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Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia

  • Luca Maurillo
  • Francesco Buccisano
  • Alessandra Spagnoli
  • Maria Teresa Voso
  • Luana Fianchi
  • Cristina Papayannidis
  • Gian Luca Gaidano
  • Massimo Breccia
  • Pellegrino Musto
  • Eleonora De Bellis
  • Maria Ilaria Del Principe
  • Monia Lunghi
  • Federica Lessi
  • Giovanni Martinelli
  • Adriano Venditti
Original Article

Abstract

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.

Keywords

Acute myeloid leukemia Intensive chemotherapy Azacitidine Elderly 

Notes

Authorship Contributions

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.

References

  1. 1.
    Lowenberg B, Downing JR, Burnett A (1999) Acute myeloid leukemia. N Engl J Med 341(14):1051–1062CrossRefPubMedGoogle Scholar
  2. 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 7:1268–1274CrossRefPubMedGoogle Scholar
  3. 3.
    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):3481–3485CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ferrara F (2014) Conventional chemotherapy or hypomethylating agents for older patients with acute myeloid leukaemia? Hematol Oncol 32:1–9CrossRefPubMedGoogle Scholar
  5. 5.
    Kantarjian H, Ravandi F, O’brien S et al (2010) Intensive chemotherapy does not benefit most older patients (age 70 years or older) with acute myeloid leukemia. Blood 116:4422–4429CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Frohling S, Schlenk RF, Kayser S et al (2006) Cytogenetics and age are the major determinants of outcome in intensively treated acute myeloid leukemia patients older than 60 years: results from the AMLSG trial AML HD98-B. Blood 108:63–73CrossRefGoogle Scholar
  7. 7.
    Bullinger L, Dohner K, Dohner H (2017) Genomics of acute myeloid leukemia diagnosis and pathways. J Clin Oncol 35:934–946CrossRefPubMedGoogle Scholar
  8. 8.
    Juliusson G, Lazarevic V, Horsted AS et al (2012) Acute myeloid leukemia in the real world: why population-based registries are needed. Blood 119:3890–3899CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Oran B, Weisdorf DJ (2012) Survival for older patients with acute myeloid leukemia: a population based study. Hematologica 97:1916–1924CrossRefGoogle Scholar
  10. 10.
    Ferrara F (2011) Treatment of unfit patients with acute myeloid leukemia: a still open clinical challenge. Clin Lymphoma Myeloma Leuk 11:10–16CrossRefPubMedGoogle Scholar
  11. 11.
    Alibhai SM, Leach M, Minden MD, Brandwein J (2009) Outcomes and quality of care in acute myeloid leukemia over 40 years. Cancer 115:2903–2911CrossRefPubMedGoogle Scholar
  12. 12.
    Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C (2015) Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol 94:1127–1138CrossRefPubMedPubMedCentralGoogle Scholar
  13. 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 24:3895–3803CrossRefPubMedGoogle Scholar
  14. 14.
    Sudan N, Rossetti JM, Shadduck RK, Latsko J, Lech JA, Kaplan RB, Kennedy M, Gryn JF, Faroun Y, Lister J (2006) Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 107:1839–1843CrossRefPubMedGoogle Scholar
  15. 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):562–569CrossRefPubMedGoogle Scholar
  16. 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):1014–1022CrossRefPubMedGoogle Scholar
  17. 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 89:410–416CrossRefPubMedGoogle Scholar
  18. 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 93:1825–1838CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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 39:296–306CrossRefPubMedGoogle Scholar
  20. 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):291–299CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    van der Helm LH, Veeger NJ, Kooy M et al (2013) Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. Leuk Res 37:877–882CrossRefPubMedGoogle Scholar
  22. 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):E415CrossRefPubMedGoogle Scholar
  23. 23.
    Quintás-Cardama A, Ravandi F, Liu-Dumlao T et al (2012) Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 120:4840–4845CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Gupta N, Miller A, Gandhi S, Ford LA, Vigil CE, Griffiths EA, Thompson JE, Wetzler M, Wang ES (2015 Jul) Comparison of epigenetic versus standard induction chemotherapy for newly diagnosed acute myeloid leukemia patients ≥60 years old. Am J Hematol 90:639–646CrossRefPubMedGoogle Scholar
  25. 25.
    van der Helm LH, Scheepers ER, Veeger NJ et al (2013) Azacitidine might be beneficial in a subgroup of older AML patients compared to intensive chemotherapy: a single centre retrospective study of 227 consecutive patients. J Hematol Oncol 6:29CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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 21:4642–4649CrossRefPubMedGoogle Scholar
  27. 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 361:1235–1248CrossRefPubMedGoogle Scholar
  28. 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 28:596–604CrossRefPubMedGoogle Scholar
  29. 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):1067–1072CrossRefPubMedPubMedCentralGoogle Scholar
  30. 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 115:5746–5751CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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 375:2023–2036CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Luca Maurillo
    • 1
  • Francesco Buccisano
    • 1
    • 2
  • Alessandra Spagnoli
    • 3
  • Maria Teresa Voso
    • 1
    • 2
  • Luana Fianchi
    • 4
  • Cristina Papayannidis
    • 5
  • Gian Luca Gaidano
    • 6
  • Massimo Breccia
    • 7
  • Pellegrino Musto
    • 8
  • Eleonora De Bellis
    • 1
  • Maria Ilaria Del Principe
    • 1
    • 2
  • Monia Lunghi
    • 6
  • Federica Lessi
    • 9
  • Giovanni Martinelli
    • 5
  • Adriano Venditti
    • 1
    • 2
  1. 1.Division of Hematology, Tor Vergata Foundation PolyclinicRomeItaly
  2. 2.Hematology, Department of Biomedicine e PreventionTor Vergata UniversityRomeItaly
  3. 3.Department of Public Health and Infectious DiseaseLa Sapienza UniversityRomeItaly
  4. 4.Hematology“Sacro Cuore” Catholic UniversityRomeItaly
  5. 5.Department of Experimental, Diagnostic and Specialty Medicine, Institute of Hematology “L. and A. Seràgnoli”University of BolognaBolognaItaly
  6. 6.Division of Hematology, Department of Translation MedicineUniversity of Eastern PiedmontNovaraItaly
  7. 7.Division of Cellular Biotechnologies and HematologyUniversity SapienzaRomeItaly
  8. 8.Scientific Direction, Referral Cancer Center of BasilicataIRCCS-CROB, Scientific Institute of Research and CureRionero in VultureItaly
  9. 9.Division of Hematology and Clinical ImmunologyUniversity of PaduaPaduaItaly

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