Aims: To investigate the safety and efficacy of the triple therapy of decitabine, idarubicin, and cytarabine in the treatment of refractory or recurrent acute myeloid leukemia (R/R AML). Methods: We conducted a single-center retrospective study in which decitabine treatment was administered prior to full-dose idarubicin and cytarabine (D-IA) for 21 R/R AML patients. Results: After 1 cycle of D-IA, 10/21 (47.6%) patients experienced a complete remission (CR) and 2/21 (9.5%) showed a partial response. There was a 1-month response rate (RR) in 12/21 patients (57.14%); these patients achieved CR after 2 cycles of D-IA. Five of these 12 (40%) patients then received sequential allogeneic stem cell transplantation. At the last follow-up date, 9/21 (42.8%) patients had survived, and 7/21 (33.3%) were in continuous CR. Hematological toxicity and infections were the most prominent toxicities of this regimen. Other toxicities included nausea, vomiting, bleeding, and liver enzyme abnormalities. No mortalities were recorded due to treatment-related toxicity during remission. Conclusions: The combination was well tolerated, and the RR was encouraging. Our study suggests that D-IA may offer a novel and potentially effective treatment regimen for R/R AML patients.

Byrd JC, Mrozek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, Pettenati MJ, Patil SR, Rao KW, Watson MS, Koduru PR, Moore JO, Stone RM, Mayer RJ, Feldman EJ, Davey FR, Schiffer CA, Larson RA, Bloomfield CD: Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002;100:4325-4336.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000;96:4075-4083.
Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, Rees J, Hann I, Stevens R, Burnett A, Goldstone A: The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998;92:2322-2333.
Weinberg OK, Seetharam M, Ren L, Seo K, Ma L, Merker JD, Gotlib J, Zehnder JL, Arber DA: Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system. Blood 2009;113:1906-1908.
Sironi S, Wagner M, Kuett A, Drolle H, Polzer H, Spiekermann K, Rieger C, Fiegl M: Microenvironmental hypoxia regulates FLT3 expression and biology in AML. Sci Rep 2015;5:17550.
Hatzimichael E, Georgiou G, Benetatos L, Briasoulis E: Gene mutations and molecularly targeted therapies in acute myeloid leukemia. Am J Blood Res 2013;3:29-51.
Ivanoff S, Gruson B, Chantepie SP, Lemasle E, Merlusca L, Harrivel V, Charbonnier A, Votte P, Royer B, Marolleau JP: 5-Azacytidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy. Am J Hematol 2013;88:601-605.
Sohn SK, Moon JH: Survey of expert opinions and related recommendations regarding bridging therapy using hypomethylating agents followed by allogeneic transplantation for high-risk MDS. Crit Rev Oncol Hematol 2015;95:243-250.
Baylin SB, Ohm JE: Epigenetic gene silencing in cancer - a mechanism for early oncogenic pathway addiction? Nat Rev Cancer 2006;6:107-116.
Gallipoli P, Giotopoulos G, Huntly BJ: Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia. Ther Adv Hematol 2015;6:103-119.
Issa JP, Baylin SB, Herman JG: DNA methylation changes in hematologic malignancies: biologic and clinical implications. Leukemia 1997;11(suppl 1):S7-S11.
Melki JR, Clark SJ: DNA methylation changes in leukaemia. Semin Cancer Biol 2002;12:347-357.
Egger G, Liang G, Aparicio A, Jones PA: Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004;429:457-463.
Ritchie EK, Feldman EJ, Christos PJ, Rohan SD, Lagassa CB, Ippoliti C, Scandura JM, Carlson K, Roboz GJ: Decitabine in patients with newly diagnosed and relapsed acute myeloid leukemia. Leuk Lymphoma 2013;54:2003-2007.
Grishina O, Schmoor C, Dohner K, Hackanson B, Lubrich B, May AM, Cieslik C, Muller MJ, Lubbert M: DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. BMC Cancer 2015;15:430.
Zhu CY, Liu SY, Niu JH, Zhang Q, Yang H, Zhu HY, Yu L, Jing Y: Clinical resarch of decitabine combined with modified CAG regimen for treatment of relapsed or refractory acute myeloid leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi 2015;23:88-93.
Li J, Chen Y, Zhu Y, Zhou J, Xu Y, Li Y, Yu K, Pan L, Wang J, Ding J, Gu J, Zhou S, Shi J, Hong M, Xu J, Pan L, Duan L, Zhang R, Zhang S, Zhu H, Lu H, Liu P, Qiu H, Wu H, Qian S: Efficacy and safety of decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin in newly diagnosed elderly patients with acute myeloid leukemia. Oncotarget 2015;6:6448-6458.
