Predictive factors for response and survival in elderly acute myeloid leukemia patients treated with hypomethylating agents: a real-life experience.
Aged
Aged, 80 and over
Antimetabolites, Antineoplastic
/ therapeutic use
Azacitidine
/ therapeutic use
Bone Marrow
/ pathology
Cause of Death
Cell Count
DNA Methylation
/ drug effects
DNA, Neoplasm
/ chemistry
Decitabine
/ therapeutic use
Disease Progression
Disease-Free Survival
Female
Hemoglobins
/ analysis
Humans
Infections
/ etiology
Kaplan-Meier Estimate
Leukemia, Myeloid, Acute
/ drug therapy
Male
Middle Aged
Neoplastic Stem Cells
Proportional Hazards Models
Retrospective Studies
Treatment Outcome
Acute myeloid leukemia
Azacitidine
Decitabine
Hypomethylating agents
Real-life
Unfit patients
Journal
Annals of hematology
ISSN: 1432-0584
Titre abrégé: Ann Hematol
Pays: Germany
ID NLM: 9107334
Informations de publication
Date de publication:
Oct 2020
Oct 2020
Historique:
received:
28
05
2020
accepted:
10
08
2020
pubmed:
20
8
2020
medline:
2
10
2020
entrez:
20
8
2020
Statut:
ppublish
Résumé
Predictive factors of response to hypomethylating agents (HMA) in elderly acute myeloid leukemia (AML) patients remain unclear in the real-life setting and no direct comparison between azacitidine (AZA) and decitabine (DEC) has been carried out. We retrospectively evaluated 110 AML patients treated with HMA (78 AZA, 32 DEC) as first-line therapy outside of clinical trials. Median age was 75 years (range 58-87). The median overall survival (OS) of the entire cohort was 8.0 months (95% CI 6.1-10), without significant differences among the subgroups: AZA 8.8 months vs DEC 6.3 months (p = 0.291). HMA treatment yielded an overall response rate (ORR) of 40% (AZA 37% vs DEC 47%, p = 0.237). A stable disease (SD) after 4 HMA cycles was not associated with a worse survival outcome compared with an early optimal response. Factors independently associated with a better OS were transfusion independence during treatment (p = 0.049), achievement of an optimal response to treatment (p < 0.001), and a baseline hemoglobin level ≥ 9.25 (p = 0.018). A bone marrow (BM) blast count ≥ 30% (p < 0.001) and a therapy-related AML (p = 0.008) remain poor survival predictors. Of the available biologic features, an adverse risk category according to the ELN classification was significantly associated with a shorter survival over the intermediate risk category (p = 0.034). Disease progression remains the primary cause of death. Infectious complications were more severe (p = 0.036) and occurred earlier (p = 0.006) in the DEC group compared with that of the AZA group. In conclusion, clinical prognostic factors associated to response and survival have been identified without significant associations concerning overall outcomes between the two HMAs.
