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Hypomethylating agent combination strategies in myelodysplastic syndromes: hopes and shortcomings

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Pages 1022-1036 | Received 02 Jun 2016, Accepted 21 Aug 2016, Published online: 21 Sep 2016

References

  • Ades L, Itzykson R, Fenaux P. Myelodysplastic syndromes. Lancet. 2014;383:2239–2252.
  • 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;117:7121–7125.
  • SEER cancer statistics review, 1975–2011[Internet]. Bethesda, MD: National Cancer Institute; April 2014; [cited 2016]. Available from: http://seer.cancer.gov/csr/1975_2011/.
  • Schanz J, Tuchler H, Sole F, et al. New comprehensive cytogenetic scoring system for primary myelodysplastic syndromes (MDS) and oligoblastic acute myeloid leukemia after MDS derived from an international database merge. J Clin Oncol. 2012;30:820–829.
  • Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120:2454–2465.
  • Malcovati L, Della Porta MG, Strupp C, et al. Impact of the degree of anemia on the outcome of patients with myelodysplastic syndrome and its integration into the WHO classification-based prognostic scoring system (WPSS). Haematologica. 2011;96:1433–1440.
  • Della Porta MG, Tuechler H, Malcovati L, et al. Validation of WHO classification-based prognostic scoring system (WPSS) for myelodysplastic syndromes and comparison with the revised international prognostic scoring system (IPSS-R). A study of the international working group for prognosis in myelodysplasia (IWG-PM). Leukemia. 2015;29:1502–1513.
  • Blau O, Blau IW. Some aspects of allogeneic stem cell transplantation in patients with myelodysplastic syndrome: advances and controversy. Stem Cells Cloning. 2014;7:101–108.
  • Mufti GJ, Potter V. Myelodysplastic syndromes: who and when in the course of disease to transplant. Hematol Am Soc Hematol Educ Prog. 2012;2012:49–55.
  • Zeidan AM, Linhares Y, Gore SD. Current therapy of myelodysplastic syndromes. Blood Rev. 2013;27:243–259.
  • Hollenbach PW, Nguyen AN, Brady H, et al. A comparison of azacitidine and decitabine activities in acute myeloid leukemia cell lines. PLoS One. 2010;5:e9001
  • Christman JK. 5-azacytidine and 5-aza-2'-deoxycytidine as inhibitors of DNA methylation: mechanistic studies and their implications for cancer therapy. Oncogene. 2002;21:5483–5495.
  • FDA approval for azacitidine – National Cancer Institute [Internet]; 2016 Jan 24]. Available from: http://www.cancer.gov/about-cancer/treatment/drugs/fda-azacitidine.
  • FDA approval for decitabine – National Cancer Institute [Internet]; [2016 Jan 24]. Available from: http://www.cancer.gov/about-cancer/treatment/drugs/fda-decitabine.
  • 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;20:2429–2440.
  • Silverman LR, McKenzie DR, Peterson BL, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: Studies 8421, 8921, and 9221 by the cancer and leukemia group B. J Clin Oncol. 2006;24:3895–3903.
  • 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 randomized, open-label, phase III study. Lancet Oncol. 2009;10:223–232.
  • Kantarjian H, Issa JP, Rosenfeld CS, et al. Decitabine improves patient outcomes in myelodysplastic syndromes: results of a phase III randomized study. Cancer. 2006;106:1794–1803.
  • Craddock C, Quek L, Goardon N, et al. Azacitidine fails to eradicate leukemic stem/progenitor cell populations in patients with acute myeloid leukemia and myelodysplasia. Leukemia. 2013;27:1028–1036.
  • Eberharter A, Becker PB. Histone acetylation: a switch between repressive and permissive chromatin. Second in review series on chromatin dynamics. EMBO Rep. 2002;3:224–229.
  • Santini V, Melnick A, Maciejewski JP, et al. Epigenetics in focus: pathogenesis of myelodysplastic syndromes and the role of hypomethylating agents. Crit Rev Oncol Hematol. 2013;88:231–245.
  • West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124:30–39.
