve the survival of patients with PTCLs. Declarations Ethical standards statement : All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5). Statement of informed consent : Informed consent was obtained from all patients for being included in the study. Competing interests : The authors declare that there is no conflict of interest regarding the publication of this paper. Author Contributions: Hao-rui Shen, Jia-zhu Wu and Jin-hua Liang prepared the manuscript; Wei Xu and Li Wang designed the research; Hua Yin and Hao-rui Shen performed the data collection, Jia-Zhu Wu,Rui Gao and Jin-Hua Liang analyzed the data; Hua-Yin, Yue Li, Rui Gao and Xin-Yu Zhang performed statistical analysis; Hao-Rui Shen, Jia-Zhu Wu, Jin-Hua Liang, Yue Li, Xin-Yu Zhang, Yi-Lin Kong and Bi-Hui Pan clinically managed patients. Jian-yong Li, Wei Xu and Li Wang critically reviewed and analyzed results. Funding : This research was funded by the National Natural Science Foundation of China (grant number 82200887 and 82370194), the Social Development Project of Jiangsu Province Science and Technology Plan (grant number BE2023775 and BE2023780), Nature Science Foundation for Youth of Jiangsu Province (grant number BK20220716)，China Postdoctoral Science Foundation (grant number 2022M711404), Yong Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (grant number PY2021028). References Swerdlow SH, Campo E, Pileri SA et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127: 2375-2390. Fiore D, Cappelli LV, Broccoli A et al. Peripheral T cell lymphomas: from the bench to the clinic. Nat Rev Cancer 2020; 20: 323-342. Sun J, Yang Q, Lu Z et al. Distribution of lymphoid neoplasms in China: analysis of 4,638 cases according to the World Health Organization classification. 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Am J Hematol 2022; 97: 623-629. Wang J, Su N, Fang Y et al. Comparison of Chemotherapy Combined With Chidamide Versus Chemotherapy in the Frontline Treatment for Peripheral T-Cell Lymphoma. Front Immunol 2022; 13: 835103. Guo W, Wang X, Li J et al. Chidamide Maintenance Therapy Following Induction Therapy in Patients With Peripheral T-Cell Lymphoma Who Are Ineligible for Autologous Stem Cell Transplantation: Case Series From China. Front Oncol 2022; 12: 875469. Timmins MA, Wagner SD, Ahearne MJ. The new biology of PTCL-NOS and AITL: current status and future clinical impact. Br J Haematol 2020; 189: 54-66. Palomero T, Couronne L, Khiabanian H et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 2014; 46: 166-170. Odejide O, Weigert O, Lane AA et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2014; 123: 1293-1296. Additional Declarations No competing interests reported. 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Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jia-Zhu","middleName":"","lastName":"Wu","suffix":""},{"id":264531744,"identity":"f6910b4f-e933-44e4-8549-223282ce15d4","order_by":2,"name":"Jin-Hua Liang","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin-Hua","middleName":"","lastName":"Liang","suffix":""},{"id":264531745,"identity":"63ca3978-9416-4b5c-acaa-95dc845bead9","order_by":3,"name":"Yue Li","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yue","middleName":"","lastName":"Li","suffix":""},{"id":264531746,"identity":"d4583848-7407-4998-ada4-afaac4aad674","order_by":4,"name":"Xin-Yu Zhang","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xin-Yu","middleName":"","lastName":"Zhang","suffix":""},{"id":264531747,"identity":"d10f6b7b-cbb0-4903-9d82-140f6fd65dd6","order_by":5,"name":"Yi-Lin Kong","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yi-Lin","middleName":"","lastName":"Kong","suffix":""},{"id":264531748,"identity":"00d14a08-d018-4f66-bde1-b0a39739f68b","order_by":6,"name":"Bi-Hui Pan","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Bi-Hui","middleName":"","lastName":"Pan","suffix":""},{"id":264531749,"identity":"f0c01481-1b72-457d-bdf0-7f7a9508ac42","order_by":7,"name":"Rui Gao","email":"","orcid":"","institution":"Department of Endocrinology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Rui","middleName":"","lastName":"Gao","suffix":""},{"id":264531750,"identity":"f6139f9b-5cbd-4c22-ba70-3fdfbc4f53df","order_by":8,"name":"Jian-Yong Li","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jian-Yong","middleName":"","lastName":"Li","suffix":""},{"id":264531751,"identity":"0bdf6e98-e5e6-4079-b2a7-9072d53d2c44","order_by":9,"name":"Li Wang","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Wang","suffix":""},{"id":264531752,"identity":"7777bfdb-1cb5-4e54-8b24-e16db7a097c5","order_by":10,"name":"Hua Yin","email":"","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Yin","suffix":""},{"id":264531753,"identity":"b83ad0b8-b11a-473a-bba8-bb14b07ba4f6","order_by":11,"name":"Wei Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3UlEQVRIiWNgGAWjYLCCBAMJHjZm5mNgDhs7UVoKbOT42dvSgCygFmairPmQZizZc8YMrIWBkBaDGzmGDx4YHE7ccCPn24OPP7bJ8zEzMH74mINbi+SMHGODBLCW3O2GMxJuG7YxMzBLztyGWwu/RO42CaiWbdI8CbcZgVrYmHnxaGGTyN3+A6Il5xlIiz1BLSBbgIEM9j4bSEsiQS2SPe8/Ax0GDmQzyRlpt5PbmBmb8frF4Hha4scff8BR+Uzig81t2/ntzQc/fMSjBRtgbCBN/SgYBaNgFIwCDAAA2jdPWsWTRt0AAAAASUVORK5CYII=","orcid":"","institution":"Department of Hematology, The First Afliated Hospital of Nanjing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Wei","middleName":"","lastName":"Xu","suffix":""}],"badges":[],"createdAt":"2023-12-25 13:44:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3804699/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3804699/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":49091128,"identity":"72053ed5-66a6-42d2-9776-12abde31dcfa","added_by":"auto","created_at":"2024-01-03 01:48:16","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":226224,"visible":true,"origin":"","legend":"\u003cp\u003eThe PFS and OS curves (A and B) for the whole cohort. The median PFS and OS of the patients who received first-line maintenance therapy were significantly better compared to patients who received chidamide as salvage treatment maintenance (C and D). Kaplan-Meier curves of PFS (E) and OS (F) for different pathological subtypes.