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Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) characterized by its T-follicular helper (TFH) phenotype. Relapsed and refractory disease is common in AITL and often associated with a poor prognosis. The presence of epigenetic abnormalities, immune dysregulation, hyperinflammation and active angiogenesis in AITL offers potential targets for histone deacetylase (HDAC) inhibitors and immunomodulatory drugs (IMiDs). Herein, we present a case of AITL with multiple relapses over a decade. Following intensive chemotherapy and autologous stem cell transplantation (ASCT), the patient relapsed with extensive nodal and extranodal involvement, particularly pulmonary lesions, and subsequently pursued chemo-free treatments. Initially, the patient exhibited a remarkable response to single-agent chidamide, the first oral HDAC inhibitor. Soon after developing resistance to chidamide, continuous treatment with lenalidomide led to an impressive sustained complete remission lasting 64 months, followed by a diminished response for an additional 11 months. Genetic profiling of the patient revealed mutations in KMT2D and ARID1A, along with chromosomal aberrations such as del(5q). Notably, genes commonly mutated in AITL, including RHOA, TET2, DNMT3A, and IDH2, were absent in this case. A review of the literature highlights the heterogeneous genomic landscape of AITL and the diversity of treatment options available, underscoring the importance of tailored approaches to overcome resistance and improve outcomes in this distinct lymphoma subtype. [ABSTRACT FROM AUTHOR]

Objectives: T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL. Methods: We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results: All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170–1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1). Conclusion: Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated. [ABSTRACT FROM AUTHOR]

Background: Chidamide is subtype-selective histone deacetylase (HDAC) inhibitor that showed promising result in clinical trials to improve prognosis of angioimmunoblastic T-cell lymphoma (AITL) patients. However, in real world settings, contradictory reports existed as to whether chidamide improve overall survival (OS). Therefore, we aimed to develop an interpretable machine learning (Machine learning)-based model to predict the 2-year overall survival of AITL patients based on chidamide usage and baseline features. Methods: A total of 183 patients with AITL were randomly divided into training set and testing set. We used 5 ML algorithms to build predictive models. Recursive feature elimination (RFE) method was used to filter for the most important features. The ML models were interpreted and the relevance of the selected features was determined using the Shapley additive explanations (SHAP) method and the local interpretable model-agnostic explanationalgorithm. Results: A total of 183 patients with newly diagnosed AITL from 2012 to 2022 from 3 centers in China were enrolled in our study. Seventy-one patients were dead within 2 years after diagnosis. Five ML algorithms were built based on chidamide usage and 16 baseline features to predict 2-year OS. Catboost model presented to be the best predictive model. After RFE screening, 12 variables demonstrated the best performance (AUC = 0.8651). Using chidamide ranked third among all the variables that correlated with 2-year OS. Conclusion: This study demonstrated that the Catboost model with 12 variables could effectively predict the 2-year OS of AITL patients. Combining chidamide in the treatment therapy was positively correlated with longer OS of AITL patients. [ABSTRACT FROM AUTHOR]

Background: Angioimmunoblastic T-cell lymphoma (AITL) is known for its unfavorable survival prognosis. Chidamide has shown efficacy in relapsed/ refractory AITL, but its efficacy in newly diagnosed AITL is uncertain Objective: This retrospective research aimed to evaluate the effectiveness and safety of chidamide when used with doxorubicin, cyclophosphamide, prednisone, and vincristine (CHOP) in comparison to CHOP by itself for individuals newly diagnosed with AITL, and to examine the impact of transplantation. Method: This was an analysis that compared outcomes among patients who received chidamide + CHOP on a clinical trial vs. historical controls who received CHOP alone, enrolling a total of sixty-six treatment-naive AITL patients between April 2014 and November 2022. Among them, thirty-three received chidamide in addition to CHOP (chidamide group), while thirty-three received CHOP alone (control group). The clinical characteristics were balanced between the two groups. All patients were scheduled to undergo up to six courses of treatment before transplantation. Results: The chidamide group had a significantly longer median overall survival (OS) compared to the control group, with a median OS that was not reached, as opposed to 20 months in the control group (p = 0.002). In the control group, the median progression-free survival (PFS) was 11 months, while in the chidamide group, it was 22 months (p = 0.080). In the high-risk group (IPI ≥ 3), the chidamide group demonstrated notably superior complete response (CR) and overall response rate (ORR) compared to the control cohort (p = 0.002, p = 0.034). The PFS and OS in the chidamide group were not reached, and there were significant differences compared to the control group (p = 0.007, p = 0.003). The median OS of the transplanted group was longer than the nontransplanted group (p = 0.004). On multivariate analysis, chidamide group reduced the hazards of death in the total cohort. Conclusion: As the study was non-random and retrospective, Chidamide combined with chemotherapy should be tested in randomized trials given its potential to improve prognosis in treatment-naive AITL patients. Furthermore, autologous hematopoietic stem cell transplantation (auto-HSCT) has demonstrated enhanced overall survival in individuals with AITL. [ABSTRACT FROM AUTHOR]

Objective To observe the effect of chidamide combined with traditional medicine in the treatment of relapsed/refractory cutaneous T-cell lymphoma (R/R CTCL). Methods Chidamide-based therapy was used to treat patients with cutaneous T-cell lymphoma who had failed systemic treatment regimens, experienced disease progression, or developed treatment resistance. The therapeutic effect and adverse reactions were observed. Results Two patients diagnosed with advanced mycosis fungoides (T3N1M0B0, stage II B) and primary cutaneous peripheral T-cell lymphoma, not otherwise specified (T3bN0M0) were included. After treatment with chidamide in combination with traditional medicine, the patient diagnosed with mycosis fungoides achieved complete clinical remission and maintained disease stability for at least 1 year, with adverse reactions of neutropenia and thrombocytopenia. The patient diagnosed with primary cutaneous peripheral T-cell lymphoma achieved partial remission with no apparent adverse reactions. Conclusion Chidamide has a good therapeutic effect on patients with relapsed/refractory cutaneous T-cell lymphoma, with hematologic adverse reactions being the main adverse effects. [ABSTRACT FROM AUTHOR]

Background: In relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. Methods: A cohort of 27 ineligible patients with R/R DLBCL participated in an open — label, single — arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one‐week discontinuation period, in conjunction with intravenous R‐GDP every 21 days. Results: Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C‐R‐GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%–83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%–49.9%) and a partial response rate of 33.3% (95% CI: 29.3%–37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow‐up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression‐free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. Conclusions: Chidamide combined with R‐GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation. [ABSTRACT FROM AUTHOR]

In this prospective, multicenter, Phase 2 clinical trial (NCT02987244), patients with peripheral T-cell lymphomas (PTCLs) who had responded to first-line chemotherapy with cyclophosphamide, doxorubicin or epirubicin, vincristine or vindesine, etoposide, and prednisone (Chi-CHOEP) were treated by autologous stem cell transplantation (ASCT) or with chidamide maintenance or observation. A total of 85 patients received one of the following interventions: ASCT (n = 15), chidamide maintenance (n = 44), and observation (n = 26). estimated 3 PFS and OS rates were 85.6%, 80.8%, and 49.4% (P = 0.001). The two-year OS rates were 85.6%, 80.8%, and 69.0% (P = 0.075).The ASCT and chidamide maintenance groups had significantly better progression-free survival (PFS) than the observation group (P = 0.001, and P = 0.01, respectively). The overall survival (OS) differed significantly between the chidamide maintenance group and the observation group (P = 0.041). The multivariate and propensity score matching analyses for PFS revealed better outcomes in the subjects in the chidamide maintenance than observation groups (P = 0.02). The ASCT and chidamide maintenance groups had significant survival advantages over the observation group. In the post-remission stage of the untreated PTCL patients, single-agent chidamide maintenance demonstrated superior PFS and better OS than observation. Our findings highlight the potential benefit of chidamide in this patient subset, warranting further investigation through larger prospective trials. Clinical trial registration: clinicaltrial.gov, NCT02987244. Registered 8 December 2016, http://www.clinicaltrials.gov/ct2/show/NCT02987244. [ABSTRACT FROM AUTHOR]

Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by hyperinflammation and organ failure, with a high mortality rate. Current first-line treatments for adult patients have limited efficacy and significant toxicity. The novel selective histone deacetylase inhibitor (HDACi), chidamide, has shown promise in preclinical studies for the potential treatment of HLH. Methods: An open-label, single-center study was conducted to evaluate the efficacy and safety of chidamide in combination with etoposide and glucocorticoids for the treatment of HLH in adult patients. Seventeen patients who fulfilled at least five of the eight HLH-2004 criteria were enrolled and treated with the combination therapy. The primary outcome was overall response rate (ORR), and secondary outcomes included survival, safety and tolerability, and changes in laboratory indicators. Results: A total of 17 HLH patients who met the inclusion criteria were enrolled in this study, with a male to female ratio of 1.8:1. The age range at enrollment was 31 to 71 years old, with a median age of 52 years old. The ORR was 76.5% (13/17 patients), with a complete response (CR) rate of 17.6% (3/17 patients) and a partial response (PR) rate of 58.8% (10/17 patients). The median overall survival (OS) was not achieved, with OS at 6 months and 12 months being 81% and 65%, respectively. The median progression free survival (PFS) was not achieved, with PFS at 6 months and 12 months being 68% and 55%, respectively. Hematologic toxicities is the most common. Safety profile was favorable, with very few cases of grade 3/4 toxicities observed. The results showed that the levels of sCD25, platelets, aspartate aminotransferase, lactate dehydrogenase, and albumin in these patients were significantly improved 3 weeks after treatment. Conclusion: The addition of chidamide to etoposide and glucocorticoids may be a promising new treatment option for patients with HLH, with a high ORR, manageable safety profile, and significant improvement in laboratory indicators. Further research is needed to confirm these findings and determine the optimal dosing and duration of therapy. [ABSTRACT FROM AUTHOR]

Objectives T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) are highly malignant and aggressive hematologic tumors for which there is no standard first-line treatment. Chidamide, a novel histone deacetylase inhibitor, shows great promise. We assessed the efficacy and safety of an irradiation-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) and post-transplantation chidamide maintenance in patients with T-ALL/LBL.Methods We retrospectively analyzed the clinical data of six patients with T-ALL/LBL who underwent allo-HSCT with a radiotherapy-containing pretreatment regimen and post-transplant chidamide maintenance therapy. The endpoints were relapse, graft-versus-host disease (GVHD), transplant-related mortality (TRM), progression-free survival (PFS), overall survival (OS), and adverse events (AEs).Results All of the patients had uneventful post-transplant hematopoietic reconstitution, and all achieved complete molecular remission within 30 days. All six patients survived, and two relapsed with a median relapse time of 828.5 (170–1335) days. The 1-year OS rate was 100%, the 2-year PFS rate was 66.7%, and the TRM rate was 0%. After transplantation, two patients developed grade I-II acute GVHD (2/6); grade III-IV acute and chronic GVHD were not observed. The most common AEs following chidamide administration were hematological AEs, which occurred to varying degrees in all patients; liver function abnormalities occurred in two patients (grade 2), and symptoms of malaise occurred in one patient (grade 1).Conclusion Chidamide maintenance therapy after T-ALL/LBL transplantation is safe, but the efficacy needs to be further investigated.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) characterized by its T-follicular helper (TFH) phenotype. Relapsed and refractory disease is common in AITL and often associated with a poor prognosis. The presence of epigenetic abnormalities, immune dysregulation, hyperinflammation and active angiogenesis in AITL offers potential targets for histone deacetylase (HDAC) inhibitors and immunomodulatory drugs (IMiDs). Herein, we present a case of AITL with multiple relapses over a decade. Following intensive chemotherapy and autologous stem cell transplantation (ASCT), the patient relapsed with extensive nodal and extranodal involvement, particularly pulmonary lesions, and subsequently pursued chemo-free treatments. Initially, the patient exhibited a remarkable response to single-agent chidamide, the first oral HDAC inhibitor. Soon after developing resistance to chidamide, continuous treatment with lenalidomide led to an impressive sustained complete remission lasting 64 months, followed by a diminished response for an additional 11 months. Genetic profiling of the patient revealed mutations in KMT2D and ARID1A, along with chromosomal aberrations such as del(5q). Notably, genes commonly mutated in AITL, including RHOA, TET2, DNMT3A, and IDH2, were absent in this case. A review of the literature highlights the heterogeneous genomic landscape of AITL and the diversity of treatment options available, underscoring the importance of tailored approaches to overcome resistance and improve outcomes in this distinct lymphoma subtype.

Background: Angioimmunoblastic T-cell lymphoma (AITL) is characterized by high recurrence rates and poor prognosis, and effective first-line treatment is lacking. Recently, histone deacetylase inhibitors (HDACi), such as chidamide, have been found to induce durable remissions in AITL patients. Methods: Patients with untreated AITL from March 2015 to March 2023 were retrospectively collected and divided into chemotherapy (ChT) group and chidamide combined with chemotherapy (C-ChT) group based on the firstline treatment received. The comparison of efficacy and safety between the two groups was conducted. Results: 86 patients with newly diagnosed AITL were enrolled, in which 35 patients were in the ChT group and 51 in the C-ChT group. The objective response rate (ORR) of C-ChT group was significantly higher than that of ChT group (84.3% vs. 60%, P= 0.011), and had superior progression-free survival (PFS) (27 months vs. 12 months, P= 0.025). However, no significant difference in overall survival (OS) was observed between the two groups (P= 0.225). In addition, the responding patients who received autologous stem cell transplantation (ASCT) had superior PFS compared to those who did not (P= 0.015). Conclusions: Compared with ChT regimen, C-ChT regimen was well tolerated and had superior ORR and PFS in patients with untreated AITL. ASCT may contribute to longer PFS in remission patients. [ABSTRACT FROM AUTHOR]

Background: Combination of chidamide and anti‐PD‐L1 inhibitor produce synergistic anti‐tumor effect in advanced NSCLC patients resistant to anti‐PD‐1 treatment. However, the effect of chidamide plus envafolimab has not been reported. Aims: This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti‐PD‐1 treatment. Materials and Methods: Eligible advanced NSCLC patients after resistant to anti‐PD‐1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression‐free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD‐L1, and blood TMB (bTMB) was also analyzed. Results: After a median follow‐up of 8.1 (range: 7.6–9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9–5.5) months. Biomarker analysis revealed that patients with high‐level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD‐L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low‐level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable. Discussion: High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD‐L1 and low‐level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion. Conclusion: Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a common hematological malignancy, and patients with MM are recommended to take immunomodulatory drugs such as lenalidomide along with proteasome inhibitors such as bortezomib to extend survival. However, drug resistance influences the efficacy of treatment for MM. In our study, we found that metformin and chidamide both suppressed MM cell growth in a concentration‐ and time‐dependent way (p <.001). Moreover, combined therapy with metformin and chidamide exhibited enhanced inhibition of the growth of MM cells compared with monotherapy (p <.05). Additionally, the triple‐drug combination of metformin and chidamide with lenalidomide or bortezomib was used to stimulate the MM cells, and the results revealed that metformin and chidamide treatment sensitized MM cells to lenalidomide and bortezomib. As a result, the apoptosis (p <.001) together with cell cycle arrest at G0/G1 phase (p <.05) was stimulated by lenalidomide and bortezomib, and showed significant elevation in the triple‐drug combination group compared with the lenalidomide or bortezomib treatment alone group (p <.05). Furthermore, the impacts of different drugs on glycolysis in MM cells were examined. We found that metformin and chidamide combined treatment significantly promoted glucose uptake and reduced energy production in MM cells treated with lenalidomide and bortezomib (p <.001), suggesting that metformin and chidamide affected glycolysis in MM cells and enhanced the sensitivity of lenalidomide and bortezomib in MM by regulating glucose metabolism. In conclusion, metformin and chidamide synergistically hindered MM cell growth and sensitized cells to lenalidomide/bortezomib. The findings of this study might provide novel clues to improve MM therapy. [ABSTRACT FROM AUTHOR]