  • Spange S, Wagner T, Heinzel T, et al. Acetylation of non-histone proteins modulates cellular signalling at multiple levels. Int J Biochem Cell Biol. 2009;41:185–198.
  • Carew JS, Giles FJ, Nawrocki ST. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett. 2008;269:7–17.
  • Gore SD, Baylin S, Sugar E, et al. Combined DNA methyltransferase and histone deacetylase inhibition in the treatment of myeloid neoplasms. Cancer Res. 2006;66:6361–6369.
  • Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, et al. Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood. 2006;108:3271–3279.
  • Raffoux E, Cras A, Recher C, et al. Phase 2 clinical trial of 5-azacitidine, valproic acid, and all-trans retinoic acid in patients with high-risk acute myeloid leukemia or myelodysplastic syndrome. Oncotarget. 2010;1:34–42.
  • Issa JP, Garcia-Manero G, Huang X, et al. Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia. Cancer. 2015;121:556–561.
  • Dokmanovic M, Clarke C, Marks PA. Histone deacetylase inhibitors: overview and perspectives. Mol Cancer Res. 2007;5:981–989.
  • Prebet T, Vey N. Vorinostat in acute myeloid leukemia and myelodysplastic syndromes. Expert Opin Investig Drugs. 2011;20:287–295.
  • Kirschbaum M, Gojo I, Goldberg SL, et al. A phase 1 clinical trial of vorinostat in combination with decitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. Br J Haematol. 2014;167:185–193.
  • Tan P, Wei A, Mithraprabhu S, et al. Dual epigenetic targeting with panobinostat and azacitidine in acute myeloid leukemia and high-risk myelodysplastic syndrome. Blood Cancer J. 2014;4:e170.
  • Sekeres M, Othus M, List A, et al. Additional analysis of a randomized phase II study of azacitidine monotherapy in higher-risk myelodysplastic syndromes (MDS and chronic myelomonocytic leukemia (CMML): North American intergroup study SWOG S1117. Blood. 2015;126:908.[abstract].
  • Sekeres M, Othus M, List A. A randomized phase II study of azacitidine combined with lenalidomide or with vorinostat vs. azacitidine monotherapy in higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML): North American intergroup study SWOG S1117. Blood. 2014;124:LBA–LB5.[abstract].
  • Garcia-Manero G, Sekeres MA, Egyed M, et al. Panobinostat plus azacitidine in adult patients with MDS, CMML, or AML: Results of a phase 2b study. Blood. 2015;126:2861.
  • Garcia-Manero G, Berdeja J, Komrokji R, et al. A randomized, placebo-controlled, phase II study of pracinostat in combination with azacitidine (AZA) in patients with previously untreated myelodysplastic syndrome (MDS). Blood. 2015;126:911.[abstract].
  • Prebet T, Sun Z, Figueroa ME, et al. Prolonged administration of azacitidine with or without entinostat for myelodysplastic syndrome and acute myeloid leukemia with myelodysplasia-related changes: results of the US leukemia intergroup trial E1905. J Clin Oncol. 2014;32:1242–1248.
  • Prebet T, Sun Z, Ketterling RP, et al. Azacitidine with or without entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 north american leukemia intergroup study. Br J Haematol. 2016;172:384–391.
  • Luger S, Klimek V, Cooper M, et al. Combination therapy with mocetinostat, an oral, spectrum-selective histone deacetylase (HDAC) inhibitor, and 5-azaciditine: Indication of clinical activity in MDS. Blood. 2013;122:1550.
  • FDA approval for lenalidomide – National Cancer Institute [Internet]; [2016 Jan 24]. Available from: http://www.cancer.gov/about-cancer/treatment/drugs/fda-lenalidomide.
  • Ghosh N, Grunwald MR, Fasan O, et al. Expanding role of lenalidomide in hematologic malignancies. Cancer Manag Res. 2015;7:105–119.
  • Fink E. Lenalidomide induces ubiquitination and degradation of CSNK1A1 in MDS with del (5q). Abstract 4 presented at: The 56th ASH Annual Meeting; 2014 Dec 6–9; San Fracison, CA.