Ye XN, Zhou XP, Wei JY, Xu GX, Li Y, Mao LP, Huang J, Ren YL, Mei C, Wang JH, Lou YJ, Ma LY, Yu WJ, Ye L, Xie LL, Luo YW, Hu C, Niu LM, Dou MH, Jin J, Tong HY: Epigenetic priming with decitabine followed by low-dose idarubicin/cytarabine has an increased anti-leukemic effect compared to traditional chemotherapy in high-risk myeloid neoplasms. Leuk Lymphoma 2016;57:1311-1318.
Wiedower E, Jamy O, Martin MG: Induction of acute myeloid leukemia with idarubicin, cytarabine and cladribine. Anticancer Res 2015;35:6287-6290.
Cancer Genome Atlas Research Network: Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med 2013;368:2059-2074.
Mizuno S, Chijiwa T, Okamura T, Akashi K, Fukumaki Y, Niho Y, Sasaki H: Expression of DNA methyltransferases DNMT1, 3A, and 3B in normal hematopoiesis and in acute and chronic myelogenous leukemia. Blood 2001;97:1172-1179.
Kim TK, Gore SD, Zeidan AM: Epigenetic therapy in acute myeloid leukemia: current and future directions. Semin Hematol 2015;52:172-183.
Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A, Mazur G, Mayer J, Gau JP, Chou WC, Buckstein R, Cermak J, Kuo CY, Oriol A, Ravandi F, Faderl S, Delaunay J, Lysák D, Minden M, Arthur C: Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol 2012;30:2670-2677.
Welch JS, Petti AA, Miller CA, Fronick CC, O'Laughlin M, Fulton RS, Wilson RK, Baty JD, Duncavage EJ, Tandon B, Lee YS, Wartman LD, Uy GL, Ghobadi A, Tomasson MH, Pusic I, Romee R, Fehniger TA, Stockerl-Goldstein KE, Vij R, Oh ST, Abboud CN, Cashen AF, Schroeder MA,Jacoby MA, Heath SE, Luber K, Janke MR, Hantel A, Khan N, Sukhanova MJ, Knoebel RW, Stock W, Graubert TA, Walter MJ, Westervelt P, Link DC, DiPersio JF, Ley TJ: TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med 2016;375:2023-2036.
Blum W, Garzon R, Klisovic RB, Schwind S, Walker A, Geyer S, Liu S, Havelange V, Becker H, Schaaf L, Mickle J, Devine H, Kefauver C, Devine SM, Chan KK, Heerema NA, Bloomfield CD, Grever MR, Byrd JC, Villalona-Calero M, Croce CM, Marcucci G: Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci USA 2010;107:7473-7478.
Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF: Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol 2010;28:556-561.
Qin T, Youssef EM, Jelinek J, Chen R, Yang AS, Garcia-Manero G, Issa JP: Effect of cytarabine and decitabine in combination in human leukemic cell lines. Clin Cancer Res 2007;13:4225-4232.
Li K, Hu C, Mei C, Ren Z, Vera JC, Zhuang Z, Jin J, Tong H: Sequential combination of decitabine and idarubicin synergistically enhances anti-leukemia effect followed by demethylating Wnt pathway inhibitor promoters and downregulating Wnt pathway nuclear target. J Transl Med 2014;12:167.
Carter BZ, Mak PY, Mak DH, Shi Y, Qiu Y, Bogenberger JM, Mu H, Tibes R, Yao H, Coombes KR, Jacamo RO, McQueen T, Kornblau SM, Andreeff M: Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst 2014;106:djt440.
Jing Y, Zhu CY, Zhang Q, Niu JH, Yang H, Liu SY, Zhu HY, Yu L: Clinical efficacy of decitabine combined with modified CAG regimen for relapsed-refractory acute myeloid leukemia with AML1-ETO(+). Zhongguo Shi Yan Xue Ye Xue Za Zhi 2014;22:1245-1250.
Jiang X, Wang Z, Ding B, Yin C, Zhong Q, Carter BZ, Yu G, Jiang L, Ye J, Dai M, Zhang Y, Liang S, Zhao Q, Liu Q, Meng F: The hypomethylating agent decitabine prior to chemotherapy improves the therapy efficacy in refractory/relapsed acute myeloid leukemia patients. Oncotarget 2015;6:33612-33622.
Rosinski SL, Ravandi F, Faderl S, Garcia-Manero G, Pierce S, Kantarjian HM, Estey EH: Count recovery in AML patients achieving a complete response. Blood 2009;114:2062-2062.
Faderl S, Estrov Z: Hematopoietic recovery following induction therapy of acute leukemias: prognostic implications and a new look at the definition of remission. Leuk Lymphoma 2004;45:67-71.
Benton CB, Thomas DA, Yang H, Ravandi F, Rytting M, O'Brien S, Franklin AR, Borthakur G, Dara S, Kwari M, Pierce SR, Jabbour E, Kantarjian H, Garcia-Manero G: Safety and clinical activity of 5-aza-2'-deoxycytidine (decitabine) with or without hyper-CVAD in relapsed/refractory acute lymphocytic leukaemia. Br J Haematol 2014;167:356-365.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.