Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia
The present observational study aimed to compare the efficacy of azacitidine (AZA) and intensive chemotherapy (IC) in elderly patients with untreated acute myeloid leukemia (AML), diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS), and disease-free survival (DFS). The AZA group included 89 patients; median age was 73 years (range 61–80) and median white blood cell count (WBCc) 2.5 × 109/L (range 0.27–83), 45% of the patients had BM blasts ≥ 30%, and 44 (49%) had a secondary AML (sAML). Karyotype was evaluable in 69 patients: 51 (74%) had intermediate-risk abnormalities and 18 (26%) an unfavorable risk karyotype. IC group consisted of 110 patients who received an induction course with mitoxantrone, cytarabine, and etoposide, followed by two consolidation cycles including idarubicin, cytarabine, and etoposide. Median age was 67 years (range 61–78) and median WBCc 8.0 × 109/L (range 0.69–258); 44 (40%) had a sAML. Karyotype was evaluable in 88 patients, 71 (81%) had intermediate risk, and 17 (19%) unfavorable risk karyotype. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 74 patient pairs. CR rate was significantly higher in IC vs AZA group (73 vs 25%, respectively) (p < 0.0001), but the 3-year OS rates and median OS were not significantly different (21.6 vs 11% and 15.8 vs 13 months, respectively). Our analysis suggests similar outcomes with AZA compared to IC. Controlled, randomized clinical trials are warranted to confirm this conclusion.
KeywordsAcute myeloid leukemia Intensive chemotherapy Azacitidine Elderly
FB and MTV designed research, analyzed and interpreted data.
AS performed statistical analysis.
LF, CP, MB, EDB, ML, FL, and MIDP collected and interpreted data.
MTV, PM, GLG, and GM revised the manuscript.
LM and AV designed research, analyzed and interpreted data, wrote and revised manuscript.
Compliance with ethical standards
All patients or their guardians provided written informed consent to allow collection of personal data in accordance with the Declaration of Helsinki and Italian privacy laws.
Conflict of interest
The authors disclose any relevant financial conflict of interest.
- 2.Lowenberg B, Zittoun R, Kerkhofs H et al (1989) On the value of intensive remission-induction chemotherapy in elderly patients of 65+ years with acute myeloid leukemia: a randomized phase III study of the European Organization for Research and Treatment of Cancer Leukemia Group. J Clin Oncol 7:1268–1274CrossRefGoogle Scholar
- 13.Silverman LR, McKenzie DR, Peterson BL, Holland JF, Backstrom JT, Beach CL, Larson RA, Cancer and Leukemia Group B (2006) 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 24:3895–3803CrossRefGoogle Scholar
- 15.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):562–569CrossRefGoogle Scholar
- 16.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):1014–1022CrossRefGoogle Scholar
- 17.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 89:410–416CrossRefGoogle Scholar
- 18.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 93:1825–1838CrossRefGoogle Scholar
- 19.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 39:296–306CrossRefGoogle Scholar
- 20.Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH, Kumar R, Cavenagh J, Schuh AC, Candoni A, Recher 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, Dohner 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):291–299CrossRefGoogle Scholar
- 22.Pleyer L, Döhner H, Dombret H et al (2017) Azacitidine for front-line therapy of patients with AML: reproducible efficacy established by direct comparison of international phase 3 trial data with registry data from the Austrian Azacitidine Registry of the AGMT study group. Int J Mol Sci 18(2):E415CrossRefGoogle Scholar
- 26.Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD, International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (2003) 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 21:4642–4649CrossRefGoogle Scholar
- 27.Löwenberg B, Ossenkoppele GJ, van Putten W, Schouten HC, Graux C, Ferrant A, Sonneveld P, Maertens J, Jongen-Lavrencic M, von Lilienfeld-Toal M, Biemond BJ, Vellenga E, van Marwijk Kooy M, Verdonck LF, Beck J, Döhner H, Gratwohl A, Pabst T, Verhoef G, Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON), German AML Study Group (AMLSG)., Swiss Group for Clinical Cancer Research (SAKK) Collaborative Group (2009) High-dose daunorubicin in older patients with acute myeloid leukemia. N Engl J Med 361:1235–1248CrossRefGoogle Scholar
- 28.Becker H, Marcucci G, Maharry K, Radmacher MD, Mrózek K, Margeson D, Whitman SP, Wu YZ, Schwind S, Paschka P, Powell BL, Carter TH, Kolitz JE, Wetzler M, Carroll AJ, Baer MR, Caligiuri MA, Larson RA, Bloomfield CD (2010) Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and leukemia group B study. J Clin Oncol 28:596–604CrossRefGoogle Scholar
- 29.Gore SD, Fenaux P, Santini V, Bennett JM, Silverman LR, Seymour JF, Hellstrom-Lindberg E, Swern AS, Beach CL, List AF (2013) A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial. Haematologica 98(7):1067–1072CrossRefGoogle Scholar
- 30.Ravandi F, Issa JP, Garcia-Manero G, O'Brien S, Pierce S, Shan J, Borthakur G, Verstovsek S, Faderl S, Cortes J, Kantarjian H (2009) Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 115:5746–5751CrossRefGoogle Scholar
- 31.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 375:2023–2036CrossRefGoogle Scholar