Abstract Background In relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL), a negative prognosis is frequently linked to heightened epigenetic heterogeneity. Chidamide, a selective histone deacetylase inhibitor, shows promise as a targeted therapy for R/R DLBCL by targeting abnormal epigenetic changes associated with poor prognosis. Methods A cohort of 27 ineligible patients with R/R DLBCL participated in an open — label, single — arm study. Chidamide was administered orally at a dose of 30 mg twice weekly for one week during the induction monotherapy phase. The subsequent combination therapy phase involved oral chidamide at a dose of 20 mg twice weekly for two weeks, followed by a one‐week discontinuation period, in conjunction with intravenous R‐GDP every 21 days. Results Among the cohort of 31 patients who underwent screening (median age: 67 years), 27 were ultimately included in the study, with 14 individuals successfully completing six cycles of C‐R‐GDP treatment. The overall best objective response rate was determined to be 79.1% (95% CI: 75.1%–83.3%), comprising a complete response rate of 45.8% (95% CI: 41.6%–49.9%) and a partial response rate of 33.3% (95% CI: 29.3%–37.4%). Within the subgroup of 14 patients who completed the full treatment regimen, the best objective response rate reached 100%, with 71.4% achieving complete response (n = 10) and 28.6% achieving partial response (n = 4). The median follow‐up period for these patients was 17.0 months, ranging from 3.5 to 55 months. Progression‐free survival was 5.9 months and overall survival was 48.3 months. Anemia was the most common adverse event, affecting all patients. Thrombocytopenia led to treatment interruption or dose reduction in 13 patients. Other common adverse events included hypocalcemia, hyponatremia, and hypokalemia. Three patients experienced grade 3 pneumonitis and one had grade 3 skin rash. Conclusions Chidamide combined with R‐GDP is a safe and effective treatment option for patients with R/R DLBCL who are not eligible for autologous stem cell transplantation.

Background: Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)‐positive and HER2‐negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real‐world scenarios. Methods: Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre‐ and postmenopausal women who had clinically or histologically confirmed ER‐positive, HER2‐negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non‐AIs. Efficacy analyses included progression‐free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors. Results: A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8–4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14–2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17–2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia. Conclusion: This study provided real‐world data for the use of chidamide in patients with HoR‐positive and HER2‐negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. [ABSTRACT FROM AUTHOR]

Objective: The initial therapeutic approach for diffuse large B-cell lymphoma (DLBCL) entails a rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen. However, 40% of patients exhibit suboptimal responses, with some experiencing relapse and refractory conditions. This study aimed to explore novel therapeutic strategies and elucidate their underlying mechanisms in DLBCL. Methods: Bioinformatics techniques were employed to scrutinize correlations between the HDAC1, HDAC2, HDAC3, HDAC10, BTK, MYC, TP53, and BCL2 genes in DLBCL. In vitro experiments were conducted using DB and SU-DHL-4 cells treated with chidamide, orelabrutinib, and a combination of both. Cell viability was assessed by cell counting kit-8. Cell apoptosis and the cell cycle were determined using flow cytometry. Reactive oxygen species (ROS) production and mitochondrial function were assessed through ROS and JC-1 staining. RNA sequencing and western blot analyses were conducted to elucidate the molecular mechanisms underlying the combined action of chidamide and orelabrutinib in DLBCL cells. Results: This investigation revealed markedly enhanced antiproliferative effects when chidamide was combined with orelabrutinib. Compusyn software analysis indicated a synergistic effect of chidamide and orelabrutinib in inhibiting DLBCL cell proliferation, with a combination index (CI) < 1. This synergy further manifested as augmented cell cycle arrest, apoptosis induction, the downregulation of cell cycle-associated and antiapoptotic proteins, and the upregulation of proapoptotic proteins. Furthermore, the western blot and RNA-Seq findings suggested that combining chidamide and orelabrutinib modulated the PI3K/AKT/mTOR signaling pathway, thereby promoting DLBCL cell cycle arrest and apoptosis. Conclusion: The findings of this study provide a compelling justification for the clinical utilization of chidamide and orelabrutinib to treat relapsed/refractory DLBCL. [ABSTRACT FROM AUTHOR]

Purpose: Peripheral T-cell lymphoma (PTCL) is an aggressive disease with a poor prognosis. Brentuximab vedotin (BV), an anti-CD30 monoclonal antibody linked to a microtubule-disrupting agent, has been approved for the treatment of PTCL. We evaluated a new effective combination partner of BV using non-clinical approaches that could potentially identify agents capable of improving survival times for patients with PTCL. Methods: A high-throughput screening test was used to select the most synergistic partner of BV from 14 candidate drugs that were under development or available in clinical practice for PTCL. HH cells, originating from an aggressive cutaneous T-cell lymphoma, were used as an experimental model of PTCL. Apoptotic effects of the synergistic partner of BV were further investigated in vitro and in vivo using HH-cell xenograft mice. Results: Chidamide (tucidinostat), a novel histone deacetylase inhibitor, was found to have the greatest synergistic effect with BV on HH cells. The combined effects of chidamide and BV were demonstrated in a study of HH-cell xenograft mice; mean tumor size following combined treatment was 22% of that observed in the control group, compared with 71% and 58% following chidamide and BV monotherapy, respectively. Further investigations in vitro and in vivo revealed that the levels of an anti-apoptotic protein, Bcl-2, and a rate-limiting factor of DNA replication, CDC45, were reduced in HH cells treated with chidamide combined with BV compared with the control group. Conclusion: The use of chidamide in conjunction with BV may positively affect and enhance T-cellular apoptotic pathways without offsetting each other. [ABSTRACT FROM AUTHOR]

With the innovative development of histone deacetylase inhibitors (HDACi), a class of drugs targeting epigenetic regulation mechanism, the treatment landscape for breast cancer patients is gradually changing. Both hormone receptor ⁃ positive and human epidermal growth factor receptor 2⁃negative breast cancer patients, as well as triple⁃negative breast cancer（TNBC）patients, can benefit significantly from combination therapy with HDACi. This article summarizes the research progress of HDACi in various molecular subtypes of breast cancer, with a particular focus on the treatment status in the Chinese population and exploration of rational combination therapy strategies in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Combination of chidamide and anti‐PD‐L1 inhibitor produce synergistic anti‐tumor effect in advanced NSCLC patients resistant to anti‐PD‐1 treatment. However, the effect of chidamide plus envafolimab has not been reported. Aims This study aimed to evaluate the efficacy of chidamide plus envafolimab in advanced NSCLC patients resistant toanti‐PD‐1 treatment. Materials and Methods Eligible advanced NSCLC patients after resistant to anti‐PD‐1 therapy received chidamide and envafolimab. The primary endpoint was objective response rate (ORR). The secondary end points included disease control rate (DCR), progression‐free survival (PFS), and safety. The expression of histone deacetylase 2 (HDAC2), PD‐L1, and blood TMB (bTMB) was also analyzed. Results After a median follow‐up of 8.1 (range: 7.6–9.2) months, only two patients achieved partial response. The ORR was 6.7% (2/30), DCR was 50% (15/30), and median PFS (mPFS) was 3.5 (95% confidence interval: 1.9–5.5) months. Biomarker analysis revealed that patients with high‐level HDAC2 expression had numerically superior ORR (4.3% vs. 0), DCR (52.2% vs. 0) and mPFS (3.7 vs. 1.4m). Patients with negative PD‐L1 had numerically superior DCR (52.2% vs. 33.3%) and mPFS (3.7m vs. 1.8m), so were those with low‐level bTMB (DCR: 59.1% vs. 16.7%, mPFS: 3.8 vs.1.9m). Overall safety was controllable. Discussion High HDAC2patients showed better ORR, DCR, and PFS. In addition, patient with negative PD‐L1 and low‐level bTMB had better DCR and PFS. This may be related to the epigenetic function of chidamide. However, the sample size was not big enough, so it is necessary to increase sample size to confirm the conclusion. Conclusion Combination of chidamide and envafolimab showed efficacy signals in certain NSCLC patients. But further identification of beneficial population is necessary for precision treatment.

