Systematic Review of the Efficacy and Safety of Alternative Azacitidine Regimens in Myelodysplastic Syndrome

Background 5-Azacitidine has been shown in randomized clinical trials to have a significant degree of efficacy with good tolerability in myelodysplastic syndrome (MDS) patients with intermediate/high risk according to the International Prognostic Scoring System (IPSS) score. The dosing regimen that was approved based on the AZA-001 randomized clinical trial was a 7-day 75mg/m2 regimen (7-0-0). However based on practical considerations, many centers use alternative regimens such as a 5-day 75mg/m2 (5-0-0) or 5-day followed by weekend break, followed by an additional 2-day (5-2-2) regimen at 75mg/m2. No randomized controlled trial has been done directly comparing all the different dosing regimens to ensure they attain the same efficacy as demonstrated for the 7-0-0 one. The objective of this study was to evaluate the efficacy and tolerability of the different dosing regimens of azacitidine in patients with MDS, chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia with < 30% blasts (AML). Methods A systematic review of the literature was conducted using the MEDLINE and EMBASE databases. Eligible studies were randomized controlled trials, observational prospective and observational retrospective studies of various azacitidine regimens in MDS, CMML, or AML. Key extracted data included number of patients, azacitidine dosing, and clinical outcomes as per the International Working Group (IWG). The primary clinical outcome was Objective Response Rate (ORR) defined as the sum of complete response (CR) + partial response (PR) + hematological improvement (HI) by the IWG 2006 response criteria. The primary tolerability outcome was the proportion of patients requiring azacitidine dose adjustment as part of their treatment course. We conducted a meta-analysis of simple proportions 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. Results Of the 2183 studies identified, 39 articles and 37 abstracts including 4868 patients were included in the analysis. There was a small number of studies directly comparing the different azacitidine regimens. Based on a total of two studies there was no statistical difference in terms of ORR between the 5-0-0 & 7-0-0 regimens. Based on a total of two studies, there was no statistical difference in terms of ORR between the 5-0-0 & 5-2-2 dosing regimens. The pooled proportion of ORR was 45% (variance 1.3%) for the 7-0-0 dosing regimen, 38% (variance 1.5%) for the 5-0-0 regimen, and 47% (variance 3.7%) for the 5-2-2 regimen. The 7-0-0 regimen resulted in 17% of patients requiring dose adjustment (variance 10%), the 5-0-0 regimen resulted in 34% of patients requiring dose adjustment (variance 4.3%), and the 5-2-2 regimen resulted in 25% of patients requiring dose adjustment (variance 15%). Conclusions There are few studies directly comparing the different dosing regimens of azacitidine in MDS, CMML, and AML in terms of their efficacy. Based on those studies that do, there is no statistically significant difference in terms of the ORR between the 5-0-0 & 7-0-0 treatments, and the 5-0-0 & 5-2-2 treatments. Pooled estimates for the ORR show similar results for the 3 dosing regimens evaluated, but indirect comparisons between groups were not conducted due to heterogeneity in the designs. Further studies directly comparing the azacitidine dosing regimens in MDS, CMML, and AML are required. Disclosures No relevant conflicts of interest to declare.