The Clinical Value of Decitabine Monotherapy in Patients with Acute Myeloid Leukemia.
Acute myeloid leukemia
Decitabine
Elderly
HMAs
Hypomethylating agents
Journal
Advances in therapy
ISSN: 1865-8652
Titre abrégé: Adv Ther
Pays: United States
ID NLM: 8611864
Informations de publication
Date de publication:
04 2022
04 2022
Historique:
received:
20
08
2021
accepted:
06
10
2021
pubmed:
18
11
2021
medline:
12
4
2022
entrez:
17
11
2021
Statut:
ppublish
Résumé
Decitabine (5-aza-2'-deoxycytidine) is a hypomethylating agent used in the treatment of acute myeloid leukemia (AML). Decitabine inhibits DNA methyltransferases, causing DNA hypomethylation, and leading amongst others to re-expression of silenced tumor suppressor genes. Decitabine is indicated for the treatment of adult patients with newly diagnosed de novo or secondary AML who are not eligible for standard induction chemotherapy. The initial authorization in 2012 was based on the results of the open-label, randomized, multicenter phase 3 DACO-016 trial, and supported by data from the supportive phase 2 open-label DACO-017 trial. Compared with standard care, decitabine significantly improved overall survival, event-free survival, progression-free survival, and response rate. Decitabine was generally well tolerated, offering a valuable treatment option in patients with AML irrespective of age, especially for patients achieving a complete response. Several observational "real-life" studies confirmed these results. In contrast to standard chemotherapy, the presence of adverse-risk karyotypes or TP53 mutations does not negatively impact sensitivity to hypomethylating therapy albeit with lower durability. Data suggest a potential positive effect of decitabine in patients with monosomal karyotype-positive AML. For the time being, decitabine is an appropriate option as monotherapy for patients with AML who are unfit to receive more intensive combination therapies, but emerging data suggest that decitabine-based doublet or triplet combinations may be future treatment options for patients with AML.
Identifiants
pubmed: 34786648
doi: 10.1007/s12325-021-01948-8
pii: 10.1007/s12325-021-01948-8
pmc: PMC8989816
doi:
Substances chimiques
Decitabine
776B62CQ27
DNA
9007-49-2
Azacitidine
M801H13NRU
Types de publication
Journal Article
Review
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
1474-1488Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
Références
National Cancer Institute Surveillance EaERP. SEER Cancer Statistics Review (CSR) 1975–2017: Leukemia. U.S. Department of Health and Human Services. 2021. https://seer.cancer.gov/archive/csr/1975_2017/browse_csr.php?sectionSEL=13&pageSEL=sect_13_table.16 . Accessed 5 Mar 2021.
Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological malignancies. Ann Oncol. 2007;18(Suppl 1):i3–8. https://doi.org/10.1093/annonc/mdl443 .
doi: 10.1093/annonc/mdl443
pubmed: 17311819
Sant M, Allemani C, Tereanu C, et al. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116(19):3724–34. https://doi.org/10.1182/blood-2010-05-282632 .
doi: 10.1182/blood-2010-05-282632
pubmed: 20664057
Juliusson G, Lazarevic V, Horstedt AS, Hagberg O, Hoglund M, Swedish Acute Leukemia Registry Group. Acute myeloid leukemia in the real world: why population-based registries are needed. Blood. 2012;119(17):3890–9. https://doi.org/10.1182/blood-2011-12-379008 .
doi: 10.1182/blood-2011-12-379008
pubmed: 22383796
pmcid: 3358248
Lang K, Earle CC, Foster T, Dixon D, Van Gool R, Menzin J. Trends in the treatment of acute myeloid leukaemia in the elderly. Drugs Aging. 2005;22(11):943–55. https://doi.org/10.2165/00002512-200522110-00004 .
doi: 10.2165/00002512-200522110-00004
pubmed: 16323971
Shah A, Andersson TM, Rachet B, Bjorkholm M, Lambert PC. Survival and cure of acute myeloid leukaemia in England, 1971–2006: a population-based study. Br J Haematol. 2013;162(4):509–16. https://doi.org/10.1111/bjh.12425 .