\u003c/p\u003e","description":"","filename":"Fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3804699/v1/71eb61793a4521491f1a7b5e.jpg"},{"id":49091129,"identity":"4a68a9ef-8f19-4bdf-8d8e-05b9725c9b0a","added_by":"auto","created_at":"2024-01-03 01:48:16","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":347188,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate Cox regression analysis of prognosis factors for progression-free survival (PFS).\u003c/p\u003e","description":"","filename":"Fig2.UnivariateCoxregressionanalysisofprognosisfactorsforprogressionfreesurvivalPFS..jpg","url":"https://assets-eu.researchsquare.com/files/rs-3804699/v1/4d3c2fe9b18ff7954b964463.jpg"},{"id":49091130,"identity":"964a5718-edfc-420d-a8fa-1df482a3fe2a","added_by":"auto","created_at":"2024-01-03 01:48:16","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":355094,"visible":true,"origin":"","legend":"\u003cp\u003eUnivariate Cox regression analysis of prognosis factors for overall survival (OS)\u003c/p\u003e","description":"","filename":"Fig3.UnivariateCoxregressionanalysisofprognosisfactorsforoverallsurvivalOS.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3804699/v1/8c3738465359604cede3efe3.jpg"},{"id":51895400,"identity":"3260be6e-6cd8-4cef-952e-43d157ac9d44","added_by":"auto","created_at":"2024-03-02 10:42:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":508864,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3804699/v1/42eb5c4d-ad0c-402b-b5a1-89d7a1a107d1.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The efficacy and safety of a Histone deacetylase inhibitor: chidamide as a maintenance therapy for peripheral T-cell lymphoma","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003ePeripheral T-cell lymphomad (PTCL) is a set of rare and highly heterogeneous tumors of non-Hodgkin\u0026rsquo;s lymphoma (NHL) with inferior outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The incidence of PTCL is much higher in China compared to western countries [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. The most common types of PTCLs include PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), extranodal NK/T-cell lymphoma (ENKTL), anaplastic large cell lymphoma (ALCL) and monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. There is no standard treatment for PTCL patients, although conventional chemotherapy includes cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen is widely applied, it is usually associated with a poor response and high disease relapse rates [\u003cspan additionalcitationids=\"CR6 CR7\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eHistone deacetylase (HDAC) have traditionally been described as belonging to one of the 4 classes: I, IIa, IIb, and IV, and plays important roles in oncogenesis. It triggers chromatin remodeling by inhibiting HDACs to increase the acetylation level of chromatin histones, resulting in changes in gene expression targeting multiple signaling pathways (i.e. epigenetic changes), thereby inhibiting tumor cell cycle, inducing tumor cell apoptosis, and regulating immune activity, inducing and enhancing natural killer cells (NK) and antigen-specific cytotoxic T cells (CTL) mediated tumor killing effects [\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Chidamide also plays a potential role in restoring drug sensitivity of tumor cells and inhibiting tumor metastasis and recurrence by inducing tumor stem cell differentiation and reversing epithelial mesenchymal phenotype transformation (EMT) through epigenetic regulatory [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. HDAC inhibitors, including romidepsin and belinostat, have shown efficacy in the treatment of relapse/refractory (R/R) PTCL, and they were approved by the US Food and Drug Administration (FDA) for the treatment of R/R PTCL [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Chidamide is a novel benzamide class of HDAC inhibitor (HDACi), that was approved by the Chinese Food and Drug Administration (CFDA) for the treatment of R/R PTCL patients [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the role of chidamide in PTCL maintenance therapy is still uncertain, this study aimed to assess the efficacy and safety of chidamide as a maintenance therapy after induction or salvage treatment in patients with PTCLs.