Treatment of high-risk MDS patients (pts) with -7/del(7q) with azacitidine (AZA) versus conventional care regimens (CCR): Effects on overall survival (OS)

Abstract

7033 Background: -7/del(7q) is associated with poor prognosis in MDS. In a recent phase III, randomized trial, AZA significantly prolonged OS in pts with high-risk MDS (Fenaux, Blood 2007;110,817). This analysis assessed the effect of AZA on OS in this subgroup of high- risk MDS pts with -7/del(7q). Methods: Primary inclusion criterion for the Phase III study was high-risk MDS (FAB RAEB, RAEB-T, or CMMoL and IPSS Int-2 or High). Pts were randomized to AZA (75 mg/m2/d x 7d, q28d) or CCR. CCR comprised 3 treatments: BSC only (transfusions, antibiotics, G-CSF for neutropenic infection); low-dose ara-C (20 mg/m2/d x 14d, q28d); or induction chemotherapy (7+3 regimen). No erythropoietin was allowed. Results: At baseline (BL), 57 (30 AZA, 27 CCR) of 358 pts in the total population had -7/del(7q), 35% had -7/del(7q) alone and 65% had -7del(7q) as part of complex karyotype. BL characteristics were balanced in the 2 arms: 70% male; median age, 69 years. The median Kaplan Meier difference in OS for AZA vs CCR was 8.4 months, a significant improvement (3-fold) over CCR (Table). The hazard ratio (HR) was 0.33 (95% CI: 0.16–0.68) indicating a 67% reduced risk of death in the AZA arm; this compares with an HR of 0.58 for the OS improvement with AZA vs CCR with all cytogenetic subtypes in the phase III trial. At 2 years, a 4-fold OS advantage was observed in the AZA arm with 33% of pts alive vs 8% in the CCR arm (p=0.03). Secondary endpoints support the OS advantage (Table). Significantly higher IWG 2000 response rates (CR+PR) were seen in pts with -7/del(7q) alone (64% vs 11%; p=0.03) or complex (21% vs 0; p=0.02) with AZA vs CCR, and compared favorably to the overall AZA group with IPSS good and intermediate cytogenetics. AZA was generally well tolerated. Conclusion: This phase III subgroup analysis indicates the disease modifying effect of AZA extends to unfavorable cytogenetic patterns that include -7/del(7q), and suggests AZA may represent the treatment of choice for this otherwise poor prognosis subset. OS, CR, PR, HI, and transfusion independence (TI) in RBC-dependent -7/del(7q) pts at BL (n/N,%) OS (mos) CR+PR CR RBC TI HI-E HI-P AZA 13.1 13/30, 43 8/30, 27 12/21, 57 13/26, 50 10/20, 50 CCR 4.6 1/27, 4 1/27, 4 0/19, 0 0/24, 0 2/25, 8 P value 0.003 0.0005 0.03 <0.0001 <0.0001 0.002 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Amgen, Celgene, Pharmion Corporation Pharmion Amgen, Celgene, Cephalon, Johnson & Johnson, Novartis, Pharmion, Roche Pharmion Corporation