Previous studies have showed promising but short-lived activity of sorafenib in osteosarcoma treatments. Researches have suggested ameliorated sensitivity to standard dose of conventional cancer therapies in combination with histone deacetylase inhibitors (HDACis) through various mechanisms. Herein, for the first time, we exploited the synergism of combination therapies with sorafenib and chidamide, a member of HDACis, in the control of OS using human OS cell lines and OS xenograft mouse model and discussed interactive mechanisms between the two drugs. The combination therapy exerted a strong synergism in the inhibition of OS cell proliferation, meanwhile prominently induced cell apoptosis and cell cycle arrest in G0/G1 phase in OS cells with increased expression of MCL-1, decreased expression of caspase-3 and P21, along with diminished level of the overlapped protein P-ERK1/2. Furthermore, oral administration of the combined treatment led to a more optical therapeutic outcome, including lower degrees of tumoral cell proliferation, greater extent of apoptosis, along with induction of cell cycle arrest in tumor tissues, while exhibiting minimal toxicity. This study shows that the combination of sorafenib and chidamide can combat OS in a synergistic fashion and prompts the promising development of innovative combined therapeutic strategies for OS.

Poly (ADP-ribose) polymerase inhibitor (PARPi) resistance is a new challenge for antitumor therapy. The purpose of this study was to investigate the reversal effects of chidamide on fluzoparib resistance, a PARPi, and its mechanism of action. A fluzoparib-resistant triple-negative breast cancer (TNBC) cell line was constructed, and the effects of chidamide and fluzoparib on drug-resistant cells were studied in vitro and in vivo. The effects of these drugs on cell proliferation, migration, invasiveness, the cell cycle, and apoptosis were detected using an MTT assay, wound-healing and transwell invasion assays, and flow cytometry. Bioinformatics was used to identify hub drug resistance genes and Western blots were used to assess the expression of PARP, RAD51, MRE11, cleaved Caspase9, and P-CDK1. Xenograft models were established to analyze the effects of these drugs on nude mice. In vivo results showed that chidamide combined with fluzoparib significantly inhibited the proliferation, migration, and invasiveness of drug-resistant cells and restored fluzoparib sensitivity to drug-resistant cells. The combination of chidamide and fluzoparib significantly inhibited the expression of the hub drug resistance genes RAD51 and MRE11, arrested the cell cycle at the G2/M phase, and induced cell apoptosis. The findings of this work show that chidamide combined with fluzoparib has good antineoplastic activity and reverses TNBC cell resistance to fluzoparil by reducing the expression levels of RAD51 and MRE11.

Objective To explore the effect of vemurafenib (VEM) combined with chidamide (CDM) on cellular senescence in secondary acute myeloid leukemia (sAML). Methods sAML cell lines SKM-1 and MOLM-13 were divided into control group (sAML cells), VEM group (sAML cells treated with VEM), CDM group (sAML cells treated with CDM), and COM group (sAML cells treated with VEM combined with CDM)(n=3). CCK-8 assay was used to measure the viability of sAML cells. Immunofluorescence assay was used to verified the cellular senescence of sAML cells. Flow cytometry was used to detect cell cycle and apoptosis of sAML cells. Network pharmacology and RT-qPCR were used to analyze and verify the mechanism of VEM combined with CDM. Results VEM inhibited the proliferation of sAML cells lines in a time- and dose-dependent manner(P < 0.05), the half-maximal inhibitory concentration (IC50) of VEM on SKM-1 and MOLM-13 cells was 24.15±1.18 and 11.30±0.38 μmol/L(P < 0.0001), respectively. VEM (SKM-1: 1/3 IC50-VEM, MOLM-13: 1/2 IC50-VEM) combined with CDM synergistically promoted sAML cellular senescence by upregulating TRF2 and Lamin B1, characterized cycle stagnation in G0/G1 phase(P < 0.05), inhibiting cell proliferation(P < 0.01) and promoting cell apoptosis (P < 0.05). Swiss Target Predict, TargetNe, SEA and PharmMapper discovered the core targets and signaling pathways of VEM collaborating with CDM. RT-qPCR verified that VEM collaborated with CDM to promote senescence of sAML cells through inhibiting PI3K-AKT and MAPK signaling pathways(P < 0.05). Conclusion VEM combined with CDM can induce cellular senescence of sAML cells by downregulating PI3K-AKT and MAPK signaling pathways, inhibiting proliferation and promoting apoptosis of sAML cells. VEM combined with CDM might be a new regime for patients with sAML.

Abstract Peripheral T-cell lymphomas (PTCLs) are a group of highly aggressive malignancies with generally poor prognoses, and the first-line chemotherapy of PTCL has limited efficacy. Currently, several novel targeted agents, including histone deacetylase inhibitors (HDACis), have been investigated to improve the therapeutic outcome of PTCLs. Several HDACis, such as romidepsin, belinostat, and chidamide, have demonstrated favorable clinical efficacy and safety in PTCLs. More novel HDACis and new combination therapies are undergoing preclinical or clinical trials. Mutation analysis based on next-generation sequencing may advance our understanding of the correlation between epigenetic mutation profiles and relevant targeted therapies. Multitargeted HDACis and HDACi-based prodrugs hold promising futures and offer further directions for drug design.

Abstract Background Chidamide is a selective histone deacetylase inhibitor approved for patients with hormone receptor (HoR)‐positive and HER2‐negative metastatic breast cancer (MBC). We aimed to investigate the efficacy, safety, and treatment patterns of chidamide and identify clinicopathological factors that predict the efficacy of chidamide in real‐world scenarios. Methods Consecutive MBC patients treated with chidamide from January 2020 to August 2021 across 11 institutions were enrolled in this multicenter, retrospective study. Eligible patients were pre‐ and postmenopausal women who had clinically or histologically confirmed ER‐positive, HER2‐negative MBC, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with multiple primary malignancies or missing baseline characteristics were excluded. Patients received 30 mg chidamide orally twice a week, combined with aromatase inhibitors (AIs) or non‐AIs. Efficacy analyses included progression‐free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Univariate and multivariate Cox regression analyses were performed to identify the potential efficacy predictors. Results A total of 157 patients were finally included for analysis. The median number of lines prior to chidamide was four. In the whole cohort, the median PFS was 4.2 months (95% confidence interval [CI] 3.8–4.5). The ORR was 7.5% and the CBR was 31.3%. The efficacy of chidamide was consistent in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations. Multivariate analysis indicated that patients who had liver metastases (adjusted HR = 1.66, 95% CI 1.14–2.43, adjusted p = 0.008) or ≥3 prior lines of treatment (adjusted HR = 1.80, 95% CI 1.17–2.77, adjusted p = 0.008) had significantly worse PFS. The most common AEs with chidamide were thrombocytopenia, leucopenia, neutropenia, and anemia. Conclusion This study provided real‐world data for the use of chidamide in patients with HoR‐positive and HER2‐negative MBC. Our data endorsed the use of chidamide in patients pretreated with CDK4/6 inhibitors and patients treated with different endocrine combinations.

Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/β-catenin signaling pathway in leukemia cell lines. Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed. Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments. This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML. [ABSTRACT FROM AUTHOR]

Background: ALK-negative anaplastic large cell lymphoma (ALK-ALCL) is a rare heterogeneous malignancy of T-cell origin.ALK- ALCL has a poor prognosis, with more patients experiencing relapses and refractory to treatment, and its treatment remains challenging. We report a case with bone involvement as the main clinical manifestation of recurrent, and the patient achieved significant partial remission after brentuximab vedotin(BV) combined with a modified CHEP chemotherapy containing mitoxantrone hydrochloride liposome (PLM60) with the addition of chidamide maintenance therapy and received regular follow-up, with a disease-free survival of 16 months to date. A literature review of the clinical presentation and treatment of ALCL was also conducted to identify strategies for its diagnosis and management. Conclusions: ALK-ALCL with bone involvement as the main manifestation of recurrent is relatively rare. Here, BV combined a modified CHEP chemotherapy containing mitoxantrone hydrochloride liposome was applied for the first time in a patient with relapsed ALK-ALCL, inducing remission and extending survival. However, further prospective studies with many patients are needed to determine the biological characteristics of this rare type of ALK-ALCL and relevant treatment strategies. [ABSTRACT FROM AUTHOR]

The treatment of natural killer/T-cell lymphoma (NKTCL) presents an onerous challenge, and a search for new therapeutic targets is urgently needed. Poly ADP-ribose polymerase inhibitors (PARPi) were initially used to treat breast and ovarian cancers with BRCA1/2 mutations. Their excellent antitumor efficacy led to a series of clinical trials conducted in other malignancies. However, the exploration of PARPi and their potential use in combination treatments for NKTCL remains unexplored. We treated NKTCL cell lines with fluzoparib (a novel inhibitor of PARP) and chidamide (a classical inhibitor of HDACs) to explore their cytotoxic effects in vitro. Then, their antitumor efficacy in vivo was confirmed in YT-luciferin xenograft mouse models. Fluzoparib or chidamide alone inhibited NKTCL cell proliferation in a dose-dependent manner. Cotreatment with both drugs synergistically induced excessive accumulation of DNA double-strand breaks and massive apoptotic cell death by inhibiting the DNA damage repair pathway, as shown by the decreased protein levels of p-ATM, p-BRCA1, p-ATR, and Rad51. Moreover, the combination treatment apparently increased the level of intracellular reactive oxygen species (ROS) to enhance apoptosis, and pretreatment with an ROS scavenger reduced the proapoptotic effect by 30–60% in NKTCL cell lines. In vivo, this combined regimen also showed synergistic antitumor effects in xenograft mouse models. The combination of fluzoparib and chidamide showed synergistic effects against NKTCL both in vitro and in vivo and deserves further exploration in clinical trials. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer (BC) is a prevalent disease that harms women's health, and in-depth investigations of the pathogenesis, treatment, and prevention of BC are the focus of many research programs. Chidamide (CHI) is a histone deacetylase suppressor that depresses histone deacetylase functions, thereby influencing cell growth through an epigenetic mechanism. However, CHI effects upon BC are largely unknown. Present research aimed to confirm the possibility of using CHI combined with chemotherapy drug doxorubicin (DOX) to prevent chemotherapeutic BC resistance in vivo and in vitro. Methods In this study, CCK8 (a plate colony formation assay) was applied to detect cell proliferation. Flow cytometry detection showed the apoptotic cell death of both T47D and MCF-7 cells. Nude mouse xenografts were used to detect tumor growth and pulmonary metastasis. High-throughput sequencing was used to detect expression of different genes. Results Our data showed that CHI treatment reduced BC cell proliferation, tumor growth, and cell invasion. CHI treatments stimulated BC cell apoptosis by promoting ULK2-mediated autophagy and increasing MCF-7 cell sensitivity to DOX, resulting in decreased tumor growth. Conclusion Collectively, our results illustrated that CHI enhanced DOX cytotoxicity by promoting apoptosis and autophagy in BC cells, which advised that CHI could be a candidate drug for BC patient treatments.

ABSTRACTObjective Anthracyclines and cytarabine have comprised standard induction therapy for acute myeloid leukemia (AML) for decades. Low overall survival of AML is due to non-remission or relapse after remission. Hypomethylating agent (HMA) decitabine combined with low-dose chemotherapy or other targeted agents has shown promising effect for AML in clinical trials, especially in t(8;21) acute myeloid leukemia. We previously investigated histone deacetylase inhibitor (HDACi) chidamide could regulate Wnt/β-catenin signaling pathway in leukemia cell lines.Methods Adult patients with de novo or relapsed/refractory AML who were treated with chidamide and decitabine in combination with chemotherapy (chidamide group, n = 23) or only decitabine combination with chemotherapy (decitabine group, n = 17) were analyzed.Results Chidamide group represented higher complete response rate (82.6% and 52.9%, p = 0.0430, vs. decitabine group), progression-free survival and overall survival rates (p = 0.0088 and p = 0.0139, respectively), especially for patients with de novo AML. Hematological toxicity and infections were the most common adverse events (AEs) in both groups, and they were manageable by supportive treatments.Conclusions This HDACi- and HMA-based protocol is an effective and tolerable therapy for patients with AML. The comprehensive mechanism and effects of chidamide in combination with decitabine are worth to be further explored in AML.

Purpose: The present study explored the anti-tumor effects of chidamide plus oxaliplatin on colorectal cancer (CRC) and examined its underlying mechanism.Material and Methods: First, the Combination Index (CI) of chidamide and oxaliplatin was evaluated via CCK-8 assay. Second, the effects of chidamide and oxaliplatin monotherapy and the combined treatment on cell proliferation, invasion, migration, and apoptosis were detected. Third, whole-transcriptome RNA sequencing (RNA-seq) was performed to seek the potential targeted gene by which chidamide plus oxaliplatin exerted anti-tumor effects. Fourth, the validation of the targeted gene and the signal pathway it regulated were performed. Finally, the anti-tumor effect of chidamide plus oxaliplatin on mice xenograft was examined.Results: Chidamide and oxaliplatin acted synergistically to inhibit CRC growth in vitro and in vivo (CI< 1). Besides, compared with oxaliplatin monotherapy, chidamide could significantly enhance oxaliplatin-induced inhibition in cell proliferation, invasion, and migration, and promotion in HCT-116 and RKO cell apoptosis (P< 0.05). The RNA-seq displayed that, compared to oxaliplatin monotherapy, RPS27A mRNA was evidently decreased in HCT-116 cells treated with chidamide plus oxaliplatin (P< 0.001). Then, we found RPS27A was highly expressed in CRC tissues and CRC cell lines (P< 0.001). Silence of RPS27A attenuated proliferation and induced apoptosis in HCT-116 and RKO cells via downregulation of MDM2 expression and upregulation of P53. Next, RPS27A overexpression could partially reverse chidamide plus oxaliplatin induced growth inhibition and apoptosis in HCT-116 and RKO cells (P< 0.01). RPS27A overexpression could promote the upregulation of MDM2 and downregulation of P53 after the combined treatment of chidamide with oxaliplatin.Conclusion: Chidamide and oxaliplatin acted synergistically to suppress CRC growth by the inhibition of the RPS27A-MDM2-p53 axis. [ABSTRACT FROM AUTHOR]

