The online version of this article (https://doi.org/10.1186/s12878-017-0094-8) contains supplementary material, which is available to authorized users.
5-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.
A 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.
The 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.
Indirect 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.
Additional file 1: This file includes the Medline search strategy used. (DOCX 13 kb)12878_2017_94_MOESM1_ESM.docx
Additional file 2: This file includes Tables S1, S2, and S3. The former describes the available characteristics of all patients included in this study that were reported in literature articles (abstracts did not provide sufficient information regarding baseline patient characteristics). Table S2. describes available objective response rate and survival data from literature articles retrieved for this systematic review. Table S3. is a comparison of the IWG 2000 and IWG 2006 objective response criteria. (DOCX 31 kb)12878_2017_94_MOESM2_ESM.docx
Additional file 3: This file includes the supplementary reference list for the systematic review. These references include articles and abstracts retrieved for this systematic review that were not cited in the main manuscript, but that are included in the data analysis. (DOCX 20 kb)12878_2017_94_MOESM3_ESM.docx
AMS M, Florek M. 5-Azacytidine. In: Small molecules in oncology. 2nd ed. New York: Springer Heidelberg; 2014. p. 299–324.
Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of Azacitidine in patients with the Myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20:2429–40. CrossRefPubMed
Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR, for the International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional careregimens in the treatment of higher-risk myelodysplasticsyndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223–32. CrossRefPubMedPubMedCentral
Frame D. Alternative dosing schedules for methylation inhibitors in MDS treatment. Managed Care. 2009;18(11):S15–20.
Saunthararajah Y. Key clinical observations after 5-azacytidine and decitabine treatment of myelodysplastic syndromes suggest practical solutions for better outcomes. Hematology. 2013; https://doi.org/10.1182/asheducation-2013.1.511.
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, Pinto A, Beran M, de Witte TM, Stone RM, Mittelman M, Sanz GF, Gore SD, Schiffer CA, Kantarjian H. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;108(2):419–25. CrossRefPubMed
JPT H, Altman DG, Sterne JAC. Chapter 8: assessing risk of bias in included studies. In: JPT H, Green S, editors. Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated march 2011]. The Cochrane collaboration; 2011. http://handbook-5-1.cochrane.org/. Accessed 1 June 2016.
Stukel TA, Demidenko E, Dykes J, Karagas MR. Two-stage methods for the analysis of pooled data. Statist Med. 2001;20:2115–30. CrossRef
García-Delgadoa R, de Miguelb D, Bailénc A, et al. Effectiveness and safety of different azacitidine dosage regimens inpatients with myelodysplastic syndromes or acute myeloid leukemia. Leuk Res. 2014;38:744–50. CrossRef
Gore SD, Fenaux P, Santini V, et al. A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica. 2013;98:1062–72. CrossRef
Cheson BD, Bennett JM, Kantarjian H, et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood. 2000;96:3671–4. PubMed
Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–88. PubMed
Minoia C, Sgherza N, Loseto G, et al. Azacitidine in the front-line treatment of therapy-related myeloid Neoplasms: a multicenter case series. Anticancer Res. 2015;35:461–6. PubMed
Ballya C, Adèsa L, Rennevilleb A, Seberta M, et al. Prognostic value of TP53 gene mutations in myelodysplasticsyndromes and acute myeloid leukemia treated with azacitidine. Leuk Res. 2014;38:751–5. CrossRef
Breccia M, Loglisci G, Cannella L, et al. Application of French prognostic score to patients with InternationalPrognostic scoring system intermediate-2 or high risk myelodysplasticsyndromes treated with 5-azacitidine is able to predict overall survivaland rate of response. Leuk Lymphoma. 2012;53(5):985–6. CrossRefPubMed
Gryna J, Zeigler ZR, Shadduck RK, et al. Treatment of myelodysplastic syndromes with 5-azacytidine. Leuk Res. 2002;26:893–7. CrossRef
Lee YG, Kim I, Yoon SS, et al. Comparative analysis between azacitidine and decitabine forthe treatment of myelodysplastic syndromes. Br J Hematol. 2013;161:339–47. CrossRef
Tobiasson M, Dybedahl I, Holm MS, et al. Limited clinical efficacy of azacitidine in transfusion-dependent, growth factor-resistant, low- and Int-1-risk MDS: results from the nordic NMDSG08A phase II trial. Blood Cancer J. 2014;4:1–7. CrossRef
Diamantopoulos P, Zervakis K, Papadopoulou V, et al. 5-Azacytidine in the treatment of Intermediate-2 and high-risk Myelodysplastic syndromes and acute myeloid leukemia. A five-year experience with 44 consecutive patients. Anticancer Res. 2015;35:5141–8. PubMed
- Systematic review of azacitidine regimens in myelodysplastic syndrome and acute myeloid leukemia
Roman M. Shapiro
- BioMed Central
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