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Decitabine: An effective and safe treatment for myelodysplastic syndrome and acute myeloid leukemia.Journal of Cancer Research and... 2019Decitabine is reported to be valuable in treating multiple malignant blood diseases. However, the application of decitabine in myelodysplastic syndromes (MDSs) and acute...
OBJECTIVE
Decitabine is reported to be valuable in treating multiple malignant blood diseases. However, the application of decitabine in myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) has not been fully examined. Thus, our study aimed to investigate the clinical efficacy and safety of decitabine in treating such patients.
MATERIALS AND METHODS
Clinical data of MDS or AML patients treated with decitabine were retrospectively analyzed. All the patients were regularly followed up, and the risk factors affecting clinical efficacy were also detected.
RESULTS
A total of 36 patients (MDS, n = 27; AML, n = 9) were included in the study. The response rate of MDS patients was 55%, and there were three cases (15%) of complete remission (CR), three cases (15%) of marrow CR, and five cases (15%) of hematologic improvement. It was about three cycles to achieve the best efficiencies. Gender, age, percentage of blasts in bone marrow, International Prognostic Scoring System risk group, and cytogenetic factors were not associated with response rate. The median overall survival of MDS patients was 8 (1-44) months. Agranulocytosis (P = 0.037) and severe anemia (P = 0.044) were the independent factors for prognosis. The complete response rate of AML was 33.3%. From the investigation, infection was the most common complication in our cohort, especially lung infection with the incidence of 27.8%.
CONCLUSIONS
Our data demonstrated that decitabine was effective and relatively safe in treating MDS and AML. Patients with agranulocytosis and severe anemia were prone to have poor survival, which should be monitored in clinical practice.
Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Decitabine; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Prognosis; Survival Analysis; Treatment Outcome
PubMed: 31939424
DOI: 10.4103/0973-1482.204849 -
EBioMedicine May 2022The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional...
BACKGROUND
The multiplicity, heterogeneity, and dynamic nature of human immunodeficiency virus type-1 (HIV-1) latency mechanisms are reflected in the current lack of functional cure for HIV-1. Accordingly, all classes of latency-reversing agents (LRAs) have been reported to present variable ex vivo potencies. Here, we investigated the molecular mechanisms underlying the potency variability of one LRA: the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-AzadC).
METHODS
We employed epigenetic interrogation methods (electrophoretic mobility shift assays, chromatin immunoprecipitation, Infinium array) in complementary HIV-1 infection models (latently-infected T-cell line models, primary CD4 T-cell models and ex vivo cultures of PBMCs from HIV individuals). Extracellular staining of cell surface receptors and intracellular metabolic activity were measured in drug-treated cells. HIV-1 expression in reactivation studies was explored by combining the measures of capsid p24 protein, green fluorescence protein signal, intracellular and extracellular viral RNA and viral DNA.
FINDINGS
We uncovered specific demethylation CpG signatures induced by 5-AzadC in the HIV-1 promoter. By analyzing the binding modalities to these CpG, we revealed the recruitment of the epigenetic integrator Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) to the HIV-1 promoter. We showed that UHRF1 redundantly binds to the HIV-1 promoter with different binding modalities where DNA methylation was either non-essential, essential or enhancing UHRF1 binding. We further demonstrated the role of UHRF1 in the epigenetic repression of the latent viral promoter by a concerted control of DNA and histone methylations.
INTERPRETATION
A better understanding of the molecular mechanisms of HIV-1 latency allows for the development of innovative antiviral strategies. As a proof-of-concept, we showed that pharmacological inhibition of UHRF1 in ex vivo HIV patient cell cultures resulted in potent viral reactivation from latency. Together, we identify UHRF1 as a novel actor in HIV-1 epigenetic silencing and highlight that it constitutes a new molecular target for HIV-1 cure strategies.
FUNDING
Funding was provided by the Belgian National Fund for Scientific Research (F.R.S.-FNRS, Belgium), the « Fondation Roi Baudouin », the NEAT (European AIDS Treatment Network) program, the Internationale Brachet Stiftung, ViiV Healthcare, the Télévie, the Walloon Region (« Fonds de Maturation »), « Les Amis des Instituts Pasteur à Bruxelles, asbl », the University of Brussels (Action de Recherche Concertée ULB grant), the Marie Skodowska Curie COFUND action, the European Union's Horizon 2020 research and innovation program under grant agreement No 691119-EU4HIVCURE-H2020-MSCA-RISE-2015, the French Agency for Research on AIDS and Viral Hepatitis (ANRS), the Sidaction and the "Alsace contre le Cancer" Foundation. This work is supported by 1UM1AI164562-01, co-funded by National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Institute on Drug Abuse and the National Institute of Allergy and Infectious Diseases.
Topics: Acquired Immunodeficiency Syndrome; CCAAT-Enhancer-Binding Proteins; DNA Methylation; Decitabine; Epigenetic Repression; HIV Infections; HIV-1; Humans; Ubiquitin-Protein Ligases; Virus Latency
PubMed: 35429693
DOI: 10.1016/j.ebiom.2022.103985 -
Journal For Immunotherapy of Cancer Jan 2022The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid...
