Feasibility of Therapy With Hypomethylating Agents in Patients With Renal Insufficiency
ABSTRACT To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined.
We reviewed 41 patients with a diagnosis of acute myeloid leukemia (n = 17), myelodysplastic syndromes (n = 15), and chronic myelomonocytic leukemia (n = 9) who had RI and were receiving therapy with azacitidine or decitabine. The median number of administered cycles was 3. Most patients (39; 95%) received a standard dose of the drugs at the initiation of therapy. Nine patients (22%) required treatment interruptions or discontinuation, and 10 patients (24%) required dose reductions.
The overall response rate was 63%, and 4 patients (10%) achieved a complete response. Twenty patients (51%) experienced grade 3 or 4 myelosuppression-related toxicities. Hospitalization was required in 68% of the patients. Among 12 patients with an estimated glomerular filtration rate of 29 mL per minute or less, 6 required dose reductions attributable to myelosuppression (n = 3) or to worsening renal function (n = 3). The overall survival (OS) at 18 months was 12%, and the median OS was 8.6 months.
The use of HA in patients with RI is feasible, but is associated with a higher incidence of toxicity. Dose adjustments and the use of growth factor may be necessary for some patients.
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- "This study concluded that whilst 5-aza-2′-deoxycytidine is well tolerated, it has only moderate effects on hormone-independent prostate cancer. Further, although these inhibitors may reverse aberrant DNA hypermethylation, they have previously been found to have side effects such as myelosuppression (Kantarjian et al. 2003; Schrump et al. 2006; Appleton et al. 2007; Cashen et al. 2008; Batty et al. 2010; Chuang et al. 2010), tumourigenesis (Walker and Nettesheim 1986; Schnekenburger et al. 2011; Hamm et al. 2009) and mutagenesis (Jackson-Grusby et al. 1997; Perry et al. 1992; Saunthararajah et al. 2003; Lavelle et al. 2007), which may limit their usefulness as a therapeutic drug in prostate cancer. Non-nucleoside DNMTi have also been characterised and their ability to reverse DNA hypermethylation examined in prostate cancer. "
ABSTRACT: Prostate cancer is a commonly diagnosed cancer in men and a leading cause of cancer deaths. Whilst the underlying mechanisms leading to prostate cancer are still to be determined, it is evident that both genetic and epigenetic changes contribute to the development and progression of this disease. Epigenetic changes involving DNA hypo- and hypermethylation, altered histone modifications and more recently changes in microRNA expression have been detected at a range of genes associated with prostate cancer. Furthermore, there is evidence that particular epigenetic changes are associated with different stages of the disease. Whilst early detection can lead to effective treatment, and androgen deprivation therapy has a high response rate, many tumours develop towards hormone-refractory prostate cancer, for which there is no successful treatment. Reliable markers for early detection and more effective treatment strategies are, therefore, needed. Consequently, there is a considerable interest in the potential of epigenetic changes as markers or targets for therapy in prostate cancer. Epigenetic modifiers that demethylate DNA and inhibit histone deacetylases have recently been explored to reactivate silenced gene expression in cancer. However, further understanding of the mechanisms and the effects of chromatin modulation in prostate cancer are required. In this review, we examine the current literature on epigenetic changes associated with prostate cancer and discuss the potential use of epigenetic modifiers for treatment of this disease.Clinical Epigenetics 08/2011; 2(2):151-69. DOI:10.1007/s13148-011-0041-7 · 6.22 Impact Factor
Article: Azacitidine[Show abstract] [Hide abstract]
ABSTRACT: Azacitidine (Vidaza®) is a pyrimidine nucleoside analogue of cytidine. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of patients with myelodysplastic syndromes (MDS)/acute myeloid leukaemia (AML), as well as summarizing its pharmacological properties. The randomized, multicentre Cancer and Leukemia Group B 9221 trial compared the efficacy of subcutaneous azacitidine with that of supportive care alone in patients with MDS fulfilling French-American-British (FAB) classification criteria. The overall response rate, the complete response rate and the complete plus partial response rate were significantly higher in patients receiving azacitidine than in those receiving supportive care alone. The randomized, open-label, multicentre AZA-001 trial compared the efficacy of subcutaneous azacitidine with that of conventional care in adults with higher-risk (i.e. International Prognostic Scoring System intermediate-2-risk or high-risk classification) MDS/AML. Prior to randomization, investigators preselected patients to the conventional care strategy considered most appropriate (i.e. best supportive care, low-dose cytarabine or intensive chemotherapy). The median duration of overall survival was significantly prolonged by 9.4 months in patients with higher-risk MDS receiving azacitidine versus those receiving conventional care. The survival benefit seen with azacitidine versus conventional care was maintained across various patient subgroups (e.g. in patients aged ≥75 years, in those who did not achieve complete remission and in patients with WHO-defined AML). The efficacy of subcutaneous or intravenous azacitidine was also shown in a noncomparative trial in Japanese patients with MDS fulfilling FAB classification criteria, and registry programmes in various countries support the efficacy of azacitidine in patients with MDS. Azacitidine was generally well tolerated in patients with MDS, including in the elderly. Across trials, peripheral cytopenias were the most commonly occurring adverse event in azacitidine recipients, with gastrointestinal adverse events (e.g. nausea, vomiting and diarrhoea) and injection-site reactions among the most commonly occurring non-haematological adverse events. In conclusion, azacitidine is an important agent for use in the treatment of patients with MDS/AML.Drugs 01/2012; 72(8). DOI:10.2165/11209430-000000000-00000 · 4.13 Impact Factor
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ABSTRACT: High-risk myelodysplastic syndromes present a poor prognosis, with survivals of close to only 1 year. The use of azacitidine, a DNA methyltransferase inhibitor, in this group of patients has transformed this grey image, with a demonstrated improvement in survival. Responses to survival are attained in a progressive manner, providing that the drug is used continually. This requires a good control of the adverse effects of the drug, which are primarily in the first cycles of treatment. The hematological adverse effects can be handled with transfusions and growth factors. The nonhematological adverse effects can be prevented with the use of antiemetics and a good technique of drug administration.Advances in Therapy 06/2011; 28 Suppl 4(S4):1-5. DOI:10.1007/s12325-011-0021-5 · 2.44 Impact Factor