Efficacy and Safety of Demethylation Agents for Middle/High-risk Patients with Myelodysplastic Syndrome: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

CHENQiao-lin ¹ ,  ZHAOLi ² , LINGChun ¹

1. First Hospital of Lanzhou University, Lanzhou 730000, China;
2. Department of Central Laboratory, First Hospital of Lanzhou University, Lanzhou 730000, China;

Corresponding author：

ZHAOLi, Email: zhaoli@lzu.edu.cn

Keywords：

Myelodysplastic syndrome; Demethylation agent; Decitabine; Azacitidine; Meta-analysis; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.20140179

Video：

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Objective To systematically review the effectiveness and safety of demethylation agents in patients with myelodysplastic syndrome. Methods Randomized controlled trials (RCTs) about demethylation agents in treating myelodysplastic syndrome was electronically searched in PubMed, EMbase, The Cochrane Library (Issue 3, 2013), Web of Science, CNKI, VIP, WanFang Data and CBM from inception to March 2013. Two reviewers independently screened literature according to the inclusion and exclusion criteria, extracted data, and assessed methodological quality of the included studies. Meta-analysis was performed using RevMan 5.1 software. Results A total of 4 studies involving 816 patients were finally included. The results of meta-analysis showed that:for patients with myelodysplastic syndrome at middle/advanced stage, compared with the best supportive treatment plan, demethylation agents improved complete remission (CR) (OR=19.14, 95%CI 5.33 to 68.7, P < 0.000 01), partial remission (PR) (OR=20.63, 95%CI 5.76 to 73.93, P < 0.000 01), hematological improvement (HI) (OR=3.58, 95%CI 2.40 to 5.34, P < 0.000 01), and the incidences of Grade Ⅲ or Ⅳ neutropenia (OR=3.82, 95%CI 2.67 to 5.47, P < 0.000 01), Grade Ⅲ or Ⅳ thrombocytopenia (OR=3.98, 95%CI 2.55 to 6.23, P < 0.000 01), and mortalities (OR=0.52, 95%CI 0.35 to 0.77, P < 0.000 01), all with significant differences; and part of patients suffered from Grade Ⅲ or Ⅳ thrombocytopenia and tolerable adverse reaction caused by non-hematologic change. Conclusion Current evidence suggests that demethylation agents in treating myelodysplastic syndrome have apparently curative effects. Besides, it could prolong the time of turning into acute myelocytic leukemia, reduce mortalities, and improve patients' quality of life.

Citation： CHENQiao-lin, ZHAOLi, LINGChun. Efficacy and Safety of Demethylation Agents for Middle/High-risk Patients with Myelodysplastic Syndrome: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2014, 14(9): 1097-1103. doi: 10.7507/1672-2531.20140179 Copy

1.	Germing U, Strupp C, Kungen A, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica, 2004, 89(8):905-910.
2.	Cogle CR, Craig BM, Rollison DE, et al. Incidence of the myelodysplastic syndromes using a novel claims-based algorithm:high number of uncaptured cases by cancer registries. Blood, 2011, 117(26):7121-7125.
3.	Goldberg SL, Chen E, Corral M, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol, 2010, 28(17):2847-2852.
4.	Kantarjian H, Giles F, List A, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer, 2007, 109(9):1705-1714.
5.	Neukirchen J, Blum S, Kuendgen A, et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. Eur J Haematol, 2009, 83(5):477-482.
6.	Garcia Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia, 2008, 22(3):538-543.
7.	Jadersten M, Hellstrom-Lindberg E. Myelodysplastic syndromes:biology and treatment. J Intern Med, 2009, 265(3):307-328.
8.	Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol, 1982, 51(2):189-199.
9.	Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood, 2002, 100(7):2292-2302.
10.	Mufti GJ, Steven JR, Oscier DG, et al. Myelodysplastic syndromes:a scoring system with prognostic significance. Br J Haematol, 1985, 59(3):425-433.
11.	Leone G, Teofili L, Voso MT, et al. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica, 2002, 87(12):1324-1341.
12.	Merlo A, Herman JG, Mao L, et al. 5_CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med, 1995, 1(7):686-692.
13.	Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes:Results of a phase Ⅲ randomized study. Cancer, 2006, 106(8):1794-1803.
14.	Wierda W, O Brien S, Faded S, et al. A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer, 2006, 106(2):337-345.
15.	Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviews of Interventions Version5. 1. 0[updated March 2011]. The Cochrane Collaboration, 2011. Available from:www. Cochrane-handbook. org.
16.	Kantarjian H, Issa JP, Rosenfeld CS, et al. ecitabine improves patient outcomes in myelodysplastic syndromes:results of a phase Ⅲ randomized study. Cancer, 2006, 106(8):1794-1803.
17.	Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy:final results of the randomized phase Ⅲ study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol, 2011, 29(15):1987-1996.
18.	Silverman LR, Demakos EP, Peterson BL, et al. 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(10):2429-2440.
19.	Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes:a randomised, open-label, phase Ⅲ study. Lancet Oncol, 2009, 10(3):223-232.
20.	Greenberg PL, Attar E, Bennett JM. NCCN Clinical practice guidelines in Oncology:Myelodysplastic Syndromes. J Natl Compr Canc Netw, 2011, 9(1):30-56.
21.	Atallah E, Kantarjian H. The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin. Pharmacother, 2007, 8(1):65-73.
22.	Griffiths EA. DNA Methyltransferase and Histone Deacetylase inhibitors in the treatment of Myelodysplastic Syndromes. Semin Hematol, 2008, 45(1):23-30.

