When IPSS cytogenetic subgroups were analysed, similar findings in terms of median overall survival were observed in all groups (good, intermediate, poor cytogenetics, including monosomy 7).
On analyses of age subgroups, an increase in median overall survival was observed for all groups (< 65 years, 65 years and 75 years).
Vidaza treatment was associated with a median time to death or transformation to AML of 13.0 months versus 7.6 months for those receiving CCR treatment, an improvement of 5.4 months with a stratified log-rank p-value of 0.0025.
Vidaza treatment was also associated with a reduction in cytopenias, and their related symptoms. Vidaza treatment led to a reduced need for red blood cell (RBC) and platelet transfusions. Of the patients in the azacitidine group who were RBC transfusion dependent at baseline, 45.0 % of these patients became RBC transfusion independent during the treatment period, compared with 11.4 % of the patients in the combined CCR groups (a statistically significant (p < 0.0001) difference of 33.6 % (95 % CI: 22.4, 44.6). In patients who were RBC transfusion dependent at baseline and became independent, the median duration of RBC transfusion independence was 13 months in the azacitidine group.
Response was assessed by the investigator or by the Independent Review Committee (IRC). Overall response (complete remission [CR] + partial remission [PR]) as determined by the investigator was 29 % in the azacitidine group and 12% in the combined CCR group (p = 0.0001). Overall response (CR + PR) as determined by the IRC in AZA PH GL 2003 CL 001 was 7 % (12/179) in the azacitidine group compared with 1 % (2/179) in the combined CCR group (p = 0.0113). The differences between the IRC and investigator assessments of response were a consequence of the International Working Group (IWG) criteria requiring improvement in peripheral blood counts and maintenance of these improvements for a minimum of 56 days. A survival benefit was also demonstrated in patients that had not achieved a complete/partial response following azacitidine treatment. Haematological improvement (major or minor) as determined by the IRC was achieved in 49 % of patients receiving azacitidine compared with 29 % of patients treated with combined CCR (p < 0.0001).
In patients with one or more cytogenetic abnormalities at baseline, the percentage of patients with a major cytogenetic response was similar in the azacitidine and combined CCR groups. Minor cytogenetic response was statistically significantly (p = 0.0015) higher in the azacitidine group (34 %) compared with the combined CCR group (10 %).
5.2 Pharmacokinetic properties
The pharmacokinetics of azacitidine were studied following single 75 mg/m2 doses given by subcutaneous and intravenous administration.
Absorption
Azacitidine was rapidly absorbed after subcutaneous administration with peak plasma azacitidine concentrations of 750 ± 403 ng/ml occurring at 0.5 h (the first sampling point) after dosing. The absolute bioavailability of azacitidine after subcutaneous relative to intravenous administration was approximately 89 % based on area under the curve (AUC).
Distribution
Following intravenous administration, the mean volume of distribution was 76 ± 26 l, and systemic clearance was 147 ± 47 l/h.
Metabolism
Based on in vitro data, azacitidine metabolism does not appear to be mediated by cytochrome P450 isoenzymes (CYPs), UDP-glucuronosyltr |
