Table 5.

The four large randomized phase 3 trials that evaluated the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) for the treatment of MDS.

Study	Number of patients (median age) and protocol	Patient characteristics	Clinical results	Survival
Silverman LR et al. (Reference [119]) Phase III randomized study of Azacitidine (AZA) vs. Best supportive care (BSC). Crossover allowed.	191 (68 years) AZA 75 mg/m2/d SQ for 7 days every 28 days Vs. BSC	IPSS AZA/SC %: Low 2%/6% INT-1 26%/20% INT-2 11%/16% High 9%/10%	ORR: AZA arm 60% (CR 7%, PR 16%, and HI 37%) Vs. BSC arm 5% Median time to response 64 days Median response duration 15 months Time to leukemic progression or death was delayed by 8 months in patients randomized to AZA (21 vs. 13 months, P = 0.007)	OS: AZA group 20 months vs. BSC group 14 months, P = 0.10 (53% received AZA after crossover) An analysis that accounted for crossover observed a 7-month prolongation in median OS (18 vs. 11 months, P = 0.03)
Fenaux P et al. (Reference [118]) Phase III randomized study of Azacitidine (AZA) Vs. Conventional care regimen (CCR). Crossover NOT allowed.	358 (AZA 69 years; CCR 70 years) AZA 75 mg/m2/d SQ for 7 days every 28 days Vs. CCR (best supportive care [BSC], low dose cytarabine, or intensive chemotherapy)	IPSS AZA/CCR %: Low excluded INT-1 3%/7% INT-2 43%/39% High 46%/48%	ORR in AZA arm 49% (including CR rate of 17% and PR rate of 12%). Median time to AML transformation for the AZA arm was 17.8 months compared to 11.5 months in the CCR arm. Patients in AZA arm received a median of 9 cycles	OS after a median of 21.1 month follow-up: 24.5 for AZA arm vs. 15 months in CCR arm, HR, 0.58, 95%CI 0.43–0.77, P = 0.0001). 2-year survival rate was 50.8% for AZA arm vs. 26.2% for CCR arm, P < 0.0001). Survival advantage for AZA maintained in all IPSS cytogenetic groups, in elderly patients, and in patients with 20–30% BM blasts.
Kantarjian H et al. (Reference [117]) Phase III randomized study of Decitabine (DAC) vs. Best supportive care (BSC)	170 (70) DAC 15 mg/m2 IV q 8 h for 3 days every 6 weeks Vs. BSC	IPSS DAC/BSC%: Low excluded INT-1 31%/30% INT-2 43%/44% High 26%/26%	ORR in DAC arm 17% (CR 9%; PR 8%) and 13% had HI vs. ORR of 0% in BSC arm Time to AML progression in IPSS INT-2/High DAC 12 months vs. 6.8 months in BSC arm (P = 0.03) Time to AML or death in the DAC arm was 12.1 months vs. 7.8 months in BSC arm Median response duration 10.3 months Patients in DAC arm received a median of 3 cycles of therapy	Median OS in DAC arm 14 months vs. 14.9 months in BSC arm (P = 0.636). DAC responders had a median OS of 23.5 months vs. 13.7 months for DAC nonresponders (P = .007)
Lubbert M et al. (Reference [120]) Phase III randomized study of decitabine (DAC) Vs. Best Supportive Care (BSC) in elderly patients deemed ineligible for intensive chemotherapy	233 (70) DAC 15 mg/m2 IV over 4 h 3 times a day for 3 days every 6 weeks or BSC	IPSS DAC/BSC%: Low excluded INT-1 6.7%/7% INT-2 53.8%/55.3% High 38.7%/36.8% 53% poor risk cytogenetics 32% with >20% BM blasts	CR, PR, and HI rates in DAC arm 13%, 6%, 15% respectively, compared to 0%, 0%, and 2% in BSC arm. 1-year AML transformation rate in DAC arm was 33% vs. 22% in BSC arm (P = 0.36). Patients in DAC arm received a median of 4 cycles of therapy.	Median OS for DAC arm 10.1 months vs. 8.5 m in BSC arm (P = 0.38) Median PFS in DAC arm 6.6 months vs. 3 months in BSC arm (P = 0.004) Median AML-free survival in DAC arm 8.8 months vs. 6.1 months in BSC arm (P = 0.24). Short MDS duration was independent adverse prognosticator

BSC: Best supportive care; IPSS: International Prognostic Scoring System; INT-1: Intermediate-1; INT-2: Intermediate 2; ORR: Overall response rate; CR: Complete remission; PR: Partial remission; HI: Hematologic improvement; OS: Overall survival; CCR: Conventional care regimen; AML: Acutemyeloid leukemia; PFS: Progression-free survival.