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Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma.

ABSTRACT: Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapy outcomes. Here, we examined the therapeutic effects of chidamide, a new histone deacetylase (HDAC) inhibitor, on the cell and mouse models of rituximab/chemotherapy resistant B-cell lymphoma. In Raji-4RH/RL-4RH cells, the rituximab/chemotherapy resistant B-cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest. The primary B-cell lymphoma cells from Rituximab/chemotherapy relapsed patients were sensitive to chidamide. Interestingly, chidamide triggered the cell death with the activation of autophagy in RRCLs, likely due to the lack of the pro-apoptotic proteins. Based on the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as chidamide target genes, which control the autophagy and the cell cycle, respectively. Moreover, the combination of chidamide with the chemotherapy drug cisplatin increased growth inhibition on the RRCL in a synergistic manner, and significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, these results provide a theoretic and mechanistic basis for further evaluation of the chidamide-based treatment in rituximab/chemotherapy relapsed and refractory B-cell lymphoma patients.

SUBMITTER: Xue K

PROVIDER: S-EPMC8486747 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B cell lymphoma

Project description:Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapies of these patients. A new oral histone deacetylase inhibitor, chidamide shows anti-tumor activity by activating the pro-apoptosis pathway in some other hematological malignancies, suggesting its potential application to the relapsed and refractory B cell lymphoma. In this study, we examined the therapeutic effects of chidamide on the cell and mouse models of the rituximab/chemotherapy resistant B cell lymphoma, as well as the primary B cell lymphoma cells. In Raji-4RH and RL-4RH cells, the rituximab/chemotherapy resistant B cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest, which were associated with E2F1/2 inactivation and CDK2 degradation. The primary B cell lymphoma cells from Rituximab/chemotherapy relapsed and refractory patients were also very sensitive to chidamide treatment. Interestingly, chidamide triggered the cell death via the autophagy pathway instead of the activation of apoptosis in Raji-4RH and RL-4RH cells, likely due to the lack of the pro-apoptotic proteins in these resistant cells. In the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as the direct target genes of chidamide, which control the autophagy and cell cycle respectively in RRCL treated with chidamide. Moreover, the combination of chidamide with the chemotherapy drug Cisplatin sensitized the RRCL to growth inhibition in a synergistic manner. Chidamide-Cisplatin combination significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, our studies provides a theoretic and mechanistic basis for further evaluation of the chidamide-based clinical trial for rituximab/chemotherapy relapsed and refractory B cell lymphoma patients.

2021-10-06 | GSE137359 | GEO

Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B cell lymphoma

Project description:Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B cell lymphoma

| PRJNA565234 | ENA

Salvage chemotherapy for adults with relapsed or refractory lymphoma in Malawi.

Project description:BACKGROUND:Lymphoma is highly associated with HIV in sub-Saharan Africa (SSA), which contributes to worse outcomes relative to resource-rich settings, and frequent failure of first-line chemotherapy. However, there are no second-line treatment descriptions for adults with relapsed or refractory lymphoma (RRL) in SSA. METHODS:We describe HIV+ and HIV- patients with RRL receiving salvage chemotherapy in Malawi. Patients were prospectively treated at a national teaching hospital in Lilongwe, with the modified EPIC regimen (etoposide, prednisolone, ifosfamide, cisplatin) between June 2013 and May 2016, after failing prior first-line chemotherapy. RESULTS:Among 21 patients (18 relapsed, 3 refractory), median age was 40 years (range 16-78), 12 (57%) were male. Thirteen patients (62%) were HIV+, of whom 12 (92%) were on antiretroviral therapy (ART) at initiation of salvage chemotherapy, with median CD4 cell count 139 cells/?L (range 12-529) and 11 (85%) with suppressed HIV RNA. Median number of EPIC cycles was 3 (range 1-6), and the commonest toxicity was grade 3/4 neutropenia in 19 patients (90%). Fifteen patients responded (3 complete, 12 partial, overall response rate 71%), but durations were brief. Median overall survival was 4.5 months [95% confidence interval (CI) 2.4-5.6]. However, three patients, all HIV+, experienced sustained remissions. Tolerability, response, and survival did not differ by HIV status. CONCLUSIONS:The appropriateness and cost-effectiveness of this approach in severely resource-limited environments is uncertain, and multifaceted efforts to improve first-line lymphoma treatment should be emphasized, to reduce frequency with which patients require salvage chemotherapy. TRIAL REGISTRATION:NCT02835911. Registered 19 January 2016.

| S-EPMC5551007 | biostudies-literature

Mogamulizumab versus investigator's choice of chemotherapy regimen in relapsed/refractory adult T-cell leukemia/lymphoma.

