Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

5-Azacytidine and several of its analogues are known to inhibit DNA methylation, alter gene expression, and inhibit cell growth. We report a Phase II study in which we investigated the antineoplastic activity of 5,6-dihydro-5-azacytidine and its induction of fetal hemoglobin synthesis when given by a 5-day continuous i.v. infusion of 1650 mg/m2/day that was repeated every 21 days. Fetal hemoglobin was measured in all patients; increased synthesis was found in 13 of the 17, in the absence of clinically significant anemia. Of the four patients who did not develop increased fetal hemoglobin, three had only one cycle of therapy. Fourteen patients with bronchogenic carcinoma were treated, and ten were evaluable for disease response. Five patients had disease stability of 2 or more mo, and five progressed on treatment. Three additional patients with mesothelioma were treated, and the two who were evaluable for disease response had stabilization of their disease. Fifteen of the 17 patients who received 5,6-dihydro-5-azacytidine developed a pleuritic-type chest pain, 12 had abnormal electrocardiograms, and four developed positive anti-nuclear antibodies. No significant hemopoietic, hepatic, or renal toxicities were observed. This study demonstrates that 5,6-dihydro-5-azacytidine in the dose and schedule used has no significant therapeutic activity in the treatment of lung cancer but does possess an unusual spectrum of clinical toxicities as well as the property of inducing fetal hemoglobin synthesis.
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PMID:Fetal hemoglobin gene activation in a phase II study of 5,6-dihydro-5-azacytidine for bronchogenic carcinoma. 244 May 59

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, leading to bone marrow failure and peripheral blood cytopenias. MDS is difficult to diagnose because of the absence of symptoms in the early stage of the disease; it often is discovered accidentally during routine physical examinations or blood tests. The U.S. Food and Drug Administration approved azacitidine (Vidaza, Pharmion Corporation, Boulder, CO) for the treatment of MDS. Prior to the approval of azacitidine, no approved therapies were available for the treatment of MDS. Azacitidine is believed to exert its anticancer effects by induction of hypomethylation and cytotoxicity. In clinical studies, the most common adverse events during treatment with azacitidine included nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, fatigue, injection-site erythema, constipation, neutropenia, and ecchymosis. To ensure proper treatment with azacitidine, nurses should have an understanding of dosage and administration guidelines, commonly observed adverse events, monitoring and care of adverse events, and monitoring of laboratory tests. Having a comprehensive understanding of MDS, its underlying disease characteristics, and current treatments will enable oncology nurses to provide optimal patient care.
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PMID:Advances in myelodysplastic syndrome: nursing implications of azacitidine. 1611 8

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

In the phase III AZA-001 trial, low-dose cytarabine (LDara-C), the most widely used low-dose chemotherapy in patients with higher-risk myelodysplastic syndrome (MDS) who are ineligible for intensive treatment, was found to be associated with poorer survival compared with azacitidine. This analysis further compared the efficacy and the toxicity of these two drug regimens. Before randomization, investigators preselected patients to receive a conventional care regimen, one of which was LDara-C. Of 94 patients preselected to LDara-C, 45 were randomized to azacitidine and 49 to LDara-C. Azacitidine patients had significantly more and longer haematological responses and increased red blood cell transfusion independence. Azacitidine prolonged overall survival versus LDara-C in patients with poor cytogenetic risk, presence of -7/del(7q), and French-American-British subtypes refractory anaemia with excess blasts (RAEB) and RAEB in transformation. When analyzed per patient year of drug exposure, azacitidine treatment was associated with fewer grade 3-4 cytopenias and shorter hospitalisation time than LDara-C in these higher-risk MDS patients.
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PMID:Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. 2013 25

Prolonged administration of methyl transferase inhibitors may increase response rates in myelodysplastic syndromes (MDS). Fourteen MDS patients with anemia and less than 10% marrow blasts received azacitidine 50 mg/m(2) thrice weekly for 2 weeks every 4 weeks; 7 also received weekly erythropoietin. The response rate of 43% did not improve the rates reported with other azacitidine administration schedules, so the study was closed. A decreased apoptosis of primitive erythroid progenitors and increased expression of BclX(L) was observed with treatment in responding patients compared to non-responders. Azacitidine may modulate BclX(L) and improve erythropoiesis through reduction of apoptosis in primitive erythroid progenitor population in MDS.
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PMID:Thrice weekly azacitidine does not improve hematological responses in lower-risk myelodysplastic syndromes: a study of the Hoosier Oncology Group. 2142 Jul 32