Purpose: This is a retrospective, single-center PSM study evaluating the efficacy and safety of chidamide combined with the CHOEP (C-CHOEP) regimen versus the single CHOEP regimen in patients with untreated peripheral T cell lymphomas (PTCL). Patients: Patients newly diagnosed with PTCL between January 2015 and June 2021 were recruited, and were 1:1 divided into C-CHOEP and CHOEP groups according to their first-line chemotherapy regimens. The PSM method was used to match the baseline variables to balance the confounding factors. Results: A cohort of 33 patients each in the C-CHOEP and CHOEP groups was generated after propensity score-matching (PSM). The complete remission (CR) rates of the C-CHOEP regimen were higher than that of the CHOEP regimen (56.3 vs. 25.8%, p = 0.014), whereas the duration of response of the C-CHOEP group was shorter (median DOR 30 vs. 57 months), resulting in roughly similar progression-free survival (PFS) and (overall survival) OS between the two groups. The responding patients who received chidamide maintenance therapy showed a trend of superior PFS and OS compared with patients who did not receive maintenance therapy. Conclusions: The C-CHOEP regimen was well tolerated but failed to show advantages over the CHOEP regimen in patients with untreated PTCL; however, the chidamide maintenance may contribute to a more durable response and stable long-term survival. [ABSTRACT FROM AUTHOR]

Epigenetic alterations frequently participate in the onset of hematological malignancies. Histone deacetylases (HDACs) are essential for regulating gene transcription and various signaling pathways. Targeting HDACs has become a novel treatment option for hematological malignancies. Chidamide is the first oral selective HDAC inhibitor for HDAC1, HDAC2, HDAC3, and HDAC10 and was first approved for the treatment of R/R peripheral T‐cell lymphoma by the China Food and Drug Administration in 2014. Chidamide was also approved under the name Hiyasta (HBI‐8000) in Japan in 2021. In vitro studies revealed that chidamide could inhibit proliferation and induce apoptosis via cell cycle arrest and the regulation of apoptotic proteins. In clinical studies, chidamide was also efficacious in multiple myeloma, acute leukemia and myelodysplastic syndrome. This review includes reported experimental and clinical data on chidamide monotherapy or chidamide treatment in combination with chemotherapy for various hematological malignancies, offering a rationale for the renewed exploration of this drug. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) treatment remains challenging. CD70 was reported as a promising AML-specific antigen. Preclinically, CAR T-cell with single-chain-variable fragment (scFv) or truncated CD27 targeting CD70 has been reported to treat AML. However, various disadvantages including spontaneous exhaustion, proteinase-mediated loss of functional receptors, and high immunogenicity, limited its further application to clinical settings. Alternatively, the single-variable domain on heavy chain (VHH), also known as nanobodies, with comparable binding ability and specificity, provides an optional solution. Method: We generated CD70 knocked-out novel nanobody-based anti-CD70-CAR T-cells (nb70CAR-T) with two different VHHs for antigen detection. Next, we detected the CD70 expression on primary AML blasts by flow cytometry and associated the efficacy of nb70CAR-T with the target antigen density. Finally, epigenetic modulators were investigated to regulate the CD70 expression on AML cells to promote the functionality of nb70CAR-T. Results: Our nb70CAR-T exhibited expected tumoricidal functionality against CD70-expressed cell lines and primary AML blasts. However, CD70 expression in primary AML blasts was not consistently high and nb70CAR-T potently respond to an estimated 40.4% of AML patients when the CD70 expression level was over a threshold of 1.6 (MFI ratio). Epigenetic modulators, Decitabine and Chidamide can up-regulate CD70 expression on AML cells, enhancing the treatment efficacy of nb70CAR-T. Conclusion: CD70 expression in AML blasts was not fully supportive of its role in AML targeted therapy as reported. The combinational use of Chidamide and Decitabine with nb70CAR-T could provide a new potential for the treatment of AML. [ABSTRACT FROM AUTHOR]

Currently, therapy for Chronic Myeloid Leukemia (CML) patients with the T315I mutation is a major challenge in clinical practice due to its high degree of resistance to first- and second-generation Tyrosine Kinase Inhibitors (TKIs). Chidamide, a Histone Deacetylase Inhibitor (HDACi) drug, is currently used to treat peripheral T-cell lymphoma. In this study, we investigated the anti-leukemia effects of chidamide on the CML cell lines Ba/F3 P210 and Ba/F3 T315I and primary tumor cells from CML patients with the T315I mutation. The underlying mechanism was investigated, and we found that chidamide could inhibit Ba/F3 T315I cells at G0/G1 phase. Signaling pathway analysis showed that chidamide induced H3 acetylation, downregulated pAKT expression and upregulated pSTAT5 expression in Ba/F3 T315I cells. Additionally, we found that the antitumor effect of chidamide could be exerted by regulating the crosstalk between apoptosis and autophagy. When chidamide was used in combination with imatinib or nilotinib, the antitumor effects were enhanced compared with chidamide alone in Ba/F3 T315I and Ba/F3 P210 cells. Therefore, we conclude that chidamide may overcome T315I mutation-related drug resistance in CML patients and works efficiently if used in combination with TKIs. [ABSTRACT FROM AUTHOR]

Purpose: Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed. Materials and methods: Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide. Results: Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice. Conclusion: Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is a prevalent disease that harms women's health, and in-depth investigations of the pathogenesis, treatment, and prevention of BC are the focus of many research programs. Chidamide (CHI) is a histone deacetylase suppressor that depresses histone deacetylase functions, thereby influencing cell growth through an epigenetic mechanism. However, CHI effects upon BC are largely unknown. Present research aimed to confirm the possibility of using CHI combined with chemotherapy drug doxorubicin (DOX) to prevent chemotherapeutic BC resistance in vivo and in vitro. Methods: In this study, CCK8 (a plate colony formation assay) was applied to detect cell proliferation. Flow cytometry detection showed the apoptotic cell death of both T47D and MCF-7 cells. Nude mouse xenografts were used to detect tumor growth and pulmonary metastasis. High-throughput sequencing was used to detect expression of different genes. Results: Our data showed that CHI treatment reduced BC cell proliferation, tumor growth, and cell invasion. CHI treatments stimulated BC cell apoptosis by promoting ULK2-mediated autophagy and increasing MCF-7 cell sensitivity to DOX, resulting in decreased tumor growth. Conclusion: Collectively, our results illustrated that CHI enhanced DOX cytotoxicity by promoting apoptosis and autophagy in BC cells, which advised that CHI could be a candidate drug for BC patient treatments. [ABSTRACT FROM AUTHOR]

This research aimed to explore whether Chidamide works synergistically with Dasatinib in the therapy of Acute myeloid leukemia (AML) and the potential molecular mechanism. The inhibition rate of the Dasatinib and Chidamide combination was significantly better than that of the single-drug application for HL-60 cells. The combination of Dasatinib and Chidamide significantly enhanced the Abnormal histone deacetylase (HDAC) inhibitory activity of Chidamide in Kasumi-1 and HL-60 cells. In the combined group, the proportion of S phase was significantly decreased, and the proportions of G2/M phase were significantly increased. The inhibitory rate of CD34+ CD38− HL-60 cells or Kasumi-1 cells was elevated when the cells were disposed with both Chidamide and Dasatinib. Dasatinib and Chidamide had synergistic antitumor effect. The combination with Dasatinib enhanced the HDAC inhibitory activity of Chidamide, promoted cell apoptosis and cell-cycle arrest of AML cells, and enhanced the inhibition of leukemia stem cell proliferation. [ABSTRACT FROM AUTHOR]