Identifiants
pubmed: 32813071
doi: 10.1007/s00277-020-04217-w
pii: 10.1007/s00277-020-04217-w
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
DNA, Neoplasm
0
Hemoglobins
0
Decitabine
776B62CQ27
Azacitidine
M801H13NRU
Types de publication
Comparative Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
2405-2416Références
Döhner H, Weisdorf DJ, Bloomfield CD (2015) Acute myeloid leukemia. N Engl J Med 373(12):1136–1152. https://doi.org/10.1056/NEJMra1406184
doi: 10.1056/NEJMra1406184
pubmed: 26376137
Acute myeloid leukemia - Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/amyl.html . Accessed 15 February 2020
Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR (2013) Outcome of older patients with acute myeloid leukemia: an analysis of SEER data over 3 Decades. Cancer. 119(15):2720–2727. https://doi.org/10.1002/cncr.28129
doi: 10.1002/cncr.28129
pubmed: 23633441
Appelbaum FR, Gundacker H, Head DR, Slovak ML, Willman CL, Godwin JE, Anderson JE, Petersdorf SH (2006) Age and acute myeloid leukemia. Blood. 107(9):3481–3485. https://doi.org/10.1182/blood-2005-09-3724
doi: 10.1182/blood-2005-09-3724
pubmed: 16455952
pmcid: 1895766
Prassek VV, Rothenberg-Thurley M, Sauerland MC, Herold T, Janke H, Ksienzyk B (2018) Genetics of acute myeloid leukemia in the elderly: mutation spectrum and clinical impact in intensively treated patients aged 75 years or older. Haematologica. 103(11):1853–1861. https://doi.org/10.3324/haematol.2018.191536
doi: 10.3324/haematol.2018.191536
pubmed: 29903761
pmcid: 6278991
Pleyer L, Greil R (2015) Digging deep into “dirty” drugs - modulation of the methylation machinery. Drug Metab Rev 47(2):252–279. https://doi.org/10.3109/03602532.2014.995379
doi: 10.3109/03602532.2014.995379
pubmed: 25566693
pmcid: 4733942
Herman JG, Baylin SB (2003) Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349(21):2042–2054. https://doi.org/10.1056/NEJMra023075
doi: 10.1056/NEJMra023075
pubmed: 14627790
Derissen EJB, Beijnen JH, Schellens JHM (2013) Concise drug review: azacitidine and decitabine. Oncologist. 18(5):619–624. https://doi.org/10.1634/theoncologist.2012-0465
doi: 10.1634/theoncologist.2012-0465
pubmed: 23671007
pmcid: 3662854
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 C, Silverman LR, International Vidaza High-Risk MDS Survival Study Group (2009) Efficacy of AZA compared with conventional care regimens in the treatment of higher-risk MDS. Lancet Oncol 10(3):223–232. https://doi.org/10.1016/S1470-2045(09)70003-8
doi: 10.1016/S1470-2045(09)70003-8
pubmed: 19230772
pmcid: 4086808
Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, Sanz G, List AF, Gore S, Seymour JF, Dombret H, Backstrom J, Zimmerman L, McKenzie D, Beach CL, Silverman LR (2010) Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 28(4):562–569. https://doi.org/10.1200/JCO.2009.23.8329
doi: 10.1200/JCO.2009.23.8329
pubmed: 20026804
Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Récher C, Sandhu I, Bernal del Castillo T, al-Ali HK, Martinelli G, Falantes J, Noppeney R, Stone RM, Minden MD, McIntyre H, Songer S, Lucy LM, Beach CL, Döhner H (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with >30% blasts. Blood. 126(3):291–299. https://doi.org/10.1182/blood-2015-01-621664
doi: 10.1182/blood-2015-01-621664
pubmed: 25987659
pmcid: 4504945
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 (2012) 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 30(21):2670–2677. https://doi.org/10.1200/JCO.2011.38.9429
