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Jean-pierre Issa - One of the best experts on this subject based on the ideXlab platform.
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Decitabine and its role in the treatment of hematopoietic malignancies.
Leukemia & Lymphoma, 2020Co-Authors: Elizabeth R. Plimack, Hagop M Kantarjian, Jean-pierre IssaAbstract:DNA methylation is responsible for abnormal silencing of many genes, including tumor suppressor genes, in cancer. Decitabine, an S-phase specific inhibitor of DNA methyltransferase, has been shown to decrease levels of abnormal methylation in neoplasia. Though initially investigated at high doses as a cytotoxic agent, recent studies show that when administered at low doses, the hypomethylating activity of Decitabine is increased with a demonstrated increase in activity in hematopoietic malignancies. Multiple clinical trials, both in the United States and in Europe, have demonstrated the efficacy of Decitabine in acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS). Recently approved by the United States Food and Drug Administration for the treatment of (MDS), Decitabine represents an effective and well-tolerated therapeutic option in this disease, for which treatment options were previously scarce. While the activity in MDS is promising, primary and secondary resistance rem...
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Decitabine effect on human tumor expression of various transporters
Journal of Clinical Oncology, 2016Co-Authors: David J Stewart, Maria I Nunez, Jaroslav Jelinek, Sanjay Gupta, Jean-pierre Issa, Razelle Kurzrock, David S Hong, Ignacio I WistubaAbstract:2540 Background: We reported that immunohistochemistry (IHC) expression of the platinum/copper transporter CTR1 in human tumors correlated inversely with DNA methylation and was increased by the DNA demethylating agent Decitabine (D. Stewart et al, Proc ASCO 2008). Decitabine also increased expression of folate transporters in platinum-resistant cell lines that have decreased expression of folate transporters and of small GTPases such as RHOA that regulate endocytosis (D Shen et al. Br J Cancer 2004). Methods: Tumors were biopsied pre Decitabine and on cycle 1 day 12 in 31 patients with refractory malignancies in a phase I study of Decitabine given days 1–5 ± 8–12 each cycle. We used IHC to assess the folate carriers FOLR1 and RFC1, the glucose transporter GLUT4 and the endocytosis regulating small GTPase RHOA. Scores of 0–300 were calculated by multiplying staining intensity (0–3) by % cells staining. LINE assays were used to assess % global DNA methylation. Results: DNA methylation did not correlate wit...
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results of phase 2 randomized study of low dose Decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia
Cancer, 2015Co-Authors: Jean-pierre Issa, Guillermo Garciamanero, Xuelin Huang, Farhad Ravandi, Jorge E Cortes, Elias J Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, Hagop M KantarjianAbstract:BACKGROUND Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. METHODS The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to Decitabine in the treatment of MDS and AML. RESULTS Patients with higher risk MDS or with AML aged ≥60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous Decitabine 20 mg/m2 daily for 5 days or Decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ≥70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to Decitabine versus Decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities—particularly neurotoxicities—were higher with the combination arm. CONCLUSIONS Adding valproic acid to Decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. Cancer 2015;121:556–561. © 2014 American Cancer Society.