BACKGROUND
The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.
METHODS
We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).
RESULTS
In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.
CONCLUSION
Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Decitabine; Female; Humans; Immunotherapy; Leukemia, Myeloid, Acute; Male; Pilot Projects; Recurrence
PubMed: 35017151
DOI: 10.1136/jitc-2021-003392 -
International Journal of Cancer May 2023To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning...
Cladribine- and decitabine-containing conditioning regimen has a low post-transplant relapse rate in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome.
To reduce the risk of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT), there have been continuing efforts to optimize the conditioning regimens. Our study aimed to analyze the risk factors associated with the relapse of relapsed/refractory (R/R), high-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) post-transplant and the efficacy of a new conditioning regimen involving decitabine and cladribine. Clinical data of 125 patients with R/R AML, high-risk AML and high-risk MDS who underwent allo-HSCT were collected. In addition, 35 patients with R/R AML, high-risk AML and high-risk MDS received treatment with a new conditioning regimen including decitabine and cladribine. Cox regression analysis was used to identify risk factors associated with OS, RFS and relapse. Among 125 patients who underwent allo-HSCT, CR before allo-HSCT and matched sibling donors were independent protective factors for OS. DNMT3A abnormality was an independent risk factor for both relapse and RFS. Among 35 patients who received a new conditioning regimen containing decitabine and cladribine, only six patients relapsed and 1-year cumulative incidence of relapse was 11.7%. Moreover, this new regimen showed efficient MRD clearance early after allo-HSCT. The combined decitabine- and cladribine-based conditioning regimen showed a low relapse rate and a high survival without an increased incidence of GVHD or adverse effects and thus has potential for use in allo-HSCT for R/R AML, high-risk AML and high-risk MDS.
Topics: Humans; Cladribine; Decitabine; Graft vs Host Disease; Leukemia, Myeloid, Acute; Chronic Disease; Recurrence; Myelodysplastic Syndromes; Hematopoietic Stem Cell Transplantation; Retrospective Studies
PubMed: 36594582
DOI: 10.1002/ijc.34419 -
Hematology. American Society of... Dec 2017Remission induction with chemotherapy has long been the frontline treatment of acute myeloid leukemia (AML). However, intensive therapy is limited in frail patients by... (Review)
Review
Remission induction with chemotherapy has long been the frontline treatment of acute myeloid leukemia (AML). However, intensive therapy is limited in frail patients by its associated toxicity and higher rates of failure or relapse in patients with chemoresistant disease, such as secondary AML or poor-risk cytogenetics. Frailty and chemoresistance are more frequent in older adults with AML. In recent years, epigenetic therapies with the hypomethylating agents decitabine and azacitidine have been thoroughly explored in AML. The results of two pivotal studies carried out with these agents in older adults with newly diagnosed AML have challenged the role of intensive chemotherapy as the frontline treatment option in this high-risk population. Here, we review the results of treatment with intensive chemotherapy and hypomethylating agents in older patients with AML; discuss the patient- and disease-specific criteria to integrate into treatment decision making; and also, highlight the methodological limitations of cross-study comparison in this population.
Topics: Azacitidine; Chromosome Aberrations; Decision Making; Decitabine; Epigenesis, Genetic; Humans; Leukemia, Myeloid, Acute
PubMed: 29222236
DOI: 10.1182/asheducation-2017.1.45 -
Oncotarget Jun 2017Elderly patients with acute myeloid leukemia (AML) have limited treatment options concerned about their overall fitness and potential treatment related mortality.... (Meta-Analysis)
Meta-Analysis Review
Elderly patients with acute myeloid leukemia (AML) have limited treatment options concerned about their overall fitness and potential treatment related mortality. Although a number of clinical trials demonstrated benefits of decitabine treatment in elderly AML patients, the results remains controversial. A meta-analysis was performed to evaluate efficacy and safety of decitabine in treatment of elderly AML patients. Eligible studies were identified from PubMed, Web of Science, Embase and Cochrane Library. Nine published studies were included in the meta-analysis, enrolling 718 elderly AML patients. The efficacy outcomes were complete remission (CR), overall response rate (ORR) and overall survival (OS). Safety was evaluated based on treatment related grades 3-4 adverse events (AEs) and early death (ED) rate. Pooled estimates with 95% confidence interval (CI) for CR, ORR and OS were 27% (95% CI 19%-36%), 37% (95% CI 28%-47%) and 8.09 months (95% CI 5.77-10.41), respectively. The estimated treatment related early death (ED) incidences were within 30-days 7% (95% CI 2%-11%) and 60-days 17% (95% CI 11%-22%), respectively. Thrombocytopenia was the most common grades 3-4 AEs. Subgroup analyses of age, cytogenetics risk, AML type and bone marrow blast percentage showed no significant differences of treatment response to decitabine. In conclusion, decitabine is an effective and well-tolerated therapeutic alternative with acceptable side effects in elderly AML patients.