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design and procedure\u003c/h2\u003e \u003cp\u003eThis was a retrospective, single center, single-arm study (NCT05967949). All patients were diagnosed according to WHO 2016 tumor and hematopoietic lymphoid tissue classification for pathology [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], including AITL, PTCL-NOS, ALCL, ENKTL and MEITL. All patients were required to have achieved a complete response (CR) or partial response (PR) after induction or salvage treatment. Patients with the following conditions were excluded: (1) who were pregnant or breastfeeding; (2) who had class III or IV cardiac failure according to New York Heart Association, or had a history of acute coronary syndrome, acute heart failure, or severe ventricular arrhythmia in the previous six months; (3) positive for HIV, syphilis, HCV, or with an HBV viral load (HBV DNA)\u0026thinsp;\u0026gt;\u0026thinsp;1\u0026times;10\u003csup\u003e5\u003c/sup\u003e copies/ml; (4) with poor hepatic function defined as total bilirubin\u0026thinsp;\u0026gt;\u0026thinsp;1.5 times the upper-normal level, alanine aminotransferase (ALT) or aspartate aminotransferase (AST)\u0026thinsp;\u0026gt;\u0026thinsp;2 times the upper-normal level or \u0026gt;\u0026thinsp;5 times the upper-normal level with hepatic involvement; (5) with poor renal function defined as serum creatinine\u0026thinsp;\u0026gt;\u0026thinsp;1.5 times the upper-normal level.\u003c/p\u003e \u003cp\u003e All aspects of this study were performed in accordance with the principles of the Declaration of Helsinki (2013 No. 64). The research was approved by the Centralized Ethics Committee of The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital (the clinical registration number was 2023-SR-297). All patients provided written informed consent, and this study was registered at ClinicalTrials.gov (NCT05967949).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Treatment and Procedures\u003c/h2\u003e \u003cp\u003eThe first-line induction therapy for PTCL (except for ENKTL) patients was anthracycline based combination chemotherapy, like CHOP, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) and dose-adjusted (DA)-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin), and CPCT (chidamide, prednisone, cyclophosphamide, thalidomide) regimen was for patients who cannot tolerate chemotherapy; The first-line induction therapy for ENKTL patients was asparaginase based combination chemotherapy.\u003c/p\u003e \u003cp\u003eAfter reaching CR or PR after treatment, all patients are evaluated for the feasibility of autologous hematopoietic stem cell transplantation (ASCT). Patients received chidamide 20 mg alone twice a week as consolidation therapy after CR or PR after first-line or salvage treatment. Response assessments were performed by clinical examination and positron emission tomography (PET) / computer tomography (CT) or CT. During maintenance therapy, every 3 months in the first year, and every 6 months after 1 year. All responses were determined using the clinical and radiologic criteria of the international National Cancer Institute (NCI)-Sponsored International Working Group that focused on the use of enhanced CT scans [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e] and the Lugano 2014 criteria that focused on the use of positron emission tomography (PET)/CT [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].. Patients received chidamide treatment until disease progression or unacceptable toxicity.\u003c/p\u003e \u003cp\u003eThe main purpose of this study is to evaluate the progression-free survival (PFS), overall survival (OS) and safety of chidamide in maintenance treatment. PFS was defined as the time from the date of diagnosis to the date of recurrence or progression. OS referred to the interval between diagnosis and death due to any cause or the end of follow-up. Safety assessments included physical examinations, laboratory parameters, and adverse events (AEs), which were graded using the National Cancer Institute Common Toxicity Criteria for Adverse Events scale, version 4.0.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Statistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SPSS statistical software (version26.0), MedCalc statistical software (version 20.1.0) and GraphPad Prism (version 9.0). Categorical variables were expressed as percentage (%). Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation or median (interquartile range). Differences in continuous variables between two groups were assessed by two-tailed Student\u0026rsquo;s t-test while for differences between more groups one-way ANOVA followed by a post hoc test was used. Survival curves were drawn using the Kaplan-Meier method, and differences in survival were compared using the log-rank test. A two-sided P value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Baseline characteristics\u003c/h2\u003e \u003cp\u003eFifty-eight patients were enrolled in our study between January 2015 and July 2022, the baseline characteristics of evaluable patients are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The median age was 66 (29‒83) years old. Patients with AITL represented the largest subgroup (34, 58.6%), followed by PTCL-NOS (10, 17.2%), ALCL (8, 13.8%), ENKTL (5, 8.6%) and MEITL (1, 1.7). Thirty-four (58.6%) patients were stage III‒IV, 28 (48.3%) patients were 3‒5 of International Prognostic Index (IPI) and 38 (65.5%) were 2‒4 of Prognostic Index for T-cell lymphoma (PIT). Forty-nine patients received anthracycline based combination chemotherapy and 4 patients received CPCT as first-line therapy. All the 5 ENKTL patients received asparaginase based combination chemotherapy as first-line therapy. Tirty-nine patients received chidamide as a maintenance therapy after first-line treatment and 19 patients after salvage treatment. The median number of prior systemic therapies was 2 (2‒4). A total of 6 patients received ASCT, with 3 patients were after first-line treatment, 3 were after salvage treatment. Five of them received maintenance of chidamide after ASCT.