doi: 10.1200/JCO.2011.38.9429
pubmed: 22689805
pmcid: 4874148
Al-Ali HK, Jaekel N, Niederwieser D (2014) The role of hypomethylating agents in the treatment of elderly patients with AML. J Geriatr Oncol 5(1):89–105. https://doi.org/10.1016/j.jgo.2013.08.004
doi: 10.1016/j.jgo.2013.08.004
pubmed: 24484723
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW (2016) The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 127(20):2391–2405. https://doi.org/10.1182/blood-2016-03-643544
doi: 10.1182/blood-2016-03-643544
pubmed: 27069254
Charlson ME, Pompei P, Ales KL, MacKenzie CR (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40(5):373–383. https://doi.org/10.1016/0021-9681(87)90171-8
doi: 10.1016/0021-9681(87)90171-8
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612. https://doi.org/10.7326/0003-4819-150-9-200905050-00006
doi: 10.7326/0003-4819-150-9-200905050-00006
pubmed: 19414839
pmcid: 19414839
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, Bloomfield CD (2017) Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 129(4):424–447. https://doi.org/10.1182/blood-2016-08-733196
doi: 10.1182/blood-2016-08-733196
pubmed: 27895058
pmcid: 5291965
National Cancer Institute, Division of Cancer Treatment & Diagnosis (2017) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | Protocol Development | CTEP. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm . Accessed 16 February 2020
Thépot S, Itzykson R, Seegers V, Recher C, Raffoux E, Quesnel B, Delaunay J, Cluzeau T, Marfaing Koka A, Stamatoullas A, Chaury MP, Dartigeas C, Cheze S, Banos A, Morel P, Plantier I, Taksin AL, Marolleau JP, Pautas C, Thomas X, Isnard F, Beve B, Chait Y, Guerci A, Vey N, Dreyfus F, Ades L, Ifrah N, Dombret H, Fenaux P, Gardin C, On behalf of the Groupe Francophone des Myélodysplasies (GFM), the Acute Leukemia French Association (ALFA); the Groupe Ouest-Est des Leucémies Aiguës; Maladies du Sang (GOELAMS) (2014) Azacitidine in untreated acute myeloid leukemia: a report on 149 patients. Am J Hematol 89(4):410–416. https://doi.org/10.1002/ajh.23654
doi: 10.1002/ajh.23654
pubmed: 24375487
Ramos F, Thépot S, Pleyer L, Maurillo L, Itzykson R, Bargay J, Stauder R, Venditti A, Seegers V, Martínez-Robles V, Burgstaller S, Récher C, Debén G, Gaidano G, Gardin C, Musto P, Greil R, Sánchez-Guijo F, Fenaux P, European ALMA Investigators (2015) Azacitidine frontline therapy for unfit acute myeloid leukemia patients: clinical use and outcome prediction. Leuk Res 39(3):296–306. https://doi.org/10.1016/j.leukres.2014.12.013
doi: 10.1016/j.leukres.2014.12.013
pubmed: 25601157
Falantes J, Pleyer L, Thépot S, Almeida AM, Maurillo L, Martínez-Robles V, Stauder R, Itzykson R, Pinto R, Venditti A, Bargay J, Burgstaller S, Martínez MP, Seegers V, Cortesão E, Foncillas MÁ, Gardin C, Montesinos P, Musto P, Fenaux P, Greil R, Sanz MA, Ramos F, for the European ALMA + Investigators (2018) Real life experience with frontline azacitidine in a large series of older adults with acute myeloid leukemia stratified by MRC/LRF score: results from the expanded international E-ALMA series (E-ALMA+). Leuk Lymphoma 59(5):1113–1120. https://doi.org/10.1080/10428194.2017.1365854
doi: 10.1080/10428194.2017.1365854
pubmed: 28838276
Quintás-Cardama A, Ravandi F, Liu-Dumlao T, Brandt M, Faderl S, Pierce S, Borthakur G, Garcia-Manero G, Cortes J, Kantarjian H (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood. 120(24):4840–4845. https://doi.org/10.1182/blood-2012-06-436055