doi: 10.1111/bjh.12425
pubmed: 23786647
Dohner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424–47. https://doi.org/10.1182/blood-2016-08-733196 .
doi: 10.1182/blood-2016-08-733196
pubmed: 27895058
pmcid: 5291965
Byrd JC, Mrozek K, Dodge RK, et al. 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(13):4325–36. https://doi.org/10.1182/blood-2002-03-0772 .
doi: 10.1182/blood-2002-03-0772
pubmed: 12393746
De Angelis R, Minicozzi P, Sant M, et al. Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000–2007: results of EUROCARE-5 population-based study. Eur J Cancer. 2015;51(15):2254–68. https://doi.org/10.1016/j.ejca.2015.08.003 .
doi: 10.1016/j.ejca.2015.08.003
pubmed: 26421827
Heuser M, Ofran Y, Boissel N, et al. Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(6):697–712. https://doi.org/10.1016/j.annonc.2020.02.018 .
doi: 10.1016/j.annonc.2020.02.018
pubmed: 32171751
Grimwade D, Walker H, Harrison G, et al. The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood. 2001;98(5):1312–20. https://doi.org/10.1182/blood.v98.5.1312 .
doi: 10.1182/blood.v98.5.1312
pubmed: 11520776
de Vos D, van Overveld W. Decitabine: a historical review of the development of an epigenetic drug. Ann Hematol. 2005;84(Suppl 1):3–8. https://doi.org/10.1007/s00277-005-0008-x .
doi: 10.1007/s00277-005-0008-x
pubmed: 16220311
pmcid: 7103145
Contieri B, Duarte BKL, Lazarini M. Updates on DNA methylation modifiers in acute myeloid leukemia. Ann Hematol. 2020;99(4):693–701. https://doi.org/10.1007/s00277-020-03938-2 .
doi: 10.1007/s00277-020-03938-2
pubmed: 32025842
Momparler RL. Molecular, cellular and animal pharmacology of 5-aza-2’-deoxycytidine. Pharmacol Ther. 1985;30(3):287–99. https://doi.org/10.1016/0163-7258(85)90053-1 .
doi: 10.1016/0163-7258(85)90053-1
pubmed: 2433703
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(4):556–61. https://doi.org/10.1200/JCO.2009.23.9178 .
doi: 10.1200/JCO.2009.23.9178
pubmed: 20026803
Kantarjian HM, Thomas XG, Dmoszynska A, et al. 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(21):2670–7. https://doi.org/10.1200/JCO.2011.38.9429 .
doi: 10.1200/JCO.2011.38.9429
pubmed: 22689805
pmcid: 4874148
Nieto M, Demolis P, Behanzin E, et al. The European Medicines Agency Review of Decitabine (Dacogen) for the treatment of adult patients with acute myeloid leukemia: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2016;21(6):692–700. https://doi.org/10.1634/theoncologist.2015-0298 .
doi: 10.1634/theoncologist.2015-0298
pubmed: 27091416
pmcid: 4912358
Tomeczkowski J, Lange A, Guntert A, et al. Converging or crossing curves: untie the Gordian knot or cut it? Appropriate statistics for non-proportional hazards in decitabine DACO-016 study (AML). Adv Ther. 2015;32(9):854–62. https://doi.org/10.1007/s12325-015-0238-9 .
doi: 10.1007/s12325-015-0238-9
pubmed: 26369324
pmcid: 4604504
Mayer J, Arthur C, Delaunay J, et al. Multivariate and subgroup analyses of a randomized, multinational, phase 3 trial of decitabine vs treatment choice of supportive care or cytarabine in older patients with newly diagnosed acute myeloid leukemia and poor- or intermediate-risk cytogenetics. BMC Cancer. 2014;14:69. https://doi.org/10.1186/1471-2407-14-69 .
