Skip to main content
SpringerLink
Log in

Survival improvement of poor-prognosis AML/MDS patients by maintenance treatment with low-dose chemotherapy and differentiating agents

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

We evaluated a maintenance, post-remission treatment with low-dose chemotherapy plus differentiating agents on poor-prognosis acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients ineligible to allografting. Patients had either age over 60 and/or secondary AML, therapy-related AML, previous relapse, high-risk MDS. Forty-five patients received the maintenance therapy based on two alternated schedules: (a) 6-thioguanine + 13-cis retinoic acid + dihydroxylated vitamin D3 and (b) low-dose cytarabine + 6-mercaptopurine + all-trans retinoic acid + dihydroxylated vitamin D3. We compared their outcome, at a median follow-up of 52 months, to that of a matched population of 49 patients who stopped treatments after consolidation. Maintenance group had a lower relapse incidence (70.3 vs. 86.4 % at 5 years p = 0.007) and a longer disease-free survival (median 21.2 vs. 8.7 months, p = 0.017). The relapse reduction improved overall survival: median 40.4 months (35.9 % at 5 years) for maintenance group vs. 15.8 (14.2 % at 5 years) for controls (p = 0.005). At multivariate Cox analysis, both cytogenetic and maintenance therapies resulted independent outcome predictors for overall survival. Maintenance treatment also reduced minimal residual disease (detected by WT1 and CBFβ-MYH11) in five of eight evaluable patients. The present results suggest that our strategy of maintenance therapy might improve the outcome of poor-risk AML/MDS patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Appelbaum FR, Gundacker H, Head DR et al (2006) Age and acute myeloid leukemia. Blood 107:3481–3485

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Büchner T, Berdel WE, Haferlach C et al (2009) Age-related risk profile and chemotherapy dose response in acute myeloid leukemia: a study by the German Acute Myeloid Leukemia Cooperative Group. J Clin Oncol 27:61–69

    Article  PubMed  Google Scholar 

  3. Juliusson G, Antunovic P, Derolf A et al (2009) Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 113:4179–4187

    Article  CAS  PubMed  Google Scholar 

  4. Bello C, Yu D, Komrokji RS et al (2011) Outcomes after induction chemotherapy in patients with acute myeloid leukemia arising from myelodysplastic syndrome. Cancer 117:1463–1469

    Article  PubMed  Google Scholar 

  5. Ruutu T, Hänninen A, Järventie G et al (1997) Intensive chemotherapy of poor prognosis myelodysplastic syndromes (MDS) and acute myeloid leukemia following MDS with idarubicin and cytarabine. Leuk Res 21:133–138

    Article  CAS  PubMed  Google Scholar 

  6. De Witte T, Suciu S, Peetermans M et al (1995) Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia (sAML) following MDS of more than 6 months duration. A pilot study by the Leukemia Cooperative Group of the European Organisation for Research and Treatment in Cancer (EORTC-LCG). Leukemia 9:1805–1811

    PubMed  Google Scholar 

  7. Smith SM, Le Beau MM, Huo D et al (2003) Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series. Blood 102:43–52

    Article  CAS  PubMed  Google Scholar 

  8. Kayser S, Döhner K, Krauter J et al (2011) The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML. Blood 117:2137–2145

    Article  CAS  PubMed  Google Scholar 

  9. Godley LA, Larson RA (2008) Therapy-related myeloid leukemia. Semin Oncol 35:418–429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Wattel E, De Botton S, Luc Laï J et al (1997) Long-term follow-up of de novo myelodysplastic syndromes treated with intensive chemotherapy: incidence of long-term survivors and outcome of partial responders. Br J Haematol 98:983–991

    Article  CAS  PubMed  Google Scholar 

  11. Hast R, Hellström-Lindberg E, Ohm L et al (2003) No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease. Leukemia 17:1827–1833

    Article  CAS  PubMed  Google Scholar 

  12. Beran M, Shen Y, Kantarjian H et al (2001) High-dose chemotherapy in high-risk myelodysplastic syndrome: covariate-adjusted comparison of five regimens. Cancer 92:1999–2015

    Article  CAS  PubMed  Google Scholar 

  13. Fenaux P, Mufti GJ, Hellstrom-Lindberg E et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase iii study. Lancet Oncol 10:223–232

    Article  CAS  PubMed  Google Scholar 

  14. Bally C, Thépot S, Quesnel B et al (2013) Azacitidine in the treatment of therapy related myelodysplastic syndrome and acute myeloid leukemia (tMDS/AML): a report on 54 patients by the Groupe Francophone des Myelodysplasies (GFM). Leuk Res 37:637–640

    Article  CAS  PubMed  Google Scholar 

  15. Ganetsky A (2012) The role of decitabine for the treatment of acute myeloid leukemia. Ann Pharmacother 46:1511–1517

    Article  PubMed  Google Scholar 

  16. Joeckel TE, Lübbert M (2012) Clinical results with the DNA hypomethylating agent 5-aza-2’-deoxycytidine (decitabine) in patients with myelodysplastic syndromes: an update. Semin Hematol 49:330–341

    Article  CAS  PubMed  Google Scholar 

  17. Grimwade D (2001) 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 98:1312–1320

    Article  CAS  PubMed  Google Scholar 

  18. Rossi G, Pelizzari AM, Bellotti D et al (2000) Cytogenetic analogy between myelodysplastic syndrome and acute myeloid leukemia of elderly patients. Leukemia 14:636–641

    Article  CAS  PubMed  Google Scholar 

  19. Seedhouse C, Russell N (2007) Advances in the understanding of susceptibility to treatment-related acute myeloid leukaemia. Br J Haematol 137:513–529

    Article  CAS  PubMed  Google Scholar 

  20. Kantarjian HM, Estey EH, Keating MJ (1993) Treatment of therapy-related leukemia and myelodysplastic syndrome. Hematol Oncol Clin N Am 7:81–107

    CAS  Google Scholar 

  21. Kern W, Haferlach T, Schnittger S et al (2004) Prognosis in therapy-related acute myeloid leukemia and impact of karyotype. J Clin Oncol 22:2510–2511

    Article  PubMed  Google Scholar 

  22. Krug U, Lübbert M, Büchner T (2010) Maintenance therapy in acute myeloid leukemia revisited: will new agents rekindle an old interest? Curr Opin Hematol 17:85–90

    Article  CAS  PubMed  Google Scholar 

  23. Büchner T, Urbanitz D, Hiddemann W et al (1985) Intensified induction and consolidation with or without maintenance chemotherapy for acute myeloid leukemia (AML): two multicenter studies of the German AML Cooperative Group. J Clin Oncol 3:1583–1589

    PubMed  Google Scholar 

  24. Löwenberg B, Suciu S, Archimbaud E et al (1998) Mitoxantrone versus daunorubicin in induction-consolidation chemotherapy—the value of low-dose cytarabine for maintenance of remission, and an assessment of prognostic factors in acute myeloid leukemia in the elderly: final report. European Organization for the Research and Treatment of Cancer and the Dutch-Belgian Hemato-Oncology Cooperative Hovon Group. J Clin Oncol 16:872–881

    PubMed  Google Scholar 

  25. Buchner T, Hiddemann W, Wormann B et al (1999) Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 93:4116–4124

    CAS  PubMed  Google Scholar 

  26. Robles C, Kim KM, Oken MM et al (2000) Low-dose cytarabine maintenance therapy vs observation after remission induction in advanced acute myeloid leukemia: an Eastern Cooperative Oncology Group Trial (E5483). Leukemia 14:1349–1353

    Article  CAS  PubMed  Google Scholar 

  27. Büchner T, Hiddemann W, Berdel WE et al (2003) 6-thioguanine, cytarabine, and daunorubicin (TAD) and high-dose cytarabine and mitoxantrone (HAM) for induction, TAD for consolidation, and either prolonged