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.
"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. "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Azacitidine is now considered one of the standard-of-care agents for patients with high-risk myelodysplastic syndromes who are not candidates for high-dose chemotherapy. Considering the mechanism of action of the agent, it is critical to maintain adequate dose intensities for prolonged periods of time in order for treatment to be effective. Therefore, aggressive prevention as well as treatment of side effects is critical. The drug mainly causes hematological toxicity that is managed with growth factor support, blood transfusions, and dose and schedule adjustment. Nonhematological side effects are mainly gastrointestinal and cutaneous in nature, and can be easily managed with symptomatic treatment and correct administration techniques.
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