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Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors
Clinical Epigenetics, 2014Co-Authors: David J Stewart, Maria I Nunez, Jaroslav Jelinek, David Hong, Sanjay Gupta, Jean-pierre Issa, Ignacio I Wistuba, Razelle KurzrockAbstract:Background In 31 solid tumor patients treated with the demethylating agent Decitabine, we performed tumor biopsies before and after the first cycle of Decitabine and used immunohistochemistry (IHC) to assess whether Decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and Decitabine can reverse resistance in vitro . The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed. Results Pre-Decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy ( P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = −0.58, P = 0.006). Tumor RhoA scores increased with Decitabine ( P = 0.03), and RFC1 also increased in patients with pre-Decitabine scores ≤150 ( P = 0.004). Change in LINE1 methylation with Decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1 ). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with Decitabine, and there was a trend towards change in SLC19A1 methylation with Decitabine correlating with change in LINE1 methylation (r = 0.47, P
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outcome of patients with myelodysplastic syndrome after failure of Decitabine therapy
Cancer, 2010Co-Authors: Elias J Jabbour, Guillermo Garciamanero, Jean-pierre Issa, Susan Obrien, Farhad Ravandi, Jorge E Cortes, Nicolas Batty, Jenny Shan, Hagop M KantarjianAbstract:BACKGROUND: The prognosis of patients with myelodysplastic syndrome (MDS) after Decitabine failure is not known. METHODS: Data from 87 patients with MDS (n = 67) and chronic myelomonocytic leukemia (n = .20) after failure of Decitabine regimens were reviewed. RESULTS: After a median follow-up of 21 months from Decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12-month survival rate was 28%. The estimated 12-month survival rates were 27%, 33%, and 33%, respectively, for patients with high-risk, intermediate-2-risk, and intermediate-1-risk disease (P = .99) by the International Prognostic Scoring System. The estimated 12-month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P = .01). CONCLUSIONS: The outcome of patients after Decitabine failure is poor and appears to be predictable after Decitabine failure. Cancer 2010. © 2010 American Cancer Society.
Hagop M Kantarjian - One of the best experts on this subject based on the ideXlab platform.
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Decitabine and its role in the treatment of hematopoietic malignancies.
Leukemia & Lymphoma, 2020Co-Authors: Elizabeth R. Plimack, Hagop M Kantarjian, Jean-pierre IssaAbstract:DNA methylation is responsible for abnormal silencing of many genes, including tumor suppressor genes, in cancer. Decitabine, an S-phase specific inhibitor of DNA methyltransferase, has been shown to decrease levels of abnormal methylation in neoplasia. Though initially investigated at high doses as a cytotoxic agent, recent studies show that when administered at low doses, the hypomethylating activity of Decitabine is increased with a demonstrated increase in activity in hematopoietic malignancies. Multiple clinical trials, both in the United States and in Europe, have demonstrated the efficacy of Decitabine in acute myeloid leukemia, chronic myeloid leukemia, and myelodysplastic syndrome (MDS). Recently approved by the United States Food and Drug Administration for the treatment of (MDS), Decitabine represents an effective and well-tolerated therapeutic option in this disease, for which treatment options were previously scarce. While the activity in MDS is promising, primary and secondary resistance rem...
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Clinical experience with Decitabine in North American patients with myelodysplastic syndrome.
Annals of hematology, 2020Co-Authors: Elias Jabbour, Hagop M Kantarjian, Francis J GilesAbstract:Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (Decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that Decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose Decitabine to supportive care verified that therapy with Decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to Decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of Decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.
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an oral fixed dose combination of Decitabine and cedazuridine in myelodysplastic syndromes a multicentre open label dose escalation phase 1 study
