Prolonged survival with improved tolerability in higher‐risk myelodysplastic syndromes: azacitidine compared with low dose ara‐C

Abstract

Summary 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 haematologicalal 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.

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

“…AZA is a DNA methyltransferase inhibitor that has been proven to be effective in high-risk MDS, because it can induce hematologic responses in 50-60% of cases, delay the AML evolution, and prolong the overall survival. 8,9,37,38 On the other hand, the clinical activity of HDAC inhibitors has also demonstrated a therapeutic potential as monotherapy, but above all in combination with a large number of conventional chemotherapeutic drugs, having a synergistic effect in enhancing their anticancer activity. 39,40 That is why several combination approaches based on HDAC inhibition and other novel drugs are being tested.…”

“…7 Indeed, azacitidine (AZA) is a cytosine-nucleoside analog acting as a DNA methyltransferase inhibitor, which is currently administered to high-risk MDS patients and has proven effectiveness in prolonging the overall survival and delaying AML evolution, especially in patients with more advanced disease. 8,9 The biochemical modification of chromatin-associated histone proteins, such as acetylation of histone H3 or H4, is another epigenetic regulatory mechanism of gene expression involved in leukemogenesis. 10 This process is controlled by both histone acetyl-transferases and deacetylases, and can be prevented by histone deacetylase (HDAC) inhibitors, which can modulate chromatin structure and target other several nonhistone substrates through histone acetylation, thus determining changes in gene transcription, and also inducing other biological effects, such as apoptosis, differentiation, inhibition of angiogenesis or modulation of immune responses.…”

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

“…In particular, the risk of infection is elevated among high-risk MDS patients who often present with neutropenia [2][3][4]. Neutrophil count may further decrease following hypomethylation agents therapy [5,6] which has become the standard of care for these patients.…”

5-Azacitidine in aggressive myelodysplastic syndromes regulates chromatin structure at PU.1 gene and cell differentiation capacity

“…The use of DNA methyl transferase inhibitors (DNMTi) in intermediate-2 (int-2)/high-risk MDS and some AML patients 28 --30 have doubled the overall survival with significant improvement in most of the clinical parameters (Fenaux et al 31,32 and reviewed in Quintas-Cardama et al 33 ). AZA affects DNA methylation status of the derepressed genes 34 and may also involve histone modifications.…”