Natural killer/T cell lymphoma (NKTCL) is a highly aggressive hematological malignancy. However, there is currently no consensus on therapies for refractory/relapsed patients. In this study, we investigated the synergistic anticancer effect and potential mechanism of combining chidamide, a histone deacetylases (HDACs) inhibitor, and etoposide, a DNA‐damaging agent, in NKTCL. We demonstrated that chidamide or etoposide alone dose‐ and time‐dependently inhibited the cell viability of NKTCL cell lines, YT, NKYS and KHYG‐1. Functional experiments suggested that combined chidamide and etoposide treatment exerted synergistic antiproliferation effect and enhanced cell apoptotic death in vitro and in vivo. Furthermore, the expression of DNA damage related proteins was detected and we also examined the alternations in histone acetylation, cell cycle progression, and mitochondrial membrane potential (MMP). The results suggested that increased histone acetylation, cell cycle arrest at the G2/M phase and loss of MMP, converging to greater DNA damage, might account for the synergism of the combination of chidamide and etoposide in NKTCL. Taken together, our study provides an evident for possible application on combining HDACs inhibitors and DNA‐damaging agents for the treatment of NKTCL. [ABSTRACT FROM AUTHOR]

Extranodal natural killer (NK)/T‐cell lymphoma (ENKTL) is strongly associated with Epstein–Barr virus (EBV) and has a high prevalence in Asian and in Central and South America. About 85% of ENKTLs derive from NK cells and 15% from T‐cells. Various factors have been implicated in the development of ENKTL. Molecular pathogenesis of NK/T‐cell lymphomas include mutations of genes, involving in the Janus Kinase/signal transducer and activator of transcription pathway, RNA helicase family, epigenetic regulation, and tumor suppression. The relationship between ENKTL and human leukocyte antigen has been demonstrated. Radiotherapy plays a key role in the first‐line treatment of early‐stage. In stage III/IV diseases, non‐anthracycline‐regimens‐containing L‐asparaginase are recommended. Although clinical remission after L‐asparaginase‐based combination therapy has been achieved in the majority of patients with advanced‐stage or relapsed/refractory extranodal NK/T‐cell lymphoma‐nasal type, the long‐term overall survival is still poor. Recently, immunotherapy and new therapeutic targets have gained much attention. In this article, we discuss the pathogenesis, diagnosis, prognostic models and management options of ENKTL. [ABSTRACT FROM AUTHOR]

B-cell non-Hodgkin lymphoma (B-NHL) is a lymphoid malignancy derived from B-cells that remains difficult to treat. Moreover, relapses and refractory cases are common. Abnormalities in epigenetic mechanisms, such as imbalanced histone acetylation affecting certain genes, contribute to relapses and refractory cases. Chidamide (tucidinostat) is a novel histone deacetylase inhibitor that can reverse this epigenetic imbalance and has been approved for the treatment of T-cell malignancies. However, the use of chidamide for B-NHL remains limited, and the lack of relevant literature exacerbates this limitation. We conducted this review to summarize the anticancer activity of chidamide against B-NHL and its clinical applications to overcome drug resistance. This systematic review was conducted according to the PRISMA 2020 guidelines, using some keyword combinations from MEDLINE and EBSCO. The inclusion and exclusion criteria were also defined. Of the 131 records retrieved from databases, 16 were included in the review. Nine articles revealed that chidamide limited tumor progression by modifying the tumor microenvironment, stopping the cell cycle, inducing apoptosis and autophagy, and enhancing complement-dependent and antibody-dependent cell-mediated cytotoxicities.According to seven other studies, administering chidamide in combination with another existing therapeutic regimen may benefit not only patients with relapsed/refractory B-NHL, but also those with newly diagnosed B-NHL. Chidamide plays many important roles in limiting B-NHL progression through epigenetic modifications. Thus, combining chidamide with other anticancer drugs may be more beneficial for patients with newly diagnosed and relapsed/refractory B-NHL.

Objective To investigate the effects of combined application of chidamide (CDM) and mycophenolate mofetil (MMF) on the proliferation of secondary acute myeloid leukemia (sAML) cells. Methods Chronic myeloid leukemia blast-phase cell line K562 and myelodysplastic syndromes (MDS)-transformed leukocyte line SKM-1 were employed in the study. The cells were divided into groups according to different concentrations of intervention drugs: CDM alone groups (0.25, 0.5, 1, 2 and 4 μmol/L), MMF alone groups (0.5, 1, 2, 4 and 8 μmol/L) and combined drug groups (CDM∶MMF=1∶2), respectively. The inhibitory rate of cell proliferation was detected by CCK-8 assay after treatment for 24, 48 and 72 h, respectively. Moreover, the changes of cell cycle and apoptotic rate were determined by flow cytometry after 72 h of intervention under the optimal combined drug concentration, and its mechanism was analyzed by network pharmacology. Results CCK-8 assay showed that the combination index of the combined drug group (1 μmol/L CDM+2 μmol/L MMF) was 0.389 44 in K562 cells and 0.630 98 in SKM-1 cells. When compared with the CDM and MMF monotherapy groups, the combined treatment significantly enhanced the inhibitory effect on the proliferation of both K562 and SKM-1 cells (P < 0.01), and increased the apoptotic rate of K562 cells (P < 0.05). As compared with the MMF alone group, the combination group remarkably arrested the cell cycle at the G0/G1 phase, though which had no statistical difference with CDM alone. Subsequently, a drug-disease target protein-protein interaction (PPI) network including 66 nodes and 222 edges was constructed through network pharmacology, and 9 core targets including CDK1, CDK2, CDK4, CDK6, CDK9, SYK, BTK, KDR, and PIK3CB were screened out according to topology. Enrichment analysis indicated that various biological processes such as protein phosphorylation, cell proliferation, and apoptosis regulation were mainly involved, as well as PI3K-AKT, FOXO and other signaling pathways. Conclusion CDM combined with MMF significantly inhibits the growth of sAML cells.

Abstract Chidamide is the first oral subtype-selective histone deacetylase inhibitor approved in China for the treatment of relapsed and refractory peripheral T cell lymphoma. Due to the existence of isomers, many articles or patents have mistaken its structure. Herein we explored the synthesis of the key intermediate (E)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzoic acid (A-3) and chidamide, using the condensing agent HBTU, instead of the unstable N,N'-carbonyldiimidazole. The single crystal of chidamide was determined by X-ray diffraction study. The optimized preparation process was easy to operate, and the purity of the final product can be up to 99.76%. Moreover, the structure of chidamide was established to be (E)-N-(2-amino-4-fluorophenyl)-4-((3-(pyridin-3-yl)acrylamido)methyl)benzamide.