doi: 10.1182/blood-2012-06-436055
pubmed: 23071272
pmcid: 3952725
Filì C, Candoni A, Zannier ME, Olivieri J, Imbergamo S, Caizzi M, Nadali G, di Bona E, Ermacora A, Gottardi M, Facchinelli D, Ciancia R, Lazzarotto D, Dubbini MV, Festini G, Gherlinzoni F, Michieli MG, Semenzato G, Fanin R (2019) Efficacy and toxicity of Decitabine in patients with acute myeloid leukemia (AML): a multicenter real-world experience. Leuk Res 76:33–38. https://doi.org/10.1016/j.leukres.2018.11.015
doi: 10.1016/j.leukres.2018.11.015
pubmed: 30529681
Bocchia M, Candoni A, Borlenghi E, Defina M, Filì C, Cattaneo C, Sammartano V, Fanin R, Sciumè M, Sicuranza A, Imbergamo S, Riva M, Fracchiolla N, Latagliata R, Caizzi E, Mazziotta F, Alunni G, di Bona E, Crugnola M, Rossi M, Consoli U, Fontanelli G, Greco G, Nadali G, Rotondo F, Todisco E, Bigazzi C, Capochiani E, Molteni A, Bernardi M, Fumagalli M, Rondoni M, Scappini B, Ermacora A, Simonetti F, Gottardi M, Lambertenghi Deliliers D, Michieli M, Basilico C, Galeone C, Pelucchi C, Rossi G (2019) Real-world experience with decitabine as a first-line treatment in 306 elderly acute myeloid leukaemia patients unfit for intensive chemotherapy. Hematol Oncol 37(4):447–455. https://doi.org/10.1002/hon.2663
doi: 10.1002/hon.2663
pubmed: 31385337
Tawfik B, Sliesoraitis S, Lyerly S, Klepin HD, Lawrence J, Isom S, Ellis LR, Manuel M, Dralle S, Berenzon D, Powell BL, Pardee T (2014) Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML). Ann Hematol 93(1):47–55. https://doi.org/10.1007/s00277-013-1940-9
doi: 10.1007/s00277-013-1940-9
pubmed: 24149914
Pleyer L, Burgstaller S, Girschikofsky M, Linkesch W, Stauder R, Pfeilstocker M, Schreder M, Tinchon C, Sliwa T, Lang A, Sperr WR, Krippl P, Geissler D, Voskova D, Schlick K, Thaler J, Machherndl-Spandl S, Theiler G, Eckmüllner O, Greil R (2014) Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group. Ann Hematol 93(11):1825–1838. https://doi.org/10.1007/s00277-014-2126-9
doi: 10.1007/s00277-014-2126-9
pubmed: 24951123
pmcid: 4176957
Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, Lunghi M, D’Arco AM, Levis A, Pastore D, Di Renzo N, Santagostino A, Pavone V, Buccisano F, Musto P (2012) Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer. 118(4):1014–1022. https://doi.org/10.1002/cncr.26354
doi: 10.1002/cncr.26354
pubmed: 21761399
Bernal T, Martínez-Camblor P, Sánchez-García J, de Paz R, Luño E, Nomdedeu B, Ardanaz MT, Pedro C, Amigo ML, Xicoy B, del Cañizo C, Tormo M, Bargay J, Valcárcel D, Brunet S, Benlloch L, Sanz G, Spanish Group on Myelodysplastic Syndromes; PETHEMA Foundation; Spanish Society of Hematology (2015) Effectiveness of azacitidine in unselected high-risk myelodysplastic syndromes: results from the Spanish registry. Leukemia. 29(9):1875–1881. https://doi.org/10.1038/leu.2015.115
doi: 10.1038/leu.2015.115
pubmed: 25943181
Lübbert M, Rüter BH, Claus R, Schmoor C, Schmid M, Germing U et al (2012) A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy. Haematologica. 97(3):393–401. https://doi.org/10.3324/haematol.2011.048231
doi: 10.3324/haematol.2011.048231
pubmed: 22058219
pmcid: 3291594
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 (2016) TP53 and decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. N Engl J Med 375(21):2023–2036. https://doi.org/10.1056/NEJMoa1605949
doi: 10.1056/NEJMoa1605949
pubmed: 27959731
pmcid: 5217532