  • Kronke J, Fink EC, Hollenbach PW, et al. Lenalidomide induces ubiquitination and degradation of CK1α in del(5q) MDS. Nature. 2015;523:183–188.
  • Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood. 2008;111:86–93.
  • Giagounidis AA, Germing U, Haase S, et al. Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31. Leukemia. 2004;18:113–119.
  • Mittelman M, Filanovsky K, Rosenbaum H, et al. Azacitidine and lenalidomide combination in higher-risk myelodysplastic syndromes-preliminary results of the vilen-01 protocol. Blood. 2013;122:1576.
  • Platzbecker U, Braulke F, Kundgen A, et al. Sequential combination of azacitidine and lenalidomide in del(5q) higher-risk myelodysplastic syndromes or acute myeloid leukemia: a phase I study. Leukemia. 2013;27:1403–1407.
  • Ades L. A phase I-II study of the efficacy and safety of lenalidomide (LEN) combined to azacitidine (AZA) in higher risk MDS and AML with del 5q- – a study by the groupe francophone des myelodysplasies (GFM). Abstract 2892 presented at: ASH 57th Annual Meeting; 2015 Dec 5–8; Orlando, FL.
  • Sekeres MA, Tiu RV, Komrokji R, et al. Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood. 2012;120:4945–4951.
  • Narayan R, Garcia JS, Percival MM, et al. Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leuk Lymphoma. 2016;57:609–615.
  • DiNardo CD, Daver N, Jabbour E, et al. Sequential azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukemia: a single-arm, phase 1/2 study. Lancet Haematol. 2015;2:e12–e20.
  • Brierley CK, Steensma DP. Thrombopoiesis-stimulating agents and myelodysplastic syndromes. Br J Haematol. 2015;169:309–323.
  • Gabrilove J, Paquette R, Lyons RM, et al. Phase 2, single-arm trial to evaluate the effectiveness of darbepoetin alfa for correcting anaemia in patients with myelodysplastic syndromes. Br J Haematol. 2008;142:379–393.
  • Kelaidi C, Beyne-Rauzy O, Braun T, et al. High response rate and improved exercise capacity and quality of life with a new regimen of darbepoetin alfa with or without filgrastim in lower-risk myelodysplastic syndromes: a phase II study by the GFM. Ann Hematol. 2013;92:621–631.
  • Itzykson R, Thepot S, Beyne-Rauzy O, et al. Does addition of erythropoiesis stimulating agents improve the outcome of higher-risk myelodysplastic syndromes treated with azacitidine? Leuk Res. 2012;36:397–400.
  • Boehrer S, Beyne-Rauzy O, Prebet T, et al. Interim results of A randomized phase II trial of azacitidine (AZA) +/− epo in lower risk myelodysplastic syndrome (MDS) resistant to an erythropoietic stimulating agent (ESA) alone. Blood. 2010;116:784 (ASH Annual Meeting Abstracts).
  • Fili C, Malagola M, Follo MY, et al. Prospective phase II study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes. Clin Cancer Res. 2013;19:3297–3308.
  • 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:e189.
  • Greenberg PL, Garcia-Manero G, Moore M, et al. A randomized controlled trial of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving decitabine. Leuk Lymphoma. 2013;54:321–328.
  • Kantarjian HM, Giles FJ, Greenberg PL, et al. Phase 2 study of romiplostim in patients with low- or intermediate-risk myelodysplastic syndrome receiving azacitidine therapy. Blood. 2010;116:3163–3170.
  • Giagounidis A, Mufti GJ, Fenaux P, et al. Results of a randomized, double-blind study of romiplostim versus placebo in patients with low/intermediate-1-risk myelodysplastic syndrome and thrombocytopenia. Cancer. 2014;120:1838–1846.
  • Svensson T, Chowdhury O, Garelius H, et al. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine. Eur J Haematol. 2014;93:439–445.
  • Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared with placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): An international prospective randomized (rand) P-controlled double-blind trial (CALGB 10603/RATIFY [alliance]). Blood. 2015126:6.
  • Strati P, Kantarjian H, Ravandi F, et al. Phase I/II trial of the combination of midostaurin (PKC412) and 5-azacytidine for patients with acute myeloid leukemia and myelodysplastic syndrome. Am J Hematol. 2015;90:276–281.
