Efficacy, safety and pharmacokinetics of subcutaneous azacitidine in Chinese patients with higher risk myelodysplastic syndromes: Results from a multicenter, single-arm, open-label phase 2 study.

BACKGROUND: Azacitidine safety and efficacy were established in studies of mainly Caucasian patients. Differences in drug metabolism enzymes between Caucasian and East Asian populations prevent extrapolation of drug effects between these groups. This phase 2 study evaluated azacitidine safety, efficacy and pharmacokinetics in patients with higher-risk myelodysplastic syndromes (HR-MDS) in mainland China. METHODS: Patients aged ≥18 years with HR-MDS were to receive subcutaneous azacitidine 75 mg/m2 /day for 7 days per 28-day cycle, for ≥6 cycles. Pharmacokinetic blood samples were collected in cycle 1 predose on days 5-7, and postdose on day 7. Pharmacokinetic outcomes are descriptively compared with those of a historical North American cohort. RESULTS: Of 72 participants, 46 (64%) completed ≥6 cycles. Response rate was 96%, driven primarily by stable disease (94%); one patient achieved complete remission. Hematologic improvement was attained by 53% of patients. Azacitidine mean plasma concentration versus time profiles were similar in shape for Chinese (n = 12) and North American (n = 45) patients. Maximum plasma concentration (Cmax ) was higher in Chinese patients; however, mean azacitidine exposure (1190 ng·h/mL) was similar to the North American cohort (1021 ng·h/mL). Most common grade 3-4 treatment-emergent adverse events (TEAEs) were thrombocytopenia (69%) and neutropenia (67%). CONCLUSIONS: Azacitidine was safe and effective in Chinese patients with HR-MDS. Clinical outcomes were comparable to those for primarily Caucasian patients in the phase 3 AZA-001 study. Cmax differences between Chinese and North American patients were not associated with differences in TEAE frequency or severity. No initial azacitidine dose adjustment is required for Chinese patients with HR-MDS.

A phase I study in patients with solid or hematologic malignancies of the dose proportionality of subcutaneous Azacitidine and its pharmacokinetics in patients with severe renal impairment.

STUDY OBJECTIVE: To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25-100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses. DESIGN: Multicenter, phase I, open-label, parallel group study. SETTING: Community clinics and major academic centers. PATIENTS: Twenty-seven patients with solid or hematologic malignancies. INTERVENTIONS: Part 1 evaluated azacitidine dose proportionality in patients with normal renal function randomized to single 25, 50, 75, or 100 mg/m2 SC doses. The 75 mg/m2 dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 Cockcroft-Gault adjusted) received azacitidine 75 mg/m2 for 5 consecutive days. MEASUREMENTS AND MAIN RESULTS: PK parameters were determined using noncompartmental methods. In patients with normal renal function (n=21), azacitidine area under the plasma-time curve (AUC0-∞) and maximum observed plasma concentration (Cmax) were dose proportional within the 25-100 mg/m2 range. Concentration versus time profiles after single and multiple azacitidine 75 mg/m2 doses were similar in shape for patients with normal (n=6) or impaired renal function (n=6), with higher mean concentrations in the latter group. Higher mean exposures (AUC0-∞ and Cmax) in renally impaired patients were observed; however, individual exposure values were, with few exceptions, within the same range in both groups. No drug accumulation after multiple doses was observed in either group. Terminal half-life and time to maximum plasma concentration were comparable between groups. Azacitidine tolerability was similar in patients with normal or impaired renal function. CONCLUSION: Azacitidine is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK. Therefore, no initial azacitidine dose adjustment in patients with renal impairment is required.

Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes.

The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of <30% cellularity were considered hypocellular with data evaluable from 299 patients (azacitidine n = 154, CCR n = 145); 13% (n = 39) hypocellular, 87% (n = 260) non-hypocellular. Patient characteristics were balanced between cellularity and treatment groups. Most patients (90-100%) had 2-3 cytopenias at baseline. Median (range) azacitidine treatment cycle lengths were 35·5 (28-54) and 33·0 (15-75) d in hypocellular and non-hypocellular groups, respectively. At 33 months, median OS was not reached (NR) [95% confidence interval (CI): 19·2, NR] in hypocellular patients receiving azacitidine versus 16·9 months (95% CI: 11·1, 19·3) with CCR (P = 0·001); and in non-hypocellular patients, it was 21·1 months (95% CI: 16·2, 34·7) versus 15·3 months (95% CI: 9·3, 17·6) (P = 0·012). Azacitidine tolerance was similar regardless of cellularity. Grade 3-4 thrombocytopenia and neutropenia occurred similarly in hypocellular patients treated with azacitidine versus CCR (80% vs. 92% and 88% vs. 75%). Azacitidine OS results are consistent with those from AZA-001, regardless of cellularity, and demonstrate its safety and efficacy in higher-risk myelodysplasia with hypocellular BM.