Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Azacitidine pharmacokinetic parameters in adolescent patients with renal compromise are not available from the medical literature. We describe a 14-year-old with myelodysplastic syndrome treated with subcutaneous 5-azacitidine for disease relapse 2 years after hematopoietic stem cell transplant. Because of renal compromise, malnutrition, and poor functional status, pharmacokinetic parameters were projected from existing literature data to select the patient's first azacitidine treatment course (1.5 mg/kg/d for 7 d). Posttreatment azacitidine plasma concentrations used to calculate patient-specific pharmacokinetic parameters corroborated initial estimates and systemic exposure associated with therapeutic benefit in adults and permitted individualization of treatment.
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PMID:Azacitidine pharmacokinetics in an adolescent patient with renal compromise. 1748 13

5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.
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PMID:CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine. 1761 69

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.
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PMID:The role of azacitidine in the treatment of myelodysplastic syndromes. 1804 4

Epigenetic alterations, including methylation of key tumor suppressor genes, may play a role in the progression of prostate cancer to a castration-refractory state. Azacitidine, an agent approved for the treatment of myelodysplastic syndromes, appears to exert its antineoplastic effects partly by hypomethylating DNA that leads to the reversal of gene silencing. It is hypothesized that the addition of azacitidine to complete androgen blockade may restore the responsiveness of progressive prostate cancer to hormonal therapy. A phase II trial was designed to evaluate the activity of azacitidine to primarily modulate PSA kinetics, with supportive secondary clinical endpoints. Correlative studies will be performed to detect the biologic activity of azacitidine (increased fetal hemoglobin, plasma DNA methylation) and examine any association with anti-tumor clinical activity.
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PMID:Phase II study of azacitidine to restore responsiveness of prostate cancer to hormonal therapy. 1827 30

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 significant toxicity.
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PMID:Activity of decitabine in patients with myelodysplastic syndrome previously treated with azacitidine. 1839 28

Epigenetic factors such as DNA methylation and histone deacetylation are known to contribute to the malignant transformation of cells by silencing critical genes. Drugs that inhibit DNA methyltransferases or histone deacetylases were shown to have the potential to reactivate silenced genes and induce differentiation or apoptosis of malignant cells. The most intensively studied class of such agents is DNA methyltransferase inhibitors, including 5-azacytidine (azacitidine) and 5-aza-2'-deoxycytidine (decitabine). In 2004, azacitidine was approved for the treatment of myelodysplastic syndrome on the basis of phase II and III studies that showed a response rate (complete and partial responses) of 15%. Azacitidine is also being evaluated in clinical trials for other malignant diseases. Decitabine has response rates of 17-49% in myelodysplastic syndrome in multiple phase II and III studies and also activity in acute and chronic myelogenous leukemia. Histone deacetylase inhibitors belong to another class of epigenetic modifying agents that include depsipeptide, butyrate derivatives, suberoylanilide hydroxamic acid and valproic acid. No agent in this class has been studied in a phase III trial, but several agents have been or are being studied in phase II trials. Further research is needed to determine the appropriate patient selection and dosing schedules.
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PMID:Review: recent clinical trials in epigenetic therapy. 1847 69

Azacitidine is a pyrimidine nucleoside analog of cytidine with hypomethylating and antileukemia activity. Azacitidine has been shown to have survival benefits in patients with high-risk myelodysplastic syndrome (MDS), and has activity in the treatment of acute myelogenous leukemia (AML). It is administered by subcutaneous (s.c.) or intravenous (i.v.) injection daily at a dose of 75 mg/m(2) for 7 days every 4 weeks. An oral formulation would facilitate dosing, reduce administration side effects and potentially maximize azacitidine pharmacologic action. Previously, oral formulations of this class of agent have failed due to rapid catabolism by cytidine deaminase and hydrolysis in aqueous environments. Development of a film-coated formulation has circumvented this difficulty. In a formulation feasibility pilot study, four subjects with solid malignant tumors, AML or MDS received single oral doses of 60 or 80 mg azacitidine. Subjects demonstrated measurable plasma concentrations of azacitidine, allowing bioavailability comparisons to be made to historical pharmacokinetic data for s.c. azacitidine. Subjects safely tolerated 80 mg, a dose for which the mean bioavailability was 17.4% of historic s.c. exposure. No severe drug-related toxicities were observed. These data suggest that oral azacitidine is bioavailable in humans and should be studied in formal phase 1 trials.
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PMID:A pilot pharmacokinetic study of oral azacitidine. 1854 3