The Lancet Haematology, 2019Co-Authors: Michael R Savona, Olatoyosi Odenike, Philip C Amrein, David P Steensma, Amy E Dezern, Laura C Michaelis, Stefan Faderl, Wael Harb, Hagop M Kantarjian, James N LowderAbstract:Summary Background Decitabine, a DNA methyltransferase 1 inhibitor or DNA hypomethylating compound, is not readily orally bioavailable because of rapid clearance by cytidine deaminase (CDA) in the gut and liver. This dose-escalation study, guided by pharmacokinetic and pharmacodynamic observations, evaluated whether simultaneous oral administration with the novel CDA inhibitor cedazuridine increases Decitabine bioavailability for the treatment of myelodysplastic syndromes. Methods In this phase 1 study, we enrolled patients aged 18 years or older with myelodysplastic syndromes or chronic myelomonocytic leukaemia. Eligible patients were assigned to cohorts to receive escalating oral doses of Decitabine and cedazuridine. The starting dose was Decitabine 20 mg and cedazuridine 40 mg. Treatment cycles lasted 28 days, with 5 days of drug administration. In cycle 1, each patient received a cohort-defined dose of oral Decitabine on day −3, a 1-h intravenous infusion of Decitabine 20 mg/m2 on day 1, and cohort-defined doses of oral Decitabine plus cedazuridine on days 2–5. In cycles 2 and beyond, the oral Decitabine and cedazuridine were given on days 1–5. The dose of cedazuridine was escalated first and Decitabine was escalated once CDA inhibition by cedazuridine approached the maximum effect. The drug dose was escalated if mean Decitabine area under the curve (AUC) of the oral drug was less than 90% of that for intravenous Decitabine in the cohort and if no dose-limiting toxicity was observed. Dose-limiting toxicity was defined as a grade 3 or greater non-haematologic toxicity or grade 4 haematologic toxicity lasting more than 14 days and unrelated to the underlying disease. Once the Decitabine AUC target range set as the primary endpoint, and established with intravenous Decitabine, was reached at a dose deemed to be safe, the cohort that most closely approximated intravenous Decitabine exposure was expanded to 18 evaluable patients. The primary objectives were to assess the safety of Decitabine plus cedazuridine, and to determine the dose of each drug needed to achieve a mean AUC for Decitabine exposure similar to that for intravenous Decitabine exposure. This study is registered with ClinicalTrials.gov, number NCT02103478. Findings Between Oct 28, 2014, and Nov 13, 2015, we enrolled 44 eligible patients (of 75 screened) with previously treated or newly diagnosed myelodysplastic syndromes or chronic myelomonocytic leukaemia; 43 of the enrolled patients were evaluable. Participants were treated in five cohorts: cohorts 1–4 included six evaluable patients each; cohort 5 included 19 patients in a 13-patient expansion. Dose-dependent increases in Decitabine AUC and peak plasma concentration occurred with each cohort dose escalation. There was no evident increase in toxicity compared with that reported for intravenous Decitabine. Decitabine 30 mg and 40 mg plus cedazuridine 100 mg produced mean day-5 Decitabine AUCs (146 ng × h/mL for Decitabine 30 mg, and 221 ng × h/mL for Decitabine 40 mg) closest to the mean intravenous-Decitabine AUC (164 ng × h/mL). The most common grade 3 or more adverse events were thrombocytopenia (18 [41%] of 44 patients), neutropenia (13 [30%]), anaemia (11 [25%]), leukopenia (seven [16%]), febrile neutropenia (seven [16%]), and pneumonia (seven [16%]). Four (9%) patients died because of adverse events, none of which was considered drug related, and three (7%) patients died more than 30 days after discontinuing treatment because of progressive disease (two [5%]) and respiratory failure (one [2%]). Interpretation Oral Decitabine plus cedazuridine emulated the pharmacokinetics of intravenous Decitabine, with a similar safety profile and dose-dependent demethylation. Clinical responses were similar to intravenous Decitabine treatment for 5 days. Further study of Decitabine plus cedazuridine as an alternative to parenteral therapy or in combination with other new oral agents for myeloid disorders is warranted. Funding Astex Pharmaceuticals, Inc.
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results of phase 2 randomized study of low dose Decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia
Cancer, 2015Co-Authors: Jean-pierre Issa, Guillermo Garciamanero, Xuelin Huang, Farhad Ravandi, Jorge E Cortes, Elias J Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, Hagop M KantarjianAbstract:BACKGROUND Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. METHODS The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to Decitabine in the treatment of MDS and AML. RESULTS Patients with higher risk MDS or with AML aged ≥60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous Decitabine 20 mg/m2 daily for 5 days or Decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ≥70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to Decitabine versus Decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities—particularly neurotoxicities—were higher with the combination arm. CONCLUSIONS Adding valproic acid to Decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. Cancer 2015;121:556–561. © 2014 American Cancer Society.
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Pharmacokinetic evaluation of Decitabine for the treatment of leukemia.
