On May 19, 2004, azacitidine (5-azacytidine; Vidaza(trade mark); Pharmion Corporation, Boulder, CO, http://www.pharmion.com) for injectable suspension received regular approval by the U.S. Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome (MDS). This report summarizes the basis for this approval. Effectiveness was demonstrated in one randomized, controlled trial comparing azacitidine administered s.c. with best supportive care (observation group) and in two single-arm studies, one in which azacitidine was administered s.c. and in the other in which it was administered i.v. The dose of azacitidine, 75 mg/m2/day for 7 days every 28 days, was the same in all three studies. In the randomized trial, study participants were well matched with respect to age, sex, race, performance status, MDS subtype, and use of transfusion during the 3 months before study entry. Patients in the observation arm were permitted by protocol to cross over to azacitidine treatment if their disease progressed according to prespecified criteria. During the course of the study, more than half of the patients in the observation arm did cross over to the azacitidine treatment arm. The primary efficacy end point was the overall response rate. Response consisted of complete or partial normalization of blood cell counts and of bone marrow morphology. The response rate in the azacitidine arm was about 16%; there were no responses in the observation arm. The response rates in the two single-arm studies were similar (13% and 19%). The responses were sustained, with median durations of 11 months and 17 months respectively. Responding patients who were transfusion dependent at study entry lost the need for transfusions. In addition, about 19% of patients had less than partial responses (termed improvement), and two-thirds of them became transfusion independent. Common adverse events associated with azacitidine treatment were gastrointestinal (nausea, vomiting, diarrhea, constipation, and anorexia), hematologic (neutropenia, thrombocytopenia), fevers, rigors, ecchymoses, petechiae, injection site events, arthralgia, headache, and dizziness. Liver function abnormalities occurred in 16% of patients with intercurrent hepatobiliary disorders and in two patients with previously diagnosed liver cirrhosis. Renal failure occurred in patients during sepsis and hypotension. There were no deaths attributed to azacitidine. Azacitidine, the first drug approved by the U.S. FDA for MDS, has a favorable safety profile and provides a clinical benefit of eliminating transfusion dependence and complete or partial normalization of blood counts and bone marrow blast percentages in responding patients.
[1]
J. Veselý.
Mode of action and effects of 5-azacytidine and of its derivatives in eukaryotic cells.
,
1985,
Pharmacology & therapeutics.
[2]
P. Ritch,et al.
Evaluation of continuous infusion low‐dose 5‐azacytidine in the treatment of myelodysplastic syndromes
,
1991,
American journal of hematology.
[3]
H. Gralnick,et al.
Proposals for the classification of the myelodysplastic syndromes
,
1982,
British journal of haematology.
[4]
L. Li,et al.
Phase specificity of 5-azacytidine against mammalian cells in tissue culture.
,
1970,
Cancer research.
[5]
D. Christiansen,et al.
Methylation of p15INK4B is common, is associated with deletion of genes on chromosome arm 7q and predicts a poor prognosis in therapy-related myelodysplasia and acute myeloid leukemia
,
2003,
Leukemia.
[6]
B. Leyland-Jones,et al.
Biochemistry of azacitidine: a review.
,
1987,
Cancer treatment reports.
[7]
S. Friedman.
The inhibition of DNA(cytosine-5)methylases by 5-azacytidine. The effect of azacytosine-containing DNA.
,
1981,
Molecular pharmacology.
[8]
J. Raymond,et al.
Treatment of myelodysplastic syndromes with 5-azacytidine.
,
2002,
Leukemia research.
[9]
D. V. Von Hoff,et al.
5-Azacytidine. A new anticancer drug with effectiveness in acute myelogenous leukemia.
,
1976,
Annals of internal medicine.
[10]
J. Holland,et al.
Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B.
,
2002,
Journal of clinical oncology : official journal of the American Society of Clinical Oncology.
[11]
Hypermethylation of the p15INK4B gene in myelodysplastic syndromes.
,
1997
.
[12]
V. Wilson,et al.
Inhibition of DNA methylation by 5-azacytidine.
,
1983,
Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer.
[13]
B. Chabner,et al.
Deamination of 5-azacytidine by a human leukemia cell cytidine deaminase.
,
1973,
Biochemical pharmacology.