Topics: Aged; Antimetabolites, Antineoplastic; Azacitidine; Decitabine; Humans; Leukemia, Myeloid, Acute; Male
PubMed: 28489568
DOI: 10.18632/oncotarget.17241 -
Cells Aug 2020Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted... (Review)
Review
Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.
Topics: Animals; Antimetabolites, Antineoplastic; Azacitidine; Cell Line, Tumor; DNA Methylation; Decitabine; Epigenesis, Genetic; Humans; Urinary Bladder Neoplasms
PubMed: 32784599
DOI: 10.3390/cells9081850 -
Blood Sep 2012In this issue of Blood, Yan et al study the anatomy of azanuceoside methylation reversal.
In this issue of Blood, Yan et al study the anatomy of azanuceoside methylation reversal.
Topics: Antimetabolites, Antineoplastic; Azacitidine; Biomarkers, Tumor; DNA Methylation; Decitabine; Female; Gene Expression Profiling; Genome, Human; Humans; Leukemia, Myeloid, Acute; Male
PubMed: 22996655
DOI: 10.1182/blood-2012-08-443952 -
Blood Advances Sep 2020Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the...
Outcome after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is adversely affected by relapse to a considerable degree. To exploit the graft-versus-leukemia effect more effectively, we assessed the feasibility of early initiation of epigenetic therapy with panobinostat and decitabine after allo-HSCT and before donor lymphocyte infusion (DLI) in poor-risk patients with acute myeloid leukemia (AML) or refractory anemia with excess blasts with International Prognostic Scoring System score ≥1.5. A total of 140 poor-risk patients with AML aged 18 to 70 years were registered, and 110 proceeded to allo-HSCT. Three dose levels were evaluated for dose-limiting toxicities, including panobinostat monotherapy 20 mg at days 1, 4, 8, and 11 of a 4-week cycle (PNB mono group) and panobinostat combined with either decitabine 20 mg/m2 (PNB/DAC20 group) or decitabine 10 mg/m2 (PNB/DAC10 group) at days 1 to 3 of every 4-week cycle. After phase 1, the study continued as phase 2, focusing on completion of protocol treatment and treatment outcome. PNB mono and PNB/DAC10 were feasible, whereas PNB/DAC20 was not related to prolonged cytopenia. Sixty of 110 patients who underwent transplantation were eligible to receive their first DLI within 115 days after allo-HSCT. Grade 3 and 4 adverse events related to panobinostat and decitabine were observed in 23 (26%) of the 87 patients, and they received epigenetic therapy. Cumulative incidence of relapse was 35% (standard error [SE] 5), and overall survival and progression-free survival at 24 months were 50% (SE 5) and 49% (SE 5). Post-allo-HSCT epigenetic therapy with panobinostat alone or in combination with low-dose decitabine is feasible and is associated with a relatively low relapse rate. The trial was registered at the European Clinical Trial Registry, https://www.clinicaltrialsregister.eu, as ECT2012-003344-74.
Topics: Adolescent; Adult; Aged; Decitabine; Hematopoietic Stem Cell Transplantation; Humans; Lymphocytes; Middle Aged; Panobinostat; Transplantation, Homologous; Young Adult
PubMed: 32936907
DOI: 10.1182/bloodadvances.2020002074 -
Clinical Epigenetics Sep 2022Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark...
Azacytidine (AzaC) and decitabine (AzadC) are cytosine analogs that covalently trap DNA methyltransferases, which place the important epigenetic mark 5-methyl-2'-deoxycytidine by methylating 2'-deoxycytidine (dC) at the C5 position. AzaC and AzadC are used in the clinic as antimetabolites to treat myelodysplastic syndrome and acute myeloid leukemia and are explored against other types of cancer. Although their principal mechanism of action is known, the downstream effects of AzaC and AzadC treatment are not well understood and the cellular prerequisites that determine sensitivity toward AzaC and AzadC remain elusive. Here, we investigated the effects and phenotype of AzaC and AzadC exposure on the acute myeloid leukemia cell line MOLM-13. We found that while AzaC and AzadC share many effects on the cellular level, including decreased global DNA methylation, increased formation of DNA double-strand breaks, transcriptional downregulation of important oncogenes and similar changes on the proteome level, AzaC failed in contrast to AzadC to induce apoptosis efficiently in MOLM-13. The only cellular marker that correlated with this clear phenotypical outcome was the level of hydroxy-methyl-dC, an additional epigenetic mark that is placed by TET enzymes and repressed in cancer cells. Whereas AzadC increased hmdC substantially in MOLM-13, AzaC treatment did not result in any increase at all. This suggests that hmdC levels in cancer cells should be monitored as a response toward AzaC and AzadC and considered as a biomarker to judge whether AzaC or AzadC treatment leads to cell death in leukemic cells.
Topics: Azacitidine; Cell Line; DNA; DNA Methylation; Decitabine; Humans; Leukemia, Myeloid, Acute
PubMed: 36089606
DOI: 10.1186/s13148-022-01329-0