doi: 10.1186/1471-2407-14-69
pubmed: 24498872
pmcid: 3928608
He J, Xiu L, De Porre P, Dass R, Thomas X. Decitabine reduces transfusion dependence in older patients with acute myeloid leukemia: results from a post hoc analysis of a randomized phase III study. Leuk Lymphoma. 2015;56(4):1033–42. https://doi.org/10.3109/10428194.2014.951845 .
doi: 10.3109/10428194.2014.951845
pubmed: 25098427
Kadia TM, Thomas XG, Dmoszynska A, et al. Decitabine improves outcomes in older patients with acute myeloid leukemia and higher blast counts. Am J Hematol. 2015;90(7):E139–41. https://doi.org/10.1002/ajh.24036 .
doi: 10.1002/ajh.24036
pubmed: 25858582
pmcid: 4478207
European Medicines Agency. Dacogen (decitabine): Summary of Product Characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/dacogen-epar-product-information_en.pdf . Accessed 5 Mar 2021.
Meers S, Bailly B, Vande Broek I, et al. Real-world data confirming the efficacy and safety of decitabine in acute myeloid leukaemia—results from a retrospective Belgian registry study. Acta Clin Belg. 2021;76(2):98–105. https://doi.org/10.1080/17843286.2019.1665233 .
doi: 10.1080/17843286.2019.1665233
pubmed: 31551014
Bocchia M, Candoni A, Borlenghi E, et al. Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy. Hematol Oncol. 2019;37(4):447–55. https://doi.org/10.1002/hon.2663 .
doi: 10.1002/hon.2663
pubmed: 31385337
Zeidan AM, Wang R, Wang X, et al. Clinical outcomes of older patients with AML receiving hypomethylating agents: a large population-based study in the United States. Blood Adv. 2020;4(10):2192–201. https://doi.org/10.1182/bloodadvances.2020001779 .
doi: 10.1182/bloodadvances.2020001779
pubmed: 32433746
pmcid: 7252544
Fili C, Candoni A, Zannier ME, et al. Efficacy and toxicity of decitabine in patients with acute myeloid leukemia (AML): a multicenter real-world experience. Leuk Res. 2019;76:33–8. https://doi.org/10.1016/j.leukres.2018.11.015 .
doi: 10.1016/j.leukres.2018.11.015
pubmed: 30529681
Shivarov V, Bullinger L. Expression profiling of leukemia patients: key lessons and future directions. Exp Hematol. 2014;42(8):651–60. https://doi.org/10.1016/j.exphem.2014.04.006 .
doi: 10.1016/j.exphem.2014.04.006
pubmed: 24746875
Cancer Genome Atlas Research Network, Ley TJ, Miller C, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059–74. https://doi.org/10.1056/NEJMoa1301689 .
doi: 10.1056/NEJMoa1301689
Dohner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373(12):1136–52. https://doi.org/10.1056/NEJMra1406184 .
doi: 10.1056/NEJMra1406184
pubmed: 26376137
Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med. 2010;363(25):2424–33. https://doi.org/10.1056/NEJMoa1005143 .
doi: 10.1056/NEJMoa1005143
pubmed: 21067377
pmcid: 3201818
Yan XJ, Xu J, Gu ZH, et al. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011;43(4):309–15. https://doi.org/10.1038/ng.788 .
doi: 10.1038/ng.788
pubmed: 21399634
Bullinger L, Dohner K, Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol. 2017;35(9):934–46. https://doi.org/10.1200/JCO.2016.71.2208 .
doi: 10.1200/JCO.2016.71.2208
pubmed: 28297624
Ni J, Hong J, Long Z, Li Q, Xia R, Zeng Q. Mutation profile and prognostic relevance in elderly patients with de novo acute myeloid leukemia treated with decitabine-based chemotherapy. Int J Lab Hematol. 2020;42(6):849–57. https://doi.org/10.1111/ijlh.13299 .