Expert Opinion on Drug Metabolism & Toxicology, 2011Co-Authors: Jeffrey Bryan, Hagop M Kantarjian, Guillermo Garcia-manero, Elias JabbourAbstract:Introduction: Acute myeloid leukemia (AML) is a life-threatening malignancy that primarily afflicts an elderly population. Treatment of elderly patients with intensive chemotherapy is associated with high treatment-related morbidity and mortality. Therefore, less toxic approaches involving low-dose Decitabine-based regimens are being explored in this patient population. Areas covered: This drug evaluation article discusses the rationale for targeting aberrant DNA methylation in hematologic malignancies, in particular the myelodysplastic syndromes (MDS) and AML. The authors review the pharmacokinetic data gained from low-dose Decitabine, as well as the clinical progress of Decitabine in the treatment of hematologic malignancies. Published manuscripts in English were selected from PubMed using a combination of the following search terms: acute myeloid leukemia, pharmacokinetics, Decitabine, 5-aza-2′-deoxycytidine, DNA methylation, DNA methyltransferase, myelodysplastic syndrome and leukemia. Expert opinion:...
Michael Lubbert - One of the best experts on this subject based on the ideXlab platform.
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a multicenter phase ii trial of Decitabine as first line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy
Haematologica, 2012Co-Authors: Michael Lubbert, Bjorn Ruter, Ulrich Germing, Rainer Claus, Claudia Schmoor, Mathias Schmid, Andrea Kuendgen, Volker Rethwisch, Arnold Ganser, Uwe PlatzbeckerAbstract:Background The treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (Decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20–30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts. Design and Methods To evaluate the efficacy and toxicity of Decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial Decitabine treatment (135 mg/m2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1–4). All- trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1–19) with a lower dose of Decitabine (20 mg/m2) infused over 1 hour on 3 consecutive days every 4–6 weeks. Results The complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of Decitabine treatment was 5.5 months (range, 0–57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic. Conclusions Decitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent Decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069.
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low dose Decitabine versus best supportive care in elderly patients with intermediate or high risk myelodysplastic syndrome mds ineligible for intensive chemotherapy final results of the randomized phase iii study of the european organisation for res
Journal of Clinical Oncology, 2011Co-Authors: Michael Lubbert, Stefan Suciu, Liliana Baila, Bjorn Ruter, Uwe Platzbecker, Aristoteles Giagounidis, Dominik Selleslag, Boris Labar, Ulrich Germing, Helmut R SalihAbstract:PURPOSE: To compare low-dose Decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy. PATIENTS AND METHODS: Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m(2)) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles. RESULTS: OS prolongation with Decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) -free survival (AMLFS), was significantly prolonged with Decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with Decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with Decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on Decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on Decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters. CONCLUSION: Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.
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Decitabine: Where Is the Target?.
Blood, 2005Co-Authors: Ingo Tamm, Michael Lubbert, Nicole Sattler, Mandy Wagner, Philipp D. Lecoutre, Bernd Dörken, Karin SchmelzAbstract:The methylation inhibitor 5-Aza-2′-deoxycytidine (Decitabine) has therapeutic efficacy in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Using microarray analysis, we investigated global changes in gene expression after Decitabine treatment in AML. In the AML cell line OCI-AML2, Decitabine induced the expression of 81 out of 22 000 genes; 96 genes were downregulated (X2-fold change in expression). RT-PCR analysis of 10 randomly selected genes confirmed the changes of expression in AML cells. Similar results were obtained with primary AML and MDS cells after treatment with Decitabine ex vivo and in vivo, respectively. In contrast, significantly fewer changes in gene expression and cytotoxicity were detected in normal peripheral blood mononuclear and bone marrow cells or transformed epithelial cells treated with Decitabine. Interestingly, only 50.6% of the induced genes contain putative CpG islands in the 5′ region. To further investigate the significance of promoter methylation in the induced genes, we analyzed the actual methylation status of randomly selected Decitabine-inducible genes. We detected hypermethylation exclusively in the 5′ region of the myeloperoxidase (MPO) gene. DNA methylation inversely correlated with MPO expression in newly diagnosed untreated AML patients (P
