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Azacitidine

A Review of its Use in Higher-Risk Myelodysplastic Syndromes/Acute Myeloid Leukaemia

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Summary

Abstract

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.

Pharmacological Properties

Azacitidine is a pyrimidine nucleoside analogue of cytidine. Its antineoplastic activity is attributed to DNA hypomethylation and a cytotoxic effect on abnormal haematopoietic cells in the bone marrow.

Azacitidine is incorporated into RNA, interfering with the synthesis of nucleic acids and proteins; it is also incorporated to a lesser extent into DNA. This incorporation results in cytotoxicity; azacitidine mainly affects rapidly dividing cells. In vitro, azacitidine induced concentration-dependent apoptosis in myeloid cell lines and a DNA damage response was induced in an AML-derived cell line.

Hypermethylation of the promoters of certain tumour suppression genes, resulting in their silencing, is prevalent in MDS and secondary AML. Azacitidine inhibits DNA methyltransferase activity and the methylation of newly synthesized DNA; this DNA hypomethylation may result in reactivation of silenced genes, with restoration of cancer-suppressing functions and induction of cellular differentiation. The pattern of aberrant DNA methylation has been shown to predict clinical outcome in patients with MDS, although studies in patients with MDS revealed heterogeneous results in terms of the relationship between baseline DNA methylation status/demethylating activity and the clinical response to azacitidine therapy.

Subcutaneous azacitidine is rapidly absorbed and has an absolute bioavailability of 89%. Azacitidine is metabolized via spontaneous hydrolysis and cytidine deaminase-mediated deamination. It has a mean elimination half-life of ≈41 minutes; azacitidine and/or its metabolites are predominantly excreted in the urine.

Therapeutic Efficacy

The efficacy of subcutaneous azacitidine in patients with higher-risk MDS (i.e. IPSS intermediate-2-risk or high-risk MDS) was evaluated in the randomized, open-label, multicentre AZA-001 trial. Inclusion criteria included refractory anaemia with excess blasts, refractory anaemia with excess blasts in transformation or CMML with ≥10% bone marrow blasts and a white blood cell count of <13 × 109 cells/L, defined using the French-American-British classification. When assessed according to the WHO criteria, 32% of patients enrolled in this trial had 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). Patients were then randomized 1: 1 to receive subcutaneous azacitidine 75 mg/m2/day for 7 consecutive days every 28 days for at least six cycles (n= 179) or the preselected conventional care regimen (n= 179).

In the AZA-001 trial, the median duration of overall survival (primary end-point) was significantly prolonged by 9.4 months in patients with higher-risk MDS receiving azacitidine versus those receiving conventional care. The survival benefit associated with azacitidine was seen early in the course of treatment, with Kaplan-Meier survival curves separating after ≈3 months of treatment. Estimated 2-year survival rates were 50.8% in azacitidine recipients and 26.2% in patients receiving conventional care. When survival was analyzed according to the preselected conventional care allocation, azacitidine significantly prolonged survival versus best supportive care or low-dose cytarabine, but not versus intensive chemotherapy, reflecting the small number of patients preselected to the intensive chemotherapy arm (n = 42). The survival benefit seen with azacitidine versus conventional care was maintained across various patient subgroups. For example, azacitidine prolonged survival regardless of IPSS cytogenetic status or the conventional care regimen preferred by the investigator, as well as in those with the −7/del(7q) cytogenetic abnormality, in those with WHO-defined AML, in those who did not achieve complete remission and in those aged ≥75 years.

In patients receiving azacitidine, the median time to AML transformation was significantly longer than in those receiving conventional care, and rates of complete remission, partial remission, any haematological improvement, major erythroid improvement and major platelet improvement were significantly higher. In addition, of the patients who were dependent on RBC transfusions at baseline, significantly more azacitidine than conventional care recipients became transfusion independent.

Tolerability

In the AZA-001 trial, the most commonly occurring grade 3 or 4 adverse events in patients receiving either azacitidine or conventional care were peripheral cytopenias. The risk of haematological adverse events was highest during the first two cycles of azacitidine therapy, and decreased as patients experienced restoration of haematological function. Early discontinuation because of haematological adverse events occurred in 5% of azacitidine recipients and 2% of conventional care recipients.

In azacitidine recipients, the most commonly occurring non-haematological treatment-related adverse events included injection-site reactions, nausea, vomiting, fatigue and diarrhoea. The rate of infections requiring intravenous antimicrobials was significantly lower in azacitidine recipients than in patients receiving conventional care. Deaths occurred in 11% of azacitidine recipients and 9% of conventional care recipients during the first 3 months of treatment, four deaths were considered probably related to azacitidine and one was considered probably related to low-dose cytarabine.

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    Gillian M. Keating

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Various sections of the manuscript reviewed by: G. Damaj, Department of Hematology, Amiens University Medical Center, Amiens, France; F. Dreyfus, Service d’Hématologie, Hôpital Cochin, Paris, France; F. Ferrara, Division of Hematology and Stem Cell Transplantation Unit, Cardarelli Hospital, Napoli, Italy; N. Gatterman, Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine University, Düsseldorf, Germany; T. Prébet, Department of Hematology, Institut Paoli-Calmettes, Marseille, France.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘azacitidine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE, EMBASE and AdisBase search terms were ‘azacitidine’ or ‘azacytidine’. Searches were last updated 30 October 2009.

Selection: Studies in patients with myelodysplastic syndromes who received azacitidine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Azacitidine, myelodysplastic syndromes, pharmacodynamics, pharmacokinetics, therapeutic use, tolerabiliy.

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Keating, G.M. Azacitidine. Drugs 69, 2501–2518 (2009). https://doi.org/10.2165/11202840-000000000-00000

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