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline of 58 PTCLs patients.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFirst-line (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSalvage (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e43 (74.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29 (67.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12 (32.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e15 (25.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (60.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6 (40.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026le;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19 (32.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10 (52.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9 (47.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e39 (67.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29 (74.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (25.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnn Arbor stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eI‒II\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24 (41.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14 (58.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10 (41.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIII‒IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34 (58.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25 (73.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9 (26.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG PS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0‒1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e52 (90.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30 (57.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e22 (42.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2‒4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6 (10.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5 (83.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1 (16.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALB\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;LLN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11 (19.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e9 (81.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2 (18.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026ge;LLN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47 (81.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30 (63.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e17 (36.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIPI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0‒2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30 (51.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23 (76.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7 (23.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3‒5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28 (48.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16 (57.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12 (42.9)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePIT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0‒1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e20 (34.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15 (75.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5 (25.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2‒4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38 (65.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e24 (63.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e14 (36.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathologic subtypes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34 (58.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e21 (61.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13 (38.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCL-NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10 (17.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4 (40.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6 (60.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALK\u0026thinsp;+\u0026thinsp;ALCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALK-ALCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7 (12.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3 (42.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (57.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eENKTL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5 (8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (20.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (80.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMEITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1 (1.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1 (100.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0 (0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviations: ALB, albumin; ECOG PS, Eastern Cooperative Oncology Group performance status; LLN, lower limit of normal; IPI, International Prognostic Index; PIT, Prognostic Index for T-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; PTCL-NOS, peripheral T-cell lymphoma-not otherwise specified; ENKTL, extranodal NK/T-cell lymphoma; ALCL, anaplastic large cell lymphoma; MEITL, monomorphic epitheliotropic intestinal T-cell lymphoma\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Survival and efficacy\u003c/h2\u003e \u003cp\u003eThe median follow-up time was 39 (2\u0026ndash;79) months, the median PFS was 33 months, and the median OS had not been reached (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB) for all patients. The one-year PFS and OS rates were 64.1% (95% CI, 23.3%‒71.6%) and 91.16% (95% CI, 53.2%‒96.5%), respectively; the two-year PFS and OS rates were 57.82% (95% CI, 25.3%‒74.9%) and 82.92% (95% CI, 51.4%‒92.1%), respectively; and the five-year PFS and OS rates were 36.92% (95% CI, 22.7%‒49.1%) and 77.39% (95% CI, 50.2%‒89.1%), respectively. The median PFS and OS of the patients who received first-line maintenance therapy were not reached, which were significantly better compared to patients who received chidamide as salvage treatment maintenance (the median PFS and OS were 7 and 67 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eD). The five-year PFS and OS rates of patients who received chidamide as first-line maintenance (56.52% and 91.0%, respectively) were significantly better compared to patients who received chidamide as salvage treatment maintenance (8.3% and 58.80%, respectively) (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). The median PFS of AITL was not reached, and the median PFS of PTCL-NOS, ENKTL, ALCL and EMITL were 16.5, 41, 19 and 7 months, respectively. The median OS of AITL, PTCL-NOS, ENKTL were not reached, and the median OS of ALCL and EMITL were 68 and 12 months, respectively. There was no statistical difference in PFS and OS among the different pathological subtypes, but AITL seemed to achieve a better PFS (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eE and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eF). PFS and OS were not differed significantly between patients with CR and PR after first-line treatment (the 2-year PFS was 69.0% and 64.3%, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.778; the 2-year OS was 92.1% and 83.3%, respectively, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.512).\u003c/p\u003e \u003cp\u003eAmong the 39 patients who underwent chidamide maintenance after first-line treatment, 30/39 (76.9%) patients began maintenance after reaching CR and 9/39 (23.1%) after achieving PR. Notably, 8 of 9 (88.9%) patients who were PR after first-line treatment achieved CR from PR during maintenance treatment, with a median time of 6 (3\u0026ndash;12) months. A total of 11/39 (28.2%) patients experienced disease progression during the maintenance treatment, and their median duration of remission was 6 (3‒13) months. Among them, 2 patients experienced disease progression 2 to 3 months after drug withdrawal due to COVID-19 infection. Three patients received ASCT after first-line treatment, and 2 of them received chidamide maintenance treatment after ASCT, 1 patient sustained CR during maintenance treatment and is still being followed up. One patient stopped maintenance treatment due to personal reason after 1 year, and the disease progressed 2 months later. One patient did not receive chidamide maintenance treatment after ASCT, and the disease progressed 2 years later.\u003c/p\u003e \u003cp\u003eA total of 19 patients who received maintenance treatment after salvage therapy, 9 (47.4%) received maintenance therapy after CR and 10 (52.6%) received maintenance therapy after PR. Among them, 9/19 (47.4%) had disease progression and their median duration of remission was 16 (2‒25) months. The remaining 10 patients (8 CR and 2 PR) were still undergoing maintenance treatment and follow-up. Three patients received ASCT after salvage treatment, and all of them received maintenance of chidamide after ASCT. All the 3 patient sustained CR during maintenance treatment and is still being followed up. The median duration of response (DOR) of them was 48 months (24‒60 months).\u003c/p\u003e \u003cp\u003eUp to the last follow-up date there were 29 patients who manifested a DOR more than 24 months and 8 patients with a DOR more than 60 months (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). We did not observe any meaningful differences in PFS and OS regarding any of the other clinical characteristics of age, gender, IPI, PIT, albumin (ALB), ferritin, β2-microglobulin (β2-MG) or the pathologic subtypes (Figs.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical characteristics and outcomes of individual cases with long-term DOR (\u0026gt;\u0026thinsp;60 months)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"12\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubtype\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMaintenance\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDisease staging at enrollment\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIPI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePIT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eEvaluation after induction therapy\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eASCT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eOS (months)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e \u003cp\u003eAlive (0) /Dead (1)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e69\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eALK\u003csup\u003e+\u003c/sup\u003eALCL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFirst-line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTCL-NOS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSalvage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAITL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSalvage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eIII\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003ePD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003eY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c11\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c12\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"12\"\u003ePTCL-NOS, peripheral T-cell lymphoma, not otherwise specified; ALCL, anaplastic large-cell lymphoma; AITL, angioimmunoblastic T-cell lymphoma; PIT, Prognostic Index for T-cell lymphoma; DOR, duration of response; CR, complete response; PD, progressive disease; N, no; Y, yes; Auto-HSCT, autologous hematopoietic stem cell transplantation; OS, overall survival.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Safety\u003c/h2\u003e \u003cp\u003eThe median maintenance treatment time for all patients was 16 (1\u0026ndash;72) months, and the median maintenance dose was 20 (15\u0026ndash;30) mg twice weekly. Eighteen patients took chidamide as maintenance treatment for more than 24 months, and 2 patients took chidamide for more than 60 months. The most common toxicities were hematologic toxicities, including neutropenia (42, 72.4%), anemia (23, 39.7%), and thrombocytopenia (29, 50.0%), followed by fatigue (35, 60.3%), anorexia (31, 53.4%), liver dysfunction (10, 17.2%), and pneumonia (4, 6.9%). Most adverse events were grade 1 or 2, and the grade 3‒4 adverse events were neutropenia (15/42), thrombocytopenia (7/29), fatigue (1/35), and pneumonia (2/4). Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment (two patients with severe pulmonary infections, and one patient had intolerable fatigue) due to adverse events (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). One patient stopped maintenance treatment after taking chidamide for 10 months for financial reasons and he is still in follow-up.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events of PTCL patients with chidamide maintenance treatment\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEvent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAny grade\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e \u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003en\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHematologic adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e12.1\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e72.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e25.9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e39.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNon-hematologic adverse events\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e60.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnorexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIncrease in aminotransferase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003ePTCL is a type of NHLs with strong heterogeneity and poor prognosis. Although brentuximab vedotin has been approved for the treatment of CD30 positive PTCLs, the ECHELON-2 study results showed significant benefits for ALCL patients in subgroup analysis, but not significant improvements in PFS and OS for other pathological types of patients [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. At present, it is widely believed that ASCT can improve the prognosis of PTCL patients, but PTCL patients often occur in the elderly with poor physical condition and are often unable to tolerate ASCT. A a prospective, multicenter cohort study showed the estimated 2-year OS and PFS rates for patients with AITL in the ASCT group were 93.3% and 68.8% ,and 52.9% and 41.2% in the non-ASCT group, but the median OS and PFS were not significantly different between the ASCT and non-ASCT groups for patients with PTCL NOS [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. And the role of ASCT in relapsed PTCL remains unproven [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Therefore, exploring effective maintenance treatment is imminent.\u003c/p\u003e \u003cp\u003eHDAC inhibitors have been approved to have significant anticancer potential for R/R PTCL. Chidamide is a novel member of the oral benzamide class of HDAC inhibitors. The pivotal phase II study of chidamide showed the ORR was 66.2%, and it was approved in 2014 by the CFDA for the treatment of R/R PTCL [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Previous studies showed that chidamide could inhibit proliferation and induce apoptosis via cell cycle arrest and the regulation of apoptotic proteins, and it could also activate NK-cell and antigen-specific CD8\u003csup\u003e+\u003c/sup\u003e cytotoxic T-lymphocyte-mediated cellular antitumor immunity [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Our previous study showed that chidamide could upregulate adaptive immune-associated genes in PD‐1\u003csup\u003e+\u003c/sup\u003e cells of PTCL patients, which means it may reverse the drug resistance of tumor cells [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBased on the good efficacy of chidamide in the treatment of R/R PTCL, many researchers have further explored the efficacy and safety of chidamide in newly diagnosed PTCL patients. Yawen Wang et