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characterization of dna demethylation effects induced by 5 aza 2 deoxycytidine in patients with myelodysplastic syndrome
Cancer Research, 2005Co-Authors: Cora Mund, Michael Lubbert, Bjorn Hackanson, Carlo Stresemann, Frank LykoAbstract:Azanucleoside drugs such as 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, Dacogen) function as DNA methyltransferase inhibitors in vitro and represent promising new drugs for the treatment of myelodysplastic syndrome (MDS) and acute myeloid leukemia. In this study, we aimed to determine the effect of Decitabine on the genomic methylation level in MDS patients. Comparison of different assays established micellar electrokinetic chromatography as a reliable method for the analysis of genomic methylation levels. When used for the determination of DNA methylation levels in bone marrow DNA from MDS patients during various time points of Decitabine treatment, the results revealed a significant (up to 70%) demethylation in five of seven patients. Interestingly, genome-wide demethylation appeared after karyotype normalization, which suggests demethylation of nonclonal cells. Drug-induced demethylation dynamics were also confirmed by bisulfite sequencing of pericentromeric satellite elements. Our results are the first to show a genome-wide demethylating activity of Decitabine in tumor material. In addition, our data uncovers novel targets of Decitabine-mediated demethylation that are important for the refinement of treatment schedules with demethylating drugs.
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demethylation of a hypermethylated p15 ink4b gene in patients with myelodysplastic syndrome by 5 aza 2 deoxycytidine Decitabine treatment
Blood, 2002Co-Authors: Michael Daskalakis, Tudung T. Nguyen, Per Guldberg, Gabriele Köhler, Peter A. Jones, Pierre W. Wijermans, Carvell T Nguyen, Michael LubbertAbstract:p16 and p15 , 2 inhibitors of cyclin-dependent kinases, are frequently hypermethylated in hematologic neoplasias. Decitabine, or 5-Aza-2′-deoxycytidine, reverts hypermethylation of these genes in vitro, and low-dose Decitabine treatment improves cytopenias and blast excess in ∼50% of patients with high-risk myelodysplastic syndrome (MDS). We examined p15 and p16 methylation status in bone marrow mononuclear cells from patients with high-risk MDS during treatment with Decitabine, using a methylation-sensitive primer extension assay (Ms-SNuPE) to quantitate methylation, and denaturing gradient gel electrophoresis (DGGE) and bisulfite-DNA sequencing to distinguish individually methylated alleles. p15 expression was serially examined in bone marrow biopsies by immunohistochemistry. Hypermethylation in the 5′ p15 gene region was detected in 15 of 23 patients (65%), whereas the 5′ p16 region was unmethylated in all patients. Among 12 patients with hypermethylation sequentially analyzed after at least one course of Decitabine treatment, a decrease in p15 methylation occurred in 9 and was associated with clinical response. DGGE and sequence analyses were indicative of hypomethylation induction at individual alleles. Immunohistochemical staining for p15 protein in bone marrow biopsies from 8 patients with p15 hypermethylation revealed low or absent expression in 4 patients, which was induced to normal levels during Decitabine treatment. In conclusion, frequent, selective p15 hypermethylation was reversed in responding MDS patients following treatment with a methylation inhibitor. The emergence of partially demethylated epigenotypes and re-establishment of normal p15 protein expression following the initial Decitabine courses implicate pharmacologic demethylation as a possible mechanism resulting in hematologic response in MDS.
Guillermo Garciamanero - One of the best experts on this subject based on the ideXlab platform.
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oral cedazuridine Decitabine a phase 2 pharmacokinetic pharmacodynamic randomized crossover study in mds and cmml
Blood, 2020Co-Authors: Guillermo Garciamanero, Olatoyosi Odenike, David P Steensma, Amy E Dezern, Elizabeth A Griffiths, Gail J Roboz, Richard A Wells, James K Mccloskey, Lambert Busque, Casey OconnellAbstract:: 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 endpoints: 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), % 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. ClinicalTrials.gov NCT02103478.
