-
The New England Journal of Medicine Oct 2020
Review
Topics: Azacitidine; Decitabine; Enzyme Inhibitors; Erythrocyte Transfusion; Genetic Predisposition to Disease; Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Stem Cell Transplantation; Transplantation, Homologous; Watchful Waiting
PubMed: 32997910
DOI: 10.1056/NEJMra1904794 -
Blood Aug 2020This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35... (Comparative Study)
Comparative Study Randomized Controlled Trial
This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Capsules; Cross-Over Studies; DNA Methylation; DNA-Cytosine Methylases; Decitabine; Disease Progression; Drug Combinations; Drug Monitoring; Female; Gastrointestinal Diseases; Hematologic Diseases; Humans; Kaplan-Meier Estimate; Least-Squares Analysis; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Long Interspersed Nucleotide Elements; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasm Proteins; Tablets; Uridine
PubMed: 32285126
DOI: 10.1182/blood.2019004143 -
Blood Apr 2023The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic...
The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.
Topics: Humans; Ipilimumab; Decitabine; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Recurrence; Hematopoietic Stem Cell Transplantation
PubMed: 36706355
DOI: 10.1182/blood.2022018246 -
American Journal of Hematology Feb 2021This analysis represents the longest-term follow-up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine.... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
This analysis represents the longest-term follow-up for patients with acute myeloid leukemia (AML) treated with 400 mg of venetoclax plus azacitidine or decitabine. Adults with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in an open-label, non-randomized, multicenter phase 1b trial of venetoclax with azacitidine (AZA; 75 mg/m ; days 1-7) or decitabine (DEC; 20 mg/m ; days 1-5). Endpoints included safety, response rates (complete remission [CR], CR with incomplete blood count recovery [CRi]), response duration and overall survival (OS). The median follow-up time was 29 and 40 months for patients treated with venetoclax plus AZA and DEC combinations, respectively. Key Grade ≥ 3 AEs (AZA and DEC) were febrile neutropenia (39% and 65%), anemia (30% and 26%), thrombocytopenia (25% and 23%), and neutropenia (20% and 10%). The CR/CRi rate was 71% for venetoclax plus AZA and 74% for venetoclax plus DEC. The median duration of CR/CRi was 21.9 months and 15.0 months, and the median OS was 16.4 months and 16.2 months, for venetoclax plus AZA and DEC, respectively. These results support venetoclax plus hypomethylating agents as highly effective frontline AML therapies for patients unfit for intensive chemotherapy.
Topics: Aged; Aged, 80 and over; Anemia; Antineoplastic Combined Chemotherapy Protocols; Azacitidine; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Febrile Neutropenia; Female; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Sulfonamides; Thrombocytopenia
PubMed: 33119898
DOI: 10.1002/ajh.26039 -
Signal Transduction and Targeted Therapy Oct 2023TP53 mutation (TP53) occurs in 10-20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance...
TP53 mutation (TP53) occurs in 10-20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53 remains a significant challenge in DLBCL treatment. Here we assessed TP53 in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53 independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53 patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53 DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4T/CD8T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53 patient-derived xenograft models and TP53 patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53 DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53-driven cancers.
Topics: Humans; Endogenous Retroviruses; Hematopoietic Stem Cell Transplantation; Decitabine; Transplantation, Autologous; Lymphoma, Large B-Cell, Diffuse; Rituximab; Doxorubicin; Epigenesis, Genetic; Tumor Microenvironment; Tumor Suppressor Protein p53
PubMed: 37798292
DOI: 10.1038/s41392-023-01626-x -
Cancer Oct 2021TP53 mutation (TP53 ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients;...
BACKGROUND
TP53 mutation (TP53 ) confers an adverse prognosis in acute myeloid leukemia (AML). Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 confers resistance to venetoclax. The authors investigated the outcomes of patients with TP53 AML who were treated with a 10-day decitabine and venetoclax (DEC10-VEN) (ClinicalTrials.gov identifier NCT03404193).
METHODS
Patients with newly diagnosed AML received decitabine 20 mg/m for 10 days every 4 to 6 weeks for induction, followed by decitabine for 5 days after response. The venetoclax dose was 400 mg daily. TP53 was identified in bone marrow samples using next-generation sequencing, with sensitivity of 5%. Outcomes were analyzed according to European LeukemiaNet 2017 guidelines.