  • Jilani I, Estey E, Huh Y, et al. Differences in CD33 intensity between various myeloid neoplasms. Am J Clin Pathol. 2002;118:560–566.
  • Laszlo GS, Estey EH, Walter RB. The past and future of CD33 as therapeutic target in acute myeloid leukemia. Blood Rev. 2014;28:143–153.
  • Sievers EL, Larson RA, Stadtmauer EA, et al. Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol. 2001;19:3244–3254.
  • Daver N, Kantarjian H, Ravandi F, et al. A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome. Leukemia. 2016;30:268–273.
  • Kung Sutherland MS, Walter RB, Jeffrey SC, et al. SGN-CD33A: A novel CD33-targeting antibody-drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug-resistant AML. Blood. 2013;122:1455–1463.
  • Fathi AT, Erba HP, Lancet JE, et al. SGN-CD33A plus hypomethylating agents: a novel, well-tolerated regimen with high remission rate in frontline unfit AML. Blood. 2015;126:454.
  • Hanaoka K, Suzuki M, Kobayashi T, et al. Antitumor activity and novel DNA-self-strand-breaking mechanism of CNDAC (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine) and its N4-palmitoyl derivative (CS-682). Int J Cancer. 1999;82:226–236.
  • Ravandi F, Kadia TM, Borthakur G, et al. Pooled analysis of elderly patients with newly diagnosed AML treated with sapacitabine and decitabine administered in alternating cycles. Blood. 2015;120:2630.
  • Athuluri-Divakar SK, Vasquez-Del Carpio R, Dutta K, et al. A small molecule RAS-mimetic disrupts RAS association with effector proteins to block signaling. Cell 2016;165:643–.655.
  • Garcia-Manero G, Fenaux P, Al-Kali A, et al. Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): A randomized, controlled, phase 3 trial. Lancet Oncol. 2016;17:496–508.
  • Navada SC, Garcia-Manero G, Wilhelm F, et al. A phase I/II study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Blood. 2014;124:3252.
  • Merchant A, Joseph G, Wang Q, et al. Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors. Blood. 2010;115:2391–2396.
  • Zou J, Hong Y, Tong Y, et al. Sonic hedgehog produced by bone marrow-derived mesenchymal stromal cells supports cell survival in myelodysplastic syndrome. Stem Cells Int. 2015;2015:957502.
  • Khan AA, Harrison CN, McLornan DP. Targeting of the hedgehog pathway in myeloid malignancies: still a worthy chase? Br J Haematol. 2015;170:323–335.
  • Tibes R, Al-Kali A, Oliver GR, et al. The hedgehog pathway as targetable vulnerability with 5-azacytidine in myelodysplastic syndrome and acute myeloid leukemia. J Hematol Oncol. 2015;8:114. 015-0211-8.
  • Tibes R, Kosiorek HE, Dueck AC, et al. Phase I/IB study of azacitidine and hedgehog pathway inhibition in myeloid malignancies. Blood. 2015;126:1347.
  • McKenney AS, Levine RL. Isocitrate dehydrogenase mutations in leukemia. J Clin Invest. 2013;123:3672–3677.
  • Jin J, Hu C, Yu M, et al. Prognostic value of isocitrate dehydrogenase mutations in myelodysplastic syndromes: a retrospective cohort study and meta-analysis. PLoS One 2014;9:e100206.
  • Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell. 2010;17:225–234.
  • Figueroa ME, Abdel-Wahab O, Lu C, et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell. 2010;18:553–567.
  • Losman JA, Looper RE, Koivunen P, et al. (R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible. Science. 2013;339:1621–1625.
  • DiNardo C, Stein E, Altman J, et al. AG-221, an oral, selective, first-in-class, potent inhibitor of the IDH2 mutant enzyme, induced durable responses in a phase 1 study of IDH2 mutation-positive advanced hematologic malignancies. Haematol eur hematol assoc annu meet 2015;100(s1):569 [abstr)]. Presented at: European Hematology Association Annual Meeting 2015;100(s1):569.
  • Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674.
  • Tamm I, Kornblau SM, Segall H, et al. Expression and prognostic significance of IAP-family genes in human cancers and myeloid leukemias. Clin Cancer Res. 2000;6:1796–1803.
  • Tamm I, Richter S, Scholz F, et al. XIAP expression correlates with monocytic differentiation in adult de novo AML: impact on prognosis. Hematol J. 2004;5:489–495.
  • Fulda S. Inhibitor of apoptosis (IAP) proteins in hematological malignancies: molecular mechanisms and therapeutic opportunities. Leukemia. 2014;28:1414–1422.
  • Schimmer AD, Estey EH, Borthakur G, et al. Phase I/II trial of AEG35156 X-linked inhibitor of apoptosis protein antisense oligonucleotide combined with idarubicin and cytarabine in patients with relapsed or primary refractory acute myeloid leukemia. J Clin Oncol. 2009;27:4741–4746.
  • Schimmer AD, Herr W, Hanel M, et al. Addition of AEG35156 XIAP antisense oligonucleotide in reinduction chemotherapy does not improve remission rates in patients with primary refractory acute myeloid leukemia in a randomized phase II study. Clin Lymphoma Myeloma Leuk. 2011;11:433–438.
  • Du C, Fang M, Li Y, et al. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.
  • Wu G, Chai J, Suber TL, et al. Structural basis of IAP recognition by smac/DIABLO. Nature. 2000;408:1008–1012.
  • Varfolomeev E, Blankenship JW, Wayson SM, et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007;131:669–681.
  • Steinhart L, Belz K, Fulda S. Smac mimetic and demethylating agents synergistically trigger cell death in acute myeloid leukemia cells and overcome apoptosis resistance by inducing necroptosis. Cell Death Dis. 2013;4:e802.
  • Carter BZ, Mak PY, Mak DH, et al. Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents. J Natl Cancer Inst. 2014;106:djt440.
  • Ritchie E, Agrawal A, Patel K, et al. A phase 2 study of brinipant in combination with 5-azacitidine in patient with myelodysplastic syndrome who are naive to 5-azacitidine: a preliminary analysis of phase 2a. Abstract 2904 presented at: ASH 57th Annual Meeting; 2015 Dec 5–8; Orlando, FL.
  • Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1 and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypomethylating agents. Leukemia. 2014;28:1280–1288.
  • Orskov AD, Treppendahl MB, Skovbo A, et al. Hypomethylation and up-regulation of PD-1 in T cells by azacytidine in MDS/AML patients: a rationale for combined targeting of PD-1 and DNA methylation. Oncotarget. 2015;6:9612–9626.
  • Atanackovic D, Luetkens T, Kloth B, et al. Cancer-testis antigen expression and its epigenetic modulation in acute myeloid leukemia. Am J Hematol. 2011;86:918–922.
  • Itzykson R, Kosmider O, Cluzeau T, et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia. 2011;25:1147–1152.
  • Emadi A, Faramand R, Carter-Cooper B, et al. Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia. Am J Hematol. 2015;90:E77–E79.
  • Prebet T, Gore SD, Esterni B, et al. Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol. 2011;29:3322–3327.
  • Papaemmanuil E, Gerstung M, Malcovati L, et al. Clinical and biological implications of driver mutations in myelodysplastic syndromes. Blood. 2013;122:3616–3627. quiz 3699.
  • Issa JP, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukemia: a multicentre, randomized, dose-escalation phase 1 study. Lancet Oncol. 2015;16:1099–1110.
  • Savona M. Results of first in human (FIH) phase 1 pharmacokinetic (PK) guided dose-escalation study of ASTX727, a combination of the oral cytidine deaminase inhibitor (CDAi) E7727 with oral decitabine in subjects with myelodysplastic syndrome (MDS). Abstract 1683 presented at: ASH 57th Annual Meeting; 2015 Dec 5–8; Orlando, FL.
  • Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the international working group (IWG) response criteria in myelodysplasia. Blood. 2006;108:419–425.
  • Cheson BD, Bennett JM, Kopecky KJ, et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–4649.

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