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results of phase 2 randomized study of low dose Decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia
Cancer, 2015Co-Authors: Jean-pierre Issa, Guillermo Garciamanero, Xuelin Huang, Farhad Ravandi, Jorge E Cortes, Elias J Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, Hagop M KantarjianAbstract:BACKGROUND Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. METHODS The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to Decitabine in the treatment of MDS and AML. RESULTS Patients with higher risk MDS or with AML aged ≥60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous Decitabine 20 mg/m2 daily for 5 days or Decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ≥70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to Decitabine versus Decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities—particularly neurotoxicities—were higher with the combination arm. CONCLUSIONS Adding valproic acid to Decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. Cancer 2015;121:556–561. © 2014 American Cancer Society.
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a randomized controlled trial of romiplostim in patients with low or intermediate risk myelodysplastic syndrome receiving Decitabine
Leukemia & Lymphoma, 2013Co-Authors: Peter L Greenberg, Guillermo Garciamanero, Gail J Roboz, Allen S. Yang, Michael R Moore, Lloyd E Damon, Kuolung Hu, Janet FranklinAbstract:AbstractPatients with myelodysplastic syndrome (MDS) receiving hypomethylating agents commonly develop thrombocytopenia. This double-blind study evaluated the efficacy and safety of romiplostim, a peptibody protein that increases platelets, in patients with MDS receiving Decitabine. Patients received romiplostim 750 μg (n = 15) or placebo (n = 14) and Decitabine. Median platelet counts at the beginning of each Decitabine cycle trended lower in placebo-treated than in romiplostim-treated patients. Bleeding events occurred in 43% of placebo-treated and 27% of romiplostim-treated patients, and platelet transfusions were administered to 57% of placebo-treated and 47% of romiplostim-treated patients. Overall clinical therapeutic response was achieved by 21% of placebo-treated and 33% of romiplostim-treated patients. Treatment was generally well tolerated. Progression to acute myeloid leukemia (AML) occurred in one patient per group. Adding romiplostim to Decitabine treatment is well tolerated and may be benefi...
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outcome of patients with myelodysplastic syndrome after failure of Decitabine therapy
Cancer, 2010Co-Authors: Elias J Jabbour, Guillermo Garciamanero, Jean-pierre Issa, Susan Obrien, Farhad Ravandi, Jorge E Cortes, Nicolas Batty, Jenny Shan, Hagop M KantarjianAbstract:BACKGROUND: The prognosis of patients with myelodysplastic syndrome (MDS) after Decitabine failure is not known. METHODS: Data from 87 patients with MDS (n = 67) and chronic myelomonocytic leukemia (n = .20) after failure of Decitabine regimens were reviewed. RESULTS: After a median follow-up of 21 months from Decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12-month survival rate was 28%. The estimated 12-month survival rates were 27%, 33%, and 33%, respectively, for patients with high-risk, intermediate-2-risk, and intermediate-1-risk disease (P = .99) by the International Prognostic Scoring System. The estimated 12-month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P = .01). CONCLUSIONS: The outcome of patients after Decitabine failure is poor and appears to be predictable after Decitabine failure. Cancer 2010. © 2010 American Cancer Society.
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evolution of Decitabine development accomplishments ongoing investigations and future strategies
Cancer, 2008Co-Authors: Elias Jabbour, Jean-pierre Issa, Guillermo Garciamanero, Hagop M KantarjianAbstract:Decitabine (5-aza-2′-deoxycytidine) is a hypomethylating agent with a dual mechanism of action: reactivation of silenced genes and differentiation at low doses, and cytotoxicity at high doses. The original studies in the 1980s used Decitabine as a classical anticancer drug, at its maximum clinically tolerated dose, 1500 to 2500 mg/m2 per course. At these doses, Decitabine was found to be active in leukemia, but was associated with delayed and prolonged myelosuppression. After a better understanding of epigenetics in cancer and the role of Decitabine in epigenetic (hypomethylating) therapy was gained, it was reevaluated at approximately 1/20th of the previous doses (ie, at ‘optimal biologic’ doses that modulate hypomethylation). In these dose schedules of Decitabine (100 to 150 mg/m2 per course), the drug was found to be active with manageable side effects in patients with myelodysplastic syndromes (MDS) and other myeloid tumors. Optimizing dosing schedules of Decitabine to maximize hypomethylation (low dose, high dose intensity, and multiple cycles) have further improved results, suggesting that Decitabine is an active therapy that alters the natural course of MDS. Combination therapies that augment the epigenetic effect of Decitabine will likely improve responses and extend its use for the treatment of other malignancies. Cancer 2008. ©2008 American Cancer Society.