RESULTS
Among 118 patients (median age, 72 years; age range, 49-89 years), 63 (53%) had secondary AML, 39 (33%) had AML with complex karyotype, and 35 (30%) had TP53 AML. The median TP53 variant allele frequency was 32% (interquartile range, 16%-65%), 8 patients (23%) had only a single TP53 mutation, 15 (43%) had multiple mutations, and 12 (34%) had mutation and deletion. Outcomes were significantly worse in patients who had TP53 AML compared with those who had wild-type TP53 AML, with an overall response rate of 66% vs 89% (P = .002), a complete response/complete response with incomplete hematologic recovery rate of 57% vs 77% (P = .029), and a 60-day mortality of 26% vs 4% (P < .001), respectively. Patients with TP53 versus wild-type TP53 had shorter overall survival at 5.2 versus 19.4 months, respectively (hazard ratio, 4.67; 95% CI, 2.44-8.93; P < .0001), and shorter relapse-free survival at 3.4 versus 18.9 months (hazard ratio, 4.80; 95% CI, 1.97-11.69; P < .0001), respectively. Outcomes with DEC10-VEN in patients with TP53 AML were comparable to historical results with 10-day decitabine alone.
CONCLUSIONS
Patients with TP53 AML have lower response rates and shorter survival with DEC10-VEN.
Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Humans; Leukemia, Myeloid, Acute; Middle Aged; Sulfonamides; Tumor Suppressor Protein p53
PubMed: 34255353
DOI: 10.1002/cncr.33689 -
Nature Cancer Oct 2021DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such...
DNA methylation, a key epigenetic driver of transcriptional silencing, is universally dysregulated in cancer. Reversal of DNA methylation by hypomethylating agents, such as the cytidine analogs decitabine or azacytidine, has demonstrated clinical benefit in hematologic malignancies. These nucleoside analogs are incorporated into replicating DNA where they inhibit DNA cytosine methyltransferases DNMT1, DNMT3A and DNMT3B through irreversible covalent interactions. These agents induce notable toxicity to normal blood cells thus limiting their clinical doses. Herein we report the discovery of GSK3685032, a potent first-in-class DNMT1-selective inhibitor that was shown via crystallographic studies to compete with the active-site loop of DNMT1 for penetration into hemi-methylated DNA between two CpG base pairs. GSK3685032 induces robust loss of DNA methylation, transcriptional activation and cancer cell growth inhibition in vitro. Due to improved in vivo tolerability compared with decitabine, GSK3685032 yields superior tumor regression and survival mouse models of acute myeloid leukemia.
Topics: Animals; Azacitidine; DNA; DNA Methylation; DNA Modification Methylases; Decitabine; Leukemia, Myeloid, Acute; Mice
PubMed: 34790902
DOI: No ID Found -
The Lancet. Haematology Jan 2024The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in... (Randomized Controlled Trial)
Randomized Controlled Trial
Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.
BACKGROUND
The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine.
METHODS
We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264.
FINDINGS
Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]).
INTERPRETATION
Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia.
FUNDING
Astex Pharmaceuticals.
Topics: Male; Humans; Female; Decitabine; Treatment Outcome; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Antineoplastic Combined Chemotherapy Protocols; Pneumonia
PubMed: 38135371
DOI: 10.1016/S2352-3026(23)00338-1 -
Drugs Sep 2020A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the... (Review)
Review
A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
Topics: Administration, Oral; Adult; Canada; Clinical Trials as Topic; Decitabine; Drug Approval; Drug Combinations; Drug Development; History, 21st Century; Humans; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; United States; United States Food and Drug Administration; Uridine
PubMed: 32860582
DOI: 10.1007/s40265-020-01389-7 -
Cancer Science Sep 2021Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem...
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients.
Topics: Adult; Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Myelodysplastic Syndromes; Progression-Free Survival; Prospective Studies; Recurrence; Sulfonamides; Transplantation Conditioning; Transplantation, Homologous; Young Adult
PubMed: 34185931
DOI: 10.1111/cas.15048