Relapse remains a leading cause for treatment failure after hematopoietic cell transplantation (HCT) in patients with intermediate- or high-risk myelodysplastic syndrome (MDS). To discern the impact of 5-azacitine treatment pretransplant on the risk for relapse after HCT, we analyzed the post transplant outcomes of all 54 consecutive patients with MDS or chronic myelomonocytic leukemia who received HCT from HLA-compatible donors according to pretransplant 5-azacitidine exposure. Thirty patients received a median of four (1-7) cycles of 5-azacitidine, and 24 patients did not receive 5-azacitidine before HCT. The 1-year estimates of overall survival, relapse-free survival and cumulative incidence of relapse were 47, 41 and 20%, for 5-azacitidine patients and 60, 51 and 32%, respectively, for non-5-azacytidine patients. These observations suggest that outcomes are similar in both groups with a trend toward decreased early relapse in patients receiving 5-azacitidine. 5-Azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to reach transplant and does not appear to affect transplant outcomes.
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PMID:5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. 1954 27

This study was performed to identify whether cytogenetics, International Prognostic Scoring System (IPSS), or World Health Organization Classification-Based Prognostic Scoring System are predictive of the efficacy of azacitidine in patients with myelodysplastic syndrome (MDS). We retrospectively reviewed the clinical records of 113 patients with MDS treated with azacitidine. The "response alternating disease natural history," "cytogenetic response," and "hematologic improvement" were assessed by serial bone marrow biopsy, cytogenetic study, and hemogram analyses. The complete and partial remission rates were 17.6% and 3.9% in 51 evaluable patients. There were no significant differences in response rate in the different cytogenetic/IPSS/WPSS groups. The overall hematologic response (HR) rate was 49.6%, and the HR rate was significantly greater in patients classed as "very high" risk according to the WPSS compared with other patient groups. The 1-year overall survival (OS) rate was higher among patients with HR compared with those without HR (80.9% vs 63.3%, p = 0.046), and the 1-year OS rate among patients classed as being at high risk by each criteria was similar to that of patients classed as being at low risk. The hazard ratio of death among patients with HR compared with those without HR was 0.17 (95% CI 0.04-0.69) for high + very high risk group based on WPSS. Patients in the WPSS high-risk group had an increased HR rate compared with other patient groups, and the achievement of HR was associated with a significant increase in OS. Azacitidine showed similar efficacy in all patient groups, even in patients with poor cytogenetics and in high-risk groups.
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PMID:Comparison of various criteria in predicting treatment response and prognosis of patients with myelodysplastic syndrome treated with azacitidine. 1954 27

Azacitidine (Vidaza) is a pyrimidine nucleoside analogue of cytidine. Subcutaneous azacitidine was recently approved in the EU for the treatment of adults who are not eligible for haematopoietic stem cell transplantation and who have intermediate-2-risk or high-risk myelodysplastic syndromes (MDS) [according to International Prognostic Scoring System (IPSS) criteria], chronic myelomonocytic leukaemia (CMML) with 10-29% marrow blasts without myeloproliferative disorder, or acute myeloid leukaemia (AML) with 20-30% blasts and multilineage dysplasia (according to the WHO classification). Subcutaneous azacitidine is the only drug shown to significantly prolong survival in patients with higher-risk MDS or WHO-defined AML, compared with conventional care (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). In addition, azacitidine is associated with a lower risk of AML progression and higher rates of complete remission, partial remission, haematological improvement and red blood cell (RBC) transfusion independence. Azacitidine has an acceptable tolerability profile; peripheral cytopenias are the most commonly occurring adverse event. Thus, azacitidine is a valuable option for the first-line treatment of patients with higher-risk MDS/AML.
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PMID:Azacitidine: a review of its use in higher-risk myelodysplastic syndromes/acute myeloid leukaemia. 1991 60


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