doi: 10.1111/ijlh.13299
pubmed: 32730663
Fernandez-Pol S, Ma L, Ohgami RS, Arber DA. Immunohistochemistry for p53 is a useful tool to identify cases of acute myeloid leukemia with myelodysplasia-related changes that are TP53 mutated, have complex karyotype, and have poor prognosis. Mod Pathol. 2017;30(3):382–92. https://doi.org/10.1038/modpathol.2016.206 .
doi: 10.1038/modpathol.2016.206
pubmed: 27934876
McGraw KL, Nguyen J, Komrokji RS, et al. Immunohistochemical pattern of p53 is a measure of TP53 mutation burden and adverse clinical outcome in myelodysplastic syndromes and secondary acute myeloid leukemia. Haematologica. 2016;101(8):e320–3. https://doi.org/10.3324/haematol.2016.143214 .
doi: 10.3324/haematol.2016.143214
pubmed: 27081179
pmcid: 4967580
Blum W, Garzon R, Klisovic RB, et al. Clinical response and miR-29b predictive significance in older AML patients treated with a 10-day schedule of decitabine. Proc Natl Acad Sci U S A. 2010;107(16):7473–8. https://doi.org/10.1073/pnas.1002650107 .
doi: 10.1073/pnas.1002650107
pubmed: 20368434
pmcid: 2867720
Welch JS, Petti AA, Miller CA, et al. TP53 and decitabine in acute myeloid leukemia and myelodysplastic syndromes. N Engl J Med. 2016;375(21):2023–36. https://doi.org/10.1056/NEJMoa1605949 .
doi: 10.1056/NEJMoa1605949
pubmed: 27959731
pmcid: 5217532
Becker H, Pfeifer D, Ihorst G, et al. Monosomal karyotype and chromosome 17p loss or TP53 mutations in decitabine-treated patients with acute myeloid leukemia. Ann Hematol. 2020;99(7):1551–60. https://doi.org/10.1007/s00277-020-04082-7 .
doi: 10.1007/s00277-020-04082-7
pubmed: 32504186
pmcid: 7316846
Middeke JM, Teipel R, Rollig C, et al. Decitabine treatment in 311 patients with acute myeloid leukemia: outcome and impact of TP53 mutations—a registry based analysis. Leuk Lymphoma. 2021;62(6):1432–40. https://doi.org/10.1080/10428194.2020.1864354 .
doi: 10.1080/10428194.2020.1864354
pubmed: 33399480
Wierzbowska A, Wawrzyniak E, Pluta A, et al. Decitabine improves response rate and prolongs progression-free survival in older patients with newly diagnosed acute myeloid leukemia and with monosomal karyotype: a subgroup analysis of the DACO-016 trial. Am J Hematol. 2018;93(5):E125–7. https://doi.org/10.1002/ajh.25062 .
doi: 10.1002/ajh.25062
pubmed: 29417613
Wierzbowska A, Wawrzyniak E, Siemieniuk-Rys M, et al. Concomitance of monosomal karyotype with at least 5 chromosomal abnormalities is associated with dismal treatment outcome of AML patients with complex karyotype—retrospective analysis of Polish Adult Leukemia Group (PALG). Leuk Lymphoma. 2017;58(4):889–97. https://doi.org/10.1080/10428194.2016.1219901 .
doi: 10.1080/10428194.2016.1219901
pubmed: 27561449
Lubbert M, Ruter BH, Claus R, et al. A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 2012;97(3):393–401. https://doi.org/10.3324/haematol.2011.048231 .
doi: 10.3324/haematol.2011.048231
pubmed: 22058219
pmcid: 3291594
Lubbert M, Suciu S, Hagemeijer A, et al. Decitabine improves progression-free survival in older high-risk MDS patients with multiple autosomal monosomies: results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group. Ann Hematol. 2016;95(2):191–9. https://doi.org/10.1007/s00277-015-2547-0 .