al. explored the efficacy and safety of chidamide plus prednisone, etoposide, and thalidomide (CPET) for untreated angioimmunoblastic T-cell lymphoma in a Chinese population, the results showed that the ORR and CRR of the 51 patients were 90.2 and 54.9%, respectively, and the median PFS was 42.6 months, and the median OS was not reached [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Qingqing Cai et al. compared the efficacy and safety of chemotherapy combined with chidamide (ChT\u0026thinsp;+\u0026thinsp;C) versus chemotherapy (ChT) in newly diagnosed PTCLs, they found that patients in ChT\u0026thinsp;+\u0026thinsp;C group had superior PFS compared with patients in ChT group, and the benefits of ChT\u0026thinsp;+\u0026thinsp;C are higher for patients with high IPI scores, there was no significantly statistical difference observed between the two groups in OS. It is worth noting that, the median duration of response in ChT group and ChT\u0026thinsp;+\u0026thinsp;C group were 10.0 months and 14.0 months, with no significant difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.135) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe above research indicates that chidamide combined with chemotherapy has achieved good efficacy in first-line treatment of PTCL, but how to further prolong the duration of response, improve PFS and OS is still a problem worth exploration. Wei Guo et al. reported the potential benefit of chidamide maintenance therapy after first-line therapy. The median follow-up period was 12.8 months (3.0\u0026ndash;66.6), 14 patients developed PD (29.2%), 10 of them died of lymphoma (20.8%). No patients discontinued chidamide because of AEs. The most common toxicities were neutropenia, anemia, thrombocytopenia, anorexia, and fatigue [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, we explored the efficacy and safety of chidamide as maintenance therapy either after first-line treatment or salvage treatment. During a follow-up period of 39 (2‒79) months, median PFS was 33 months and the OS median was not reached for the whole cohort, and the five-year PFS and OS rates were 36.92% and 77.39%, respectively. Further analysis showed that patients who received first-line maintenance therapy had better PFS and OS than patients who received chidamide as salvage treatment maintenance, indicating that early maintenance treatment of chidamide after reaching PR or CR in first-line treatment can help reduce recurrence rate, prolong PFS and OS with tolerable AEs.\u003c/p\u003e \u003cp\u003eNotably, 8 of 9 (88.9%) patients who were PR after first-line treatment achieved CR from PR during maintenance treatment, with a median time of 6 (3\u0026ndash;12) months, indicating that chidamide can also improve the efficacy in maintenance phase and finally get long-term remission. Among these 8 patients, 5 were diagnosed with AITL. Although there was no statistical difference in PFS and OS among the different pathological subtypes, AITL seemed to have a better PFS and OS. Meanwhile, among the 8 patients with a DOR greater than 60 months, 6 (75.0%) patients were AITL, further confirming that continuous maintenance treatment with chidamide can improve the PFS and OS for PTCLs, especially for the AITL due to its high mutations of epigenetic genes like \u003cem\u003eTET2, RhoA, IDH2\u003c/em\u003e [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. It is worth noting that a total of 6 patients received ASCT after first-line or salvage treatment, 5 of them received chidamide maintenance treatment after ASCT, and 1 patient had disease progressed after suspending maintenance treatment, while the remaining 4 patients were still remission. One patient did not receive chidamide maintenance treatment after ASCT, and the disease progressed 2 years later. The results suggested that chidamide maintenance treatment is still necessary for patients after ASCT, but due to the small number of cases, this conclusion is needed for further validation.\u003c/p\u003e \u003cp\u003eThere were several limitations to the present study. This study is a retrospective analysis, lacking contemporaneous control data, and the number of patients is small. At the same time, there is still no consensus on how long maintenance treatment should last and when maintenance medication can be discontinued, these issues are needed further exploration.\u003c/p\u003e \u003cp\u003eIn conclusion, our study indicated that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy. And we also found that it is necessary to take chidamide as maintenance therapy after ASCT to prolong the remission time. We conclude that chidamide can be used as a maintenance treatment to improve the survival of patients with PTCLs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical standards statement\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eAll procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatement of informed consent\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all patients for being included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThe authors declare that there is no conflict of interest regarding the publication of this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHao-rui Shen, Jia-zhu Wu and Jin-hua Liang prepared the manuscript; Wei Xu and Li Wang designed the research; Hua Yin and Hao-rui Shen performed the data collection, Jia-Zhu Wu,Rui Gao and Jin-Hua Liang analyzed the data; Hua-Yin, Yue