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randomized phase 2 study of low dose Decitabine vs low dose azacitidine in lower risk mds and mds mpn
Blood, 2017Co-Authors: Elias Jabbour, Xuelin Huang, Carlos E Buesoramos, Nicholas J Short, Guillermo Montalbanbravo, Wei Qiao, Hui Yang, Chong Zhao, Tapan M Kadia, Gautam BorthakurAbstract:Hypomethylating agents (HMAs) improve survival in patients with higher-risk myelodysplastic syndromes (MDS) but are less well-studied in lower-risk disease. We compared the safety and efficacy of low-dose Decitabine vs low-dose azacitidine in this group of patients. Adults with low- or intermediate 1-risk MDS or MDS/myeloproliferative neoplasm (MPN), including chronic myelomonocytic leukemia, according to the International Prognostic Scoring System, were randomly assigned using a Bayesian adaptive design to receive either azacitidine 75 mg/m 2 intravenously/subcutaneously daily or Decitabine 20 mg/m 2 intravenously daily for 3 consecutive days on a 28-day cycle. The primary outcome was overall response rate (ORR). Between November 2012 and February 2016, 113 patients were treated: 40 (35%) with azacitidine and 73 (65%) with Decitabine. The median age was 70 years; 81% of patients were intermediate 1-risk patients. The median number of cycles received was 9. The ORRs were 70% and 49% ( P = .03) for patients treated with Decitabine and azacitidine, respectively. Thirty-two percent of patients treated with Decitabine became transfusion independent compared with 16% of patients treated with azacitidine ( P = .2). Cytogenetic response rates were 61% and 25% ( P = .02), respectively. With a median follow-up of 20 months, the overall median event-free survival was 18 months: 20 and 13 months for patients treated with Decitabine and azacitidine, respectively ( P = .1). Treatment was well tolerated, with a 6-week mortality rate of 0%. The use of low-dose HMAs is safe and effective in patients with lower-risk MDS and MDS/MPN. Their effect on the natural history of lower-risk disease needs to be further studied. This trial was registered at clinicaltrials.gov (identifier NCT01720225).
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results of phase 2 randomized study of low dose Decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia
Cancer, 2015Co-Authors: Jean-pierre Issa, Guillermo Garciamanero, Xuelin Huang, Farhad Ravandi, Jorge E Cortes, Elias J Jabbour, Gautam Borthakur, Mark Brandt, Sherry Pierce, Hagop M KantarjianAbstract:BACKGROUND Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results. METHODS The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to Decitabine in the treatment of MDS and AML. RESULTS Patients with higher risk MDS or with AML aged ≥60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous Decitabine 20 mg/m2 daily for 5 days or Decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ≥70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to Decitabine versus Decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities—particularly neurotoxicities—were higher with the combination arm. CONCLUSIONS Adding valproic acid to Decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. Cancer 2015;121:556–561. © 2014 American Cancer Society.
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Decitabine and Gemtuzumab Ozogamicin In Patients with Advanced Myelofibrosis
Blood, 2010Co-Authors: Ali Al-ameri Al-ameri, Hagop M Kantarjian, Asifa Malik, Xavier Badoux, Michael Andreeff, Alfonso Quintás-cardama, Gautam BorthakurAbstract:Abstract 5061 Background: While hypomethylating agents, azacitidine and Decitabine, are approved for use in treatment of myelodysplastic syndromes (MDS), their role in treatment of myeloproliferative disorders is evolving. The modified dosing schedule of Decitabine (20 mg/m2 IV for 5 days) in MDS has shown overall response rates of approximately 40%. A clinical study of azacitidine in myelofibrosis (MF) has shown a response rate of 32%. We investigated the activity of the combination of Decitabine and gemtuzumab ozogamicin (GO) (anti-CD33 antibody), a combination with activity in patients with MDS and acute myelogenous leukemia (AML), in patients with advanced myelofibrosis. Patients and Method: We reviewed the records of patients with MF treated with the combination of Decitabine and GO. Result: Seven patients were treated till the decisions by FDA to withdraw GO from the market. Age ranged from 60–69 years (median 65 years), 5 patients were male and no of prior therapies ranged 0–4 (median2). Three patients had MF progressed to acute myeloid leukemia. Prior treatments included, hydroxyura, thalidomide, prednisone, pomolidamide etc. All patients were positive for JAK 2 V617F mutation. Cytogenetic abnormalities were seen in 4 patients (hyperdiploid, complex or -5/-7) and 3 were with diploid cytogenetics. Five patients received 3 cycles of Decitabine plus myelotarg while 2 patients had only one cycle. Four patients had stable disease, one had clearance of marrow blasts (40%>0%), two had no response. Three patients showed decreases in splenic size. Clinically significant infectious complications were encountered in 4 patients. Conclusions: The combination of Decitabine and GO showed early signs of activity in patients with MF but future investigation of this combination will be limited due to lack of access to GO. Disclosures: Borthakur:eisai: Research Funding.
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activity of Decitabine in patients with myelodysplastic syndrome previously treated with azacitidine
Leukemia & Lymphoma, 2008Co-Authors: Gautam Borthakur, Stefan Faderl, Jean-pierre Issa, Farhad Ravandi, Samih El Ahdab, Alessandra Ferrajoli, Beth Newman, Hagop M KantarjianAbstract:Azacitidine and Decitabine are the two hypomethylating agents approved by the Food and Drug Administration for the treatment of patients with myelodysplastic syndrome (MDS). The efficacy of one agent post-failure of the other is unknown. Fourteen patients with MDS post-azacitidine failure/lack of response/intolerance were treated with Decitabine. Overall three patients achieved a complete remission, and one patient had hematologic improvement, for an overall response rate of 28%. Of the responders, one stopped prior 5-azacitidine owing to disease progression, two for no response and one for severe skin toxicity. Grade 3-4 drug related side-effects were minimal. Global methylation studies in patient samples showed decrease of methylation after treatment with Decitabine. As in our previous studies, there was no difference in hypomethylation between responders and nonresponders. We conclude that clinically significant responses with Decitabine can be seen in patients post-azacitidine failure without signific...
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activity of Decitabine a hypomethylating agent in chronic myelomonocytic leukemia
Cancer, 2007Co-Authors: Ahmed Aribi, Farhad Ravandi, Jorge E Cortes, Jianqin Shan, Jan Davisson, Gautam Borthakur, Hagop M KantarjianAbstract:BACKGROUND. Hypomethylating agents have activity in myelodysplastic syndrome (MDS) and have received approval for the treatment of both MDS and chronic myelomonocytic leukemia (CMML). The specific efficacy in CMML has not been detailed in a large number of patients. The aim of the study was to evaluate the activity and safety of Decitabine in CMML. METHODS. Nineteen adults with a diagnosis of CMML treated on Decitabine studies were analyzed. Decitabine was given at 100 mg/m2 per course every 4 weeks. The median number of courses given was 9 (range, 1–18). RESULTS. Overall, 11 patients (58%) achieved complete response (CR) and 2 (11%) had hematologic improvement (HI), for an overall response rate of 69% according to the modified International Working Group (IWG) criteria. Median survival was 19 months. Severe (grade 3–4) extramedullary side effects were rare. CONCLUSIONS. Decitabine is active in CMML. Studies of combinations of Decitabine with topoisomerase I inhibitors or other active anti-CMML agents are indicated. Cancer 2007. © 2007 American Cancer Society.