A 68-year-old woman with essential thrombocythemia had been treated with hydroxycarbamide and aspirin for 13 years. She exhibited the rapid progression of anemia, and a bone marrow examination showed dysplasia of the erythroid cells, myeloid cells, and megakaryocytes. Karyotype analysis indicated complex abnormalities including der (5;21)(p10;q10). She was diagnosed with myelodysplastic syndrome (MDS), refractory anemia with excess blasts-1 (RAEB-1). Lenalidomide was started, but no improvement in anemia was recorded. Lenalidomide was discontinued due to eosinophilia, basophilia, and a skin rash. Azacitidine was administered. The patient became transfusion independent, and a complete cytogenetic response was achieved with three courses of azacitidine. However, disease progression to acute myeloid leukemia (AML) was observed after an additional two courses of azacitidine, which was resistant to induction chemotherapy. The patient died five months later from AML transformation. Azacitidine may be effective in MDS transformed from essential thrombocythemia, and also in lenalidomide-resistant MDS with the deletion of 5q.
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PMID:Effective azacitidine treatment for myelodysplastic syndrome transformed from essential thrombocythemia. 2372 86

Azacitidine is recommended for patients with higher-risk myelodysplastic syndromes (MDS) who are not eligible for intensive therapy or for patients with lower-risk MDS who have thrombocytopenia or neutropenia or have anemia that is unresponsive to other therapies. However, standard treatment with azacitidine has not been optimized and many issues about the use of azacitidine remain unresolved. The use of azacitidine is expanding rapidly, but limited comparative clinical trial data are available to (i) define the optimal use of azacitidine in patients with higher-risk MDS or around the time of allogeneic hematopoietic stem cell transplantation, (ii) identify those patients with lower-risk MDS who may benefit from treatment, and (iii) guide physicians on alternative therapies after treatment failure. Increasing evidence suggests that the clinical features, prognostic factors, and cytogenetic profiles of patients with MDS in Asia differ significantly from those of patients in Western countries, so the aim of this review is to summarize the evidence and provide practical recommendations on the use of azacitidine in patients with MDS in the Republic of Korea. Evidence considered in this review is based on published clinical data and on the clinical experience of an expert panel from the acute myeloid leukemia/MDS Working Party of the Korean Society of Hematology.
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PMID:Use of azacitidine for myelodysplastic syndromes: controversial issues and practical recommendations. 2382 77

5-Azacytidine (5-AZA) was the first drug to be approved for the treatment of high-risk myelodysplastic syndrome (MDS). The adverse event profile of this drug appears favorable compared with the conventional intensive chemotherapy that is used for MDS or acute myeloid leukemia. However, uncommon adverse events may have remained undetected in the limited number of patients that have been treated to date. The present study describes three cases/66.8 person-years (4,491 cases/100,000 person-years) of severe ischemic colitis in a single center cohort of 95 patients who were consecutively treated using subcutaneous 5-AZA. The results demonstrated a much higher incidence of colitis compared with the rates in the general population or in patients of greater ages and co-morbidities. The present study investigated whether the combination of anemia and constipation due to the co-medication of 5-HT3 receptor antagonists may explain the three cases of ischemic colitis.
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PMID:Complications of 5-azacytidine: Three cases of severe ischemic colitis in elderly patients with myelodysplastic syndrome. 2426 71

Azacitidine is the first drug to demonstrate a survival benefit for patients with MDS. However, only half of patients respond and almost all patients eventually relapse. Limited and conflicting data are available on predictive factors influencing response. We analyzed 128 patients from two institutions with MDS or AML treated with azacitidine to identify prognostic indicators. Genetic mutations in ASXL1, RUNX1, DNMT3A, IDH1, IDH2, TET2, TP53, NRAS, KRAS, FLT3, KMT2A-PTD, EZH2, SF3B1, and SRSF2 were assessed by next-generation sequencing. With a median follow up of 5.6 years median survival was 1.3 years with a response rate of 49%. The only variable with significant influence on response was del(20q). All 6 patients responded (p = 0.012) but survival was not improved. No other clinical, cytogenetic or molecular marker for response or survival was identified. Interestingly, patients from poor-risk groups as high-risk cytogenetics (55%), t-MDS/AML (54%), TP53 mutated (48%) or relapsed after chemotherapy (60%) showed a high response rate. Factors associated with shorter survival were low platelets, AML vs. MDS, therapy-related disease, TP53 and KMT2A-PTD. In multivariate analysis anemia, platelets, FLT3-ITD, and therapy-related disease remained in the model. Poor-risk factors such as del(7q)/-7, complex karyotype, ASXL1, RUNX1, EZH2, and TP53 did not show an independent impact. Thus, no clear biomarker for response and survival can be identified. Although a number of publications on predictive markers for response to AZA exist, results are inconsistent and improved response rates did not translate to improved survival. Here, we provide a comprehensive overview comparing the studies published to date.
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PMID:Efficacy of azacitidine is independent of molecular and clinical characteristics - an analysis of 128 patients with myelodysplastic syndromes or acute myeloid leukemia and a review of the literature. 2996 45

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.
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PMID:A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis. 3018 31


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