Li, Rui Gao and Xin-Yu Zhang performed statistical analysis; Hao-Rui Shen, Jia-Zhu Wu, Jin-Hua Liang, Yue Li, Xin-Yu Zhang, Yi-Lin Kong and Bi-Hui Pan clinically managed patients. Jian-yong Li, Wei Xu and Li Wang critically reviewed and analyzed results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e:\u003c/p\u003e\n\u003cp\u003eThis research was funded by the National Natural Science Foundation of China (grant number 82200887 and 82370194), the Social Development Project of Jiangsu Province Science and Technology Plan (grant number BE2023775 and BE2023780), Nature Science Foundation for Youth of Jiangsu Province (grant number BK20220716)，China Postdoctoral Science Foundation (grant number 2022M711404), Yong Scholars Fostering Fund of the First Affiliated Hospital of Nanjing Medical University (grant number PY2021028).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSwerdlow SH, Campo E, Pileri SA et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016; 127: 2375-2390.\u003c/li\u003e\n\u003cli\u003eFiore D, Cappelli LV, Broccoli A et al. 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J Clin Oncol 2015; 33: 2492-2499.\u003c/li\u003e\n\u003cli\u003eLu X, Ning Z, Li Z et al. Development of chidamide for peripheral T-cell lymphoma, the first orphan drug approved in China. Intractable Rare Dis Res 2016; 5: 185-191.\u003c/li\u003e\n\u003cli\u003eCheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin\u0026apos;s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244.\u003c/li\u003e\n\u003cli\u003eCheson BD, Fisher RI, Barrington SF et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 2014; 32: 3059-3068.\u003c/li\u003e\n\u003cli\u003eHorwitz S, O\u0026apos;Connor OA, Pro B et al. The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma. Ann Oncol 2022; 33: 288-298.\u003c/li\u003e\n\u003cli\u003ePark SI, Horwitz SM, Foss FM et al. The role of autologous stem cell transplantation in patients with nodal peripheral T-cell lymphomas in first complete remission: Report from COMPLETE, a prospective, multicenter cohort study. Cancer 2019; 125: 1507-1517.\u003c/li\u003e\n\u003cli\u003eZhang Y, Xu W, Liu H, Li J. Therapeutic options in peripheral T cell lymphoma. J Hematol Oncol 2016; 9: 37.\u003c/li\u003e\n\u003cli\u003eZhang W, Shen H, Zhang Y et al. Circulating PD-1 (+) cells may participate in immune evasion in peripheral T-cell lymphoma and chidamide enhance antitumor activity of PD-1 (+) cells. Cancer Med 2019; 8: 2104-2113.\u003c/li\u003e\n\u003cli\u003eWang Y, Zhang M, Song W et al. Chidamide plus prednisone, etoposide, and thalidomide for untreated angioimmunoblastic T-cell lymphoma in a Chinese population: A multicenter phase II trial. 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A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2014; 123: 1293-1296.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"peripheral T-cell lymphoma, chidamide, maintenance","lastPublishedDoi":"10.21203/rs.3.rs-3804699/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3804699/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis study aimed to assess the efficacy and safety of chidamide as a maintenance therapy in peripheral T-cell lymphoma.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eChidamide was given orally as a maintenance therapy after first-line or salvage treatment. Progression-free survival (PFS), overall survival (OS), and safety were analyzed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFifty-eight patients were enrolled between January 2015 and July 2022. Among 39 patients underwent first-line maintenance, 11 (28.2%) patients experienced disease progression. A total of 19 patients received maintenance treatment after salvage therapy, 9(47.4%) had disease progression and median duration of remission was 16 (2‒25) months. For all patients, the median maintenance time was 16 (1\u0026ndash;72) months, the median PFS was 33 months, and the median OS had not been reached. The median PFS and OS of the patients received first-line maintenance were not reached, significantly better than patients received salvage maintenance (median PFS and OS were 7 and 67 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009, respectively). The most common toxicities were hematologic toxicities. Twelve (20.7%) patients underwent a dose reduction and three patients discontinued treatment.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe study showed that patients with chidamide maintenance therapy had a better PFS and OS with a manageable safety profile, especially as the first-line maintenance therapy.\u003c/p\u003e\u003ch2\u003eRegistration number:\u003c/h2\u003e \u003cp\u003eClinicalTrials.gov (NCT05967949), retrospectively registered on July 23, 2023.\u003c/p\u003e","manuscriptTitle":"The efficacy and safety of a Histone deacetylase inhibitor: chidamide as a maintenance therapy for peripheral T-cell lymphoma","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-03 01:48:11","doi":"10.21203/rs.3.rs-3804699/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f19a378d-09ef-49e9-adf5-16d7d52de12a","owner":[],"postedDate":"January 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-02T10:34:07+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-03 01:48:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3804699","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3804699","identity":"rs-3804699","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}