Background: The prognosis of patients with peripheral T-cell (PTCL) or lymphoblastic T-cell lymphoma (T-LBL) remains poor under current conditioning regimens before receiving autologous stem cell transplantation (ASCT). Methods: Patients with PTCL or T-LBL were enrolled to receive ASCT using the conditioning regimen of chidamide, cladribine, gemcitabine, and busulfan (ChiCGB). Positron emission tomography-computed tomography (PET/CT) was used to evaluate the response to ASCT. Overall survival (OS) and progression-free survival (PFS) were employed to assess the patient outcome, and adverse events were used to assess the regimen's safety. The survival curve was estimated via the Kaplan-Meier method. Results: Twenty-five PTCL and 11 T-LBL patients were recruited. The median time to neutrophile and platelet engraftments was 10 days (8-13 days) and 13 days (9-31 days), respectively. The 3-year PFS and OS were 81.3 ± 7.2% and 88.5 ± 5.4% for all patients; 92.0 ± 5.4% and 81.2 ± 8.8% for PTCL patients; and both 81.8 ± 11.6% for T-LBL patients, respectively. The 3-year PFS and OS were both 92.9 ± 4.9% for patients with complete response (CR) but 50.0 ± 17.7% and 75.0 ± 15.3% for patients with non-CR, respectively. Infection was the most common non-hematological toxicity, and all toxicities were mild and controllable. Conclusions: ChiCGB was a potentially effective and well-tolerated conditioning regimen to improve the prognosis of patients with aggressive T-cell lymphoma. Future randomized controlled trials are needed to assess ChiCGB as a conditioning regimen for ASCT. [ABSTRACT FROM AUTHOR]

Objective To investigate the efficacy and safety of chidamide combined with azacitidine in treating relapsed/refractory angioimmunoblastic T⁃cell lymphoma (AITL). Methods The study was a single⁃center prospective clinical trial at Peking Union Medical College. The eligible patients were pathologically confirmed with AITL and met the criteria for relapsed/ refractory lymphoma. Treat⁃ ment included subcutaneous injection of azactidine azacitidine (100 m/d for 7 d) combined with oral chidamide (20 mg/d twice weekly) in a 4 weeks cycle. Results A total of 7 patients were enrolled from March 2021 to August 2022. The median age of disease onset was 53 (range 45-75) years and the median line of previous treatment was 2 (range 1-4) line. After treatment, complete remission (CR) was achieved in 2 cases and partial remission in 3 cases. The objective response rate was 71.4% and the CR rate was 28.6%. As of August 2022, the median follow⁃up time was 14 months (range 4-17 months). 6 patients survived and 1 patient died, and the median progres⁃ sion⁃free survival (PFS), duration of response, and overall survival (OS) of the whole group were not reached. The 1⁃year PFS and OS rates were 51.4% and 100.0%, respectively. Treatment ⁃ related adverse events were mainly hematological toxicity. The incidence of grade 3-4 neutropenia and thrombocytopenia were 28.6% (2/7) and 14.3% (1/7), respectively. Conclusions Azacitidine combined with chidamide has a high remission rate and safety profile in treating relapsed/refractory AITL, and dual epigenetic regulating drugs may serve as a second⁃line treatment option for patients with AITL. [ABSTRACT FROM AUTHOR]

Chemotherapy followed by donor lymphocyte infusion (DLI) is a promising treatment for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the best strategy for administering this therapy is still unclear. This study sought to explore the efficacy and safety of chidamide and CAG (cytarabine, aclarubicin, and granulocyte colony-stimulating factor) (CCAG) regimen followed by DLI in relapsed AML/MDS after allo-HSCT. This was a single-arm, phase II trial in patients with relapsed AML/MDS after allo-HSCT. CCAG regimen followed by DLI was given according to the inclusion and exclusion criteria. Twenty adult patients were enrolled. The median follow-up time was 12 months. The complete remission (CR) rate was 45% and the partial remission (PR) rate was 5%. The 1-year overall survival (OS) was 56.7% (95% confidence interval (95% CI), 31.6–75.6%), and the median OS was 19 months. The 1-year relapse-free survival (RFS) was 83.3% (95% CI, 27.3–97.5%). Patients relapsing more than 6 months after HSCT and achieving CR/PR after CCAG plus DLI regimen attained significantly higher survival rates. The cumulative incidence of grade III–IV acute graft-versus-host disease (aGVHD) was 9.4%. There was no treatment-related mortality (TRM). These data suggest that CCAG plus DLI regimen is safe and induces durable remission and superior survival in patients with relapsed AML/MDS after allo-HSCT. Trial registration number: ChiCTR.org identifier: ChiCTR1800017740 and date of registration: August 12, 2018. [ABSTRACT FROM AUTHOR]

Objective: We aimed to explore a new method to reverse early relapse in patients with AML1-ETO-positive acute myeloid cell transplantation. Methods: A chidamide-based 3-drug combination regimen was used in our center to treat patients with AML1-ETO-positive AML post transplantation but negative flow cytometry results. A retrospective analysis was performed of the survival rate and possible influencing factors of patients with relapse treated with this regimen in our center from January 2018 to January 2022. Results: The overall response rate was 95.8% (23/24), and the median number of treatment courses was 4 (range, 3-12 courses). The total molecular complete response (MCR) was 79.1% (19/24) after all treatments, and the molecular complete response was 37.5% (9/24) after one cycle of treatment but reached 58.3% (14/24) after four cycles; overall, the proportion of MCR increased gradually with the increase in treatment cycles. The projected 5-year overall survival rate was 73.9%. The projected 5-year leukemia-free survival rate was 64.8%, and the projected 1-year cumulative relapse rate was 35.5%. The incidence of grade II-IV graft-versus-host diseases (GVHD) was 29.2% (7/24), and that of grade III-IV GVHD was 20.8% (5/24), which could be effectively controlled by glucocorticoid therapy combined with calcineurin inhibitors The total incidence of chronic GVHD was 29.2% (7/24), and all cases were localized chronic GVHD. The total infection rate was 33.3% (8/24), mainly involving bacterial and fungal infections, and the incidence of life-threatening infections was 4.17% (1/24). The treatmentrelated mortality rate was 0%; and the total mortality rate was 20.8% (5/24). Nausea and vomiting, thrombocytopenia, and neutropenia were common adverse reactions, all of which were Common Terminology Criteria for Adverse Events grade 2-3 events and reversible after drug withdrawal. In terms of immunity, Th1 cell counts gradually increased, Th17 cell counts gradually decreased, and the Th1/Th17 ratio gradually increased after treatment. The CD8+ T lymphocyte count increased gradually, while the CD4+ T lymphocyte count did not change significantly. Conclusion: Our chidamide-based 3-drug combination regimen led to a high remission rate and tolerable adverse reactions in patients with AML1-ETO-positive post-transplant relapse, and most patients can achieve long-term survival with this regimen. [ABSTRACT FROM AUTHOR]

Abstract Background Leukemia stem cells (LSCs) are responsible for the initiation and perpetuation of acute myeloid leukemia (AML), and also represent leukemia relapse reservoirs with limited therapeutic approaches. Thus, additional treatment strategies are medical unmet needs to eliminate LSCs. Methods Cell counting kit-8 and Annexin-V-FITC/PI assays were used to examine the interaction of chidamide and apatinib on LSC-like cell lines (CD34+CD38− KG1α and Kasumi-1 cells) and primary CD34+ AML cells. AML patient-derived xenografts were established to investigate the in vivo efficacy of the combined regimen. RNA sequencing, Glutamine uptake assay, oxygen consumption assay, and western blotting were employed to explore the molecule mechanism for the cytotoxicity of chidamide with or without apatinib against LSC-like cell lines and/or primary CD34+ AML cells. Results In this study, chidamide and apatinib were synergisitc to diminish cell viability and induce apoptosis in CD34+CD38− KG1α and Kasumi-1 cells and in CD34+ primary AML cells. Importantly, chidamide combined with apatinib had more powerful in reducing leukemia burden and improving prognosis than single drug alone in an AML PDX model without significant adverse effects. Chidamide cytotoxicity was associated with decreasing glutamine uptake. The therapeutic synergy of chidamide and apatinib correlated with reprogramming of energy metabolic pathways. In addition, inactivating the VEGFR function and reducing the anti-apoptotic ability of the Bcl2 family contributed to the synergism of chidamide and apatinib in CD34+CD38− KG1α cells and CD34+ primary AML cells. Conclusion Chidamide in combination with apatinib might be a promising therapeutic strategy to get rid of the population of AML stem and progenitor cells, and thus provide a potentially curative option in the treatment of patients with AML, although further clinical evaluations are required to substantiate the conclusion.