Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia

Abstract

Background5-Azacitidine administered as a 7-day dosing regimen (7–0-0) is approved in high risk IPSS myelodysplastic syndrome (MDS) patients. Alternative regimens such as a 5-day (5–0-0) or 7-day with a weekend break (5–2-2) are commonly used. No randomized controlled trial has been done directly comparing all three dosing regimens. The objective of this study was to compare the efficacies of the 5–0-0, 5–2-2, and 7–0-0 regimens in MDS and AML.MethodsA systematic review was conducted using MEDLINE, EMBASE and CENTRAL. Eligible studies were randomized controlled trials (RCTs), observational prospective and retrospective studies. The primary clinical outcomes were Objective Response Rate (ORR) defined as the sum of complete response (CR), partial response (PR), and hematological improvement (HI) as defined by the IWG 2006 criteria. A meta-analysis of simple proportions was conducted using a random effects model with weights defined according to Laird and Mosteller. Comparisons between groups were not attempted due to the heterogeneity of study designs.ResultsThe only RCT directly comparing alternative azacitidine regimens showed no difference in ORR between the 5–0-0 and 5–2-2 regimens. All other RCTs compared a dosing regimen to conventional care. The pooled proportion of ORR was 44.8% with 95% CI (42.8%, 45.5%) for 7–0-0, 41.2% with 95% CI (39.2%, 41.9%) for 5–0-0, and 45.8% with 95% CI (42.6%, 46.4%) for 5–2-2.ConclusionsIndirect comparison of alternative azacitidine dosing regimens in MDS and AML shows a benefit for the 7-day regimen in attaining ORR. Additional RCTs are required to definitively address this comparison.Electronic supplementary materialThe online version of this article (10.1186/s12878-017-0094-8) contains supplementary material, which is available to authorized users.

High-dose regimens of hypomethylating agents promote transfusion independence in IPSS lower-risk myelodysplastic syndromes: a meta-analysis of prospective studies

“…The latter gradually declined with decreasing dose: lower TI rates were observed with DAC 20×3 and AZA 75×5 than with AZA 75×7, which was nonetheless superior to AZA 50×5. This is supported by other studies demonstrating that the standard AZA 75×7 regimen had superior efficacy to the relatively lower-dose 75×5 regimen [ 32 , 33 ]. Thus, AZA 75×7 is the recommended HMA for the treatment of LR-MDS.…”

More is less, less is more, or does it really matter? The curious case of impact of azacitidine administration schedules on outcomes in patients with myelodysplastic syndromes

“…In their recent study, Shapiro et al conducted a systematic review of the available data comparing the different azacitidine administration schedules used for treatment of MDS, explicitly the 5–0, 5–2-2, and 7–0 regimens [ 12 ]. Attempts at conducting a meta-analysis were unsuccessful given the paucity of randomized controlled studies (4 of 130 included studies, or 3%) evaluating differences in administration schedules and the significant heterogeneity of the observational studies, but an ORR for each regimen was obtained via pooled analyses of the included studies.…”

“…Shapiro et al suggest that schedules administering seven days of azacitidine treatment with or without a weekend break might have higher ORR than the other five-day schedules, but the fact that pooled results of alternative regimens cannot be directly compared limits this conclusion especially in patients with higher risk MDS. Shapiro et al duly caution that their analysis was limited by several significant biases, the heterogeneity in design of the studies included (most of which were retrospective or uncontrolled) as well as their reporting of metrics (namely ORR and OS but not CR), which precluded direct comparisons between schedules [ 12 ].…”

Azacitidine regulates DNA methylation of GADD45γ in myelodysplastic syndromes

“…Azacitidine changed the DNA methylation level of DLK1‐DIO3 region in the treatment of MDS and myelodysplastic‐related AML 20 . Systematic evaluation of azacitidine in the treatment of MDS and AML had also been paid more and more attention 21 . According to the latest research, the therapeutic effect of 5‐azacitidine in MDS was analyzed by detecting DNA methylation in peripheral blood 22 .…”