doi: 10.1007/s00277-015-2547-0
pubmed: 26596971
Greve G, Schuler J, Gruning BA, et al. Decitabine induces gene derepression on monosomic chromosomes: in vitro and in vivo effects in adverse-risk cytogenetics AML. Cancer Res. 2021;81(4):834–46. https://doi.org/10.1158/0008-5472.CAN-20-1430 .
doi: 10.1158/0008-5472.CAN-20-1430
pubmed: 33203699
Stomper J, Lubbert M. Can we predict responsiveness to hypomethylating agents in AML? Semin Hematol. 2019;56(2):118–24. https://doi.org/10.1053/j.seminhematol.2019.02.001 .
doi: 10.1053/j.seminhematol.2019.02.001
pubmed: 30926087
Stomper J, Rotondo JC, Greve G, Lubbert M. Hypomethylating agents (HMA) for the treatment of acute myeloid leukemia and myelodysplastic syndromes: mechanisms of resistance and novel HMA-based therapies. Leukemia. 2021. https://doi.org/10.1038/s41375-021-01218-0 .
doi: 10.1038/s41375-021-01218-0
pubmed: 33958699
pmcid: 8257497
Lubbert M, Ihorst G, Sander PN, et al. Elevated fetal haemoglobin is a predictor of better outcome in MDS/AML patients receiving 5-aza-2’-deoxycytidine (Decitabine). Br J Haematol. 2017;176(4):609–17. https://doi.org/10.1111/bjh.14463 .
doi: 10.1111/bjh.14463
pubmed: 27905102
Stomper J, Ihorst G, Suciu S, et al. Fetal hemoglobin induction during decitabine treatment of elderly patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: a potential dynamic biomarker of outcome. Haematologica. 2019;104(1):59–69. https://doi.org/10.3324/haematol.2017.187278 .
doi: 10.3324/haematol.2017.187278
pubmed: 30171030
pmcid: 6312014
Zhao C, Jia B, Wang M, et al. Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML. Br J Haematol. 2020;188(5):674–84. https://doi.org/10.1111/bjh.16228 .
doi: 10.1111/bjh.16228
pubmed: 31573077
Oellerich T, Schneider C, Thomas D, et al. Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML. Nat Commun. 2019;10(1):3475. https://doi.org/10.1038/s41467-019-11413-4 .
doi: 10.1038/s41467-019-11413-4
pubmed: 31375673
pmcid: 6677770
Yan P, Frankhouser D, Murphy M, et al. Genome-wide methylation profiling in decitabine-treated patients with acute myeloid leukemia. Blood. 2012;120(12):2466–74. https://doi.org/10.1182/blood-2012-05-429175 .
doi: 10.1182/blood-2012-05-429175
pubmed: 22786882
pmcid: 3448258
DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7–17. https://doi.org/10.1182/blood-2018-08-868752 .
doi: 10.1182/blood-2018-08-868752
pubmed: 30361262
pmcid: 6318429
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(2):185–93. https://doi.org/10.1111/bjh.13016 .
doi: 10.1111/bjh.13016
pubmed: 25040094
Lubbert M, Grishina O, Schmoor C, et al. Valproate and retinoic acid in combination with decitabine in elderly nonfit patients with acute myeloid leukemia: results of a multicenter, randomized, 2 × 2, phase II trial. J Clin Oncol. 2020;38(3):257–70. https://doi.org/10.1200/JCO.19.01053 .
doi: 10.1200/JCO.19.01053
pubmed: 31794324
Brunner AM, Esteve J, Porkka K, et al. Efficacy and safety of sabatolimab (MBG453) in combination with hypomethylating agents in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome: updated results from a phase Ib study. In: 63rd annual meeting of the American Society of Hematology. 2020.
Wei AH, Montesinos P, Ivanov V, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial. Blood. 2020;135(24):2137–45. https://doi.org/10.1182/blood.2020004856 .
doi: 10.1182/blood.2020004856
pubmed: 32219442
pmcid: 7290090