1. Germing U, Strupp C, Kungen A, et al. No increase in age-specific incidence of myelodysplastic syndromes. Haematologica, 2004, 89(8):905-910.
2. Cogle CR, Craig BM, Rollison DE, et al. Incidence of the myelodysplastic syndromes using a novel claims-based algorithm:high number of uncaptured cases by cancer registries. Blood, 2011, 117(26):7121-7125.
3. Goldberg SL, Chen E, Corral M, et al. Incidence and clinical complications of myelodysplastic syndromes among United States Medicare beneficiaries. J Clin Oncol, 2010, 28(17):2847-2852.
4. Kantarjian H, Giles F, List A, et al. The incidence and impact of thrombocytopenia in myelodysplastic syndromes. Cancer, 2007, 109(9):1705-1714.
5. Neukirchen J, Blum S, Kuendgen A, et al. Platelet counts and haemorrhagic diathesis in patients with myelodysplastic syndromes. Eur J Haematol, 2009, 83(5):477-482.
6. Garcia Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia, 2008, 22(3):538-543.
7. Jadersten M, Hellstrom-Lindberg E. Myelodysplastic syndromes:biology and treatment. J Intern Med, 2009, 265(3):307-328.
8. Bennett JM, Catovsky D, Daniel MT, et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol, 1982, 51(2):189-199.
9. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood, 2002, 100(7):2292-2302.
10. Mufti GJ, Steven JR, Oscier DG, et al. Myelodysplastic syndromes:a scoring system with prognostic significance. Br J Haematol, 1985, 59(3):425-433.
11. Leone G, Teofili L, Voso MT, et al. DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias. Haematologica, 2002, 87(12):1324-1341.
12. Merlo A, Herman JG, Mao L, et al. 5_CpG island methylation is associated with transcriptional silencing of the tumour suppressor p16/CDKN2/MTS1 in human cancers. Nat Med, 1995, 1(7):686-692.
13. Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes:Results of a phase Ⅲ randomized study. Cancer, 2006, 106(8):1794-1803.
14. Wierda W, O Brien S, Faded S, et al. A retrospective comparison of three sequential groups of patients with Recurrent/Refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer, 2006, 106(2):337-345.
15. Higgins JPT, Green S(editors). Cochrane Handbook for Systematic Reviews of Interventions Version5. 1. 0[updated March 2011]. The Cochrane Collaboration, 2011. Available from:www. Cochrane-handbook. org.
16. Kantarjian H, Issa JP, Rosenfeld CS, et al. ecitabine improves patient outcomes in myelodysplastic syndromes:results of a phase Ⅲ randomized study. Cancer, 2006, 106(8):1794-1803.
17. Lubbert M, Suciu S, Baila L, et al. Low-dose decitabine versus best supportive care in elderly patients with intermediate-or high-risk myelodysplastic syndrome (MDS) ineligible for intensive chemotherapy:final results of the randomized phase Ⅲ study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group. J Clin Oncol, 2011, 29(15):1987-1996.
18. Silverman LR, Demakos EP, Peterson BL, et al. 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(10):2429-2440.
19. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes:a randomised, open-label, phase Ⅲ study. Lancet Oncol, 2009, 10(3):223-232.
20. Greenberg PL, Attar E, Bennett JM. NCCN Clinical practice guidelines in Oncology:Myelodysplastic Syndromes. J Natl Compr Canc Netw, 2011, 9(1):30-56.
21. Atallah E, Kantarjian H. The role of decitabine in the treatment of myelodysplastic syndromes. Expert Opin. Pharmacother, 2007, 8(1):65-73.
22. Griffiths EA. DNA Methyltransferase and Histone Deacetylase inhibitors in the treatment of Myelodysplastic Syndromes. Semin Hematol, 2008, 45(1):23-30.

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Efficacy and Safety of Demethylation Agents for Middle/High-risk Patients with Myelodysplastic Syndrome: A Systematic Review

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