Project description:Mogamulizumab, a humanized defucosylated anti-C-C chemokine receptor 4 monoclonal antibody, has been approved in Japan for the treatment of C-C chemokine receptor 4-positive adult T-cell leukemia/lymphoma (ATL). This phase II study evaluated efficacy and safety of mogamulizumab in ATL patients with acute, lymphoma, and chronic subtypes with relapsed/refractory, aggressive disease in the US, Europe, and Latin America. With stratification by subtype, patients were randomized 2:1 to intravenous mogamulizumab 1.0 mg/kg once weekly for 4 weeks and biweekly thereafter (n=47) or investigator's choice of chemotherapy (n=24). The primary end point was confirmed overall response rate (cORR) confirmed on a subsequent assessment at 8 weeks by blinded independent review. ORR was 11% (95%CI: 4-23%) and 0% (95%CI: 0-14%) in the mogamulizumab and chemotherapy arms, respectively. Best response was 28% and 8% in the respective arms. The observed hazard ratio for progression-free survival was 0.71 (95%CI: 0.41-1.21) and, after post hoc adjustment for performance status imbalance, 0.57 (95%CI: 0.337-0.983). The most frequent treatment-related adverse (grade ≥3) events with mogamulizumab were infusion-related reaction and thrombocytopenia (each 9%). Relapsed/refractory ATL is an aggressive, poor prognosis disease with a high unmet need. Investigator's choice chemotherapy did not result in tumor response in this trial; however, mogamulizumab treatment resulted in 11% cORR, with a tolerable safety profile.

| S-EPMC6518882 | biostudies-literature

Transplant strategies in relapsed/refractory Hodgkin lymphoma.

Project description:The majority of patients with Hodgkin lymphoma (HL) are cured with initial therapy. However, high-dose therapy with autologous hematopoietic cell transplant (AHCT) allows for the cure of an additional portion of patients with relapsed or primary refractory disease. Positron emission tomography-negative complete remission before AHCT is critical for long-term disease control. Several salvage options are available with comparable response rates, and the choice can be dependent of comorbidities and logistics. Radiation therapy can also improve the remission rate and is an important therapeutic option for selected patients. Brentuximab vedotin (BV) maintenance after AHCT is beneficial in patients at high risk for relapse, especially those with more than 1 risk factor, but can have the possibility of significant side effects, primarily neuropathy. Newer agents with novel mechanisms of action are under investigation to improve response rates for patients with subsequent relapse, although are not curative alone. BV and the checkpoint inhibitors nivolumab and pembrolizumab are very effective with limited side effects and can bridge patients to curative allogeneic transplants (allo-HCT). Consideration for immune-mediated toxicities, timing of allogeneic hematopoietic cell transplant based on response, and the potential for increased graft-versus-host disease remain important. Overall, prospective investigations continue to improve outcomes and minimize toxicity for relapsed or primary refractory HL patients.

| S-EPMC5897866 | biostudies-literature

CREBBP cooperates with cell cycle machinery to attenuate chidamide sensitivity in relapsed/refractory DLBCL

Project description:Frequent inactivating mutations of histone acetyltransferase CREBBP is a characteristic feature of diffuse large B-cell lymphoma (DLBCL), highlighting the attractiveness of targeting the CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor as most patients exhibit resistance, hampering the clinical utility of the drug. Functional studies in both in vitro and in vivo models showed that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulating cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibited G2/M transition during cell cycling, as top candidates that synergistically enhanced antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrated that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while a combination of AURKA inhibitor and chidamide provides a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.

2024-02-24 | GSE167383 | GEO

Advances in the treatment of relapsed or refractory Hodgkin's lymphoma.

Project description:Hodgkin's lymphoma (HL) is diagnosed in 20,000 men and women annually in North America and Europe. Despite treatment advancements for HL resulting in an overall survival rate of 80%, patients with advanced stage disease continue to have suboptimal outcomes, with relapse rates of 30%-40%. An additional 10%-15% of patients present with primary refractory disease. For patients who relapse after initial treatment, salvage chemotherapy followed by autologous stem cell transplant in those with chemotherapy-sensitive disease is the standard of care. Patients who relapse after second-line therapy have a median survival time in the range of 6-36 months, and the optimal management of these patients remains unclear. Unfortunately, there have been no new agents approved for relapsed HL treatment since the 1970s. Consequently, clinical decision making in this population is difficult. Recently however, several agents have emerged that have shown clinical promise in this poor-risk population. This review discusses the management of these patients and also discusses several newer agents showing clinical promise in the treatment of HL.

| S-EPMC3316922 | biostudies-other

Checkpoint Inhibitors in Relapsed/Refractory Classical Hodgkin Lymphoma.