Wierzbowska A, Wawrzyniak E, Pluta A, Robak T, Mazur GJ, Dmoszynska A, Cermak J, Oriol A, Lysak D6, Arthur C, Doyle M, Xiu L, Ravandi F, Kantarjian HM (2018) 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 93(5):E125–E127. https://doi.org/10.1002/ajh.25062
doi: 10.1002/ajh.25062
pubmed: 29417613
Gavillet M, Noetzli J, Blum S, Duchosal MA, Spertini O, Lambert JF (2012) Transfusion independence and survival in patients with acute myeloid leukemia treated with 5-azacytidine. Haematologica. 97(12):1929–1931. https://doi.org/10.3324/haematol.2012.065151
doi: 10.3324/haematol.2012.065151
pubmed: 22875616
pmcid: 3590099
He J, Xiu L, De Porre P, Dass R, Thomas X (2015) 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 56(4):1033–1042. https://doi.org/10.3109/10428194.2014.951845
doi: 10.3109/10428194.2014.951845
pubmed: 25098427
Pagano L, Busca A, Candoni A, Criscuolo M, Giovanni Della Porta M, Fianchi L, Lessi F, Marchesi F, Teresa Voso M (2018) Risk of infection in elderly patients with AML and MDS treated with hypomethylating agents. Acta Biomed 89(Suppl 11):5–39. https://doi.org/10.23750/abm.v89i11-S.7988
doi: 10.23750/abm.v89i11-S.7988
Imbergamo S, Visentin A, Kostic I, Pravato S, Scomazzon E, Laurino M, Binotto G, Lessi F, Berno T, Gurrieri C, Semenzato G, Trentin L (2018) Azacitidine or decitabine frontline therapy for acute myeloid leukemia in elderly patients? EHA Open Access Library 06/14/18; Abstract 216256; PB1741 https://library.ehaweb.org/eha/2018/stockholm/216256/silvia.imbergamo.azacitidine.or.decitabine.frontline.therapy.for.acute.myeloid.html?f = menu = 14*media = 3*speaker = 664538.
Mehra M, He J, Potluri R, Loefgren C (2017) Utilization of hypomethylating agents and associated outcomes in elderly Acute Myeloid Leukemia (AML) patients: a population based study. Blood 130(Supplement 1):2157–2157. https://doi.org/10.1182/BLOOD.V130.SUPPL_1.2157.2157
doi: 10.1182/BLOOD.V130.SUPPL_1.2157.2157
Ebaid A, Cingam S, Boyce T, Babu D, Liu Q, Win K, Arana Yi C (2019) Comparative analysis for effectiveness of azacitidine versus decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes with marrow fibrosis: a single institution experience. Blood 134(Supplement_1):5099. https://doi.org/10.1182/blood-2019-131881
doi: 10.1182/blood-2019-131881
Smith BD, Beach CL, Mahmoud D, Weber L, Henk HJ (2014) Survival and hospitalization among patients with acute myeloid leukemia treated with azacitidine or decitabine in a large managed care population: a real-world, retrospective, claims-based, comparative analysis. Exp Hematol Oncol 3(1):10. https://doi.org/10.1186/2162-3619-3-10
doi: 10.1186/2162-3619-3-10
pubmed: 24666795
pmcid: 3994315
Talati C, Kuykendall A, Al-Ali N, Komrokji R, Padron E, Sallman D, List A, Sweet K, Extermann M, Lancet J (2017) Improved responses with azacitidine compared to decitabine in patients with acute myeloid leukemia in patients ≥70 with poor-risk cytogenetics. Clin Lymphoma Myeloma Leuk 17:S295. https://doi.org/10.1016/j.clml.2017.07.085
doi: 10.1016/j.clml.2017.07.085
Zeidan A, Wang R, Wang X, Shallis R, Podoltsev N, Bewersdorf JP, Huntington S, Neparidze N, Giri S, Gore S, Davidoff A, Ma X (2019) Clinical outcomes of older patients (pts) with acute myeloid leukemia (AML) receiving hypomethylating agents (HMAs): a large population-based study in the United States. Blood 134(Supplement_1):646–646. https://doi.org/10.1182/blood-2019-127398
doi: 10.1182/blood-2019-127398