Project description:Even though classical Hodgkin lymphoma is highly curable, the outcome of patients with a refractory or relapsed disease has been disappointing. Multiple lines of therapy are available for patients after their first failure, and most respond to subsequent therapies. However, there is a sizable proportion that remains relapsing/recurrent even after several lines of therapy. The overall prognosis of patients with relapsing and recurrent classical Hodgkin lymphoma (rrcHL) has been very disappointing until recently. Immune checkpoint inhibitors such as the anti-programmed death 1 (PD-1) receptor antibodies have recently been approved to treat relapsed and refractory cHL and have significantly improved the outcome of patients with rrcHL. The approved immune checkpoint inhibitors for relapsed and refractory cHL are nivolumab and pembrolizumab. In the Checkmate 205 study nivolumab demonstrated an objective response rate of 69% with an acceptable safety profile. Similarly, pembrolizumab demonstrated an overall response rate (ORR) of 69% with a complete remission rate (CRR) of 22.4% in the KEYNOTE-087 study in heavily pretreated patients with rrcHL.

| S-EPMC8297052 | biostudies-literature

Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma.

Project description:Standard treatment of transplant-eligible patients with relapsed diffuse large B-cell lymphoma (DLBCL) consists of rituximab and platinum-based chemotherapy, either ifosfamide, carboplatin, and etoposide (ICE) or dexamethasone, cytarabine, and cisplatin (DHAP), with autologous transplant consolidation for those with chemosensitive disease. Nonetheless, outcomes are suboptimal for patients failing rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We performed a multi-center phase II trial investigating the safety and efficacy of ofatumumab, a monoclonal antibody against CD20, combined with ICE or DHAP second-line therapy in patients with relapsed or refractory DLBCL, grade 3b follicular lymphoma, or transformed follicular lymphoma. Sixty-one patients were treated with either ofatumumab-ICE (35) or ofatumumab-DHAP (26). The overall response rate (ORR) was 61%, and the complete response (CR) rate was 37%. In patients with 2 or 3 adverse risk factors according to the second-line, age-adjusted, international prognostic index, the ORR was 59% and CR 31%, and in patients with early-relapsing or primary refractory disease, the ORR was 55% and CR 30%. Toxicity was largely hematologic, and stem cell mobilization was successful in 43 of 45 patients. Substitution of ofatumumab for rituximab in standard second-line regimens following failure of R-CHOP is a promising approach. This trial was registered at www.clinicaltrials.gov as NCT00823719.

| S-EPMC3724189 | biostudies-literature

Role of Roflumilast Combined with ESHAP Chemotherapy in Relapsed/Refractory Patients with Diffuse Large B-Cell Lymphoma.

Project description:PurposeThere are unmet needs associated with the current treatment strategies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) due to the poor treatment outcomes of these strategies. Roflumilast, a selective phosphodiesterase-4 inhibitor used for treating chronic obstructive pulmonary disease, is effective against B-cell malignancy via phosphoinositide 3-kinase (PI3K)-activity suppression. We analyzed the effects of roflumilast combined with ESHAP (etoposide, cisplatin, methylprednisolone, and cytarabine) chemotherapy in experimental and clinical settings.Materials and methodsAn in vitro study using lymphoma cell lines and a pilot study on relapsed/refractory DLBCL patients were conducted to investigate the effects and mechanism of the combination of roflumilast and chemotherapy. The complete response (CR), overall response rate (ORR), and 1-year progression-free survival (PFS) were analyzed.ResultsWe found that roflumilast is efficient when combined with other chemotherapy drugs, especially cytarabine. Synergistic effects between these two drugs influence the translation of mammalian target of rapamycin and myeloid cell leukemia 1, resulting in apoptosis and inhibition of B-cell lymphoma proliferation. In clinical setting, the roflumilast group showed better rates of CR (46.2% vs. 34.6%), ORR (76.9% vs. 53.8%), and 1-year PFS (50.0% vs. 25.9%) compared with the control group, though not statistically significant. The roflumilast group showed a higher incidence of asthenia and gastrointestinal adverse events. However, grade 3 or 4 adverse events were similar in both groups.ConclusionWe found that roflumilast, when combined with ESHAP chemotherapy, for relapsed/refractory DLBCL was clinically active and well tolerated. This combined treatment was able to suppress PI3K activity, which is correlated with the degree of clinical response.

| S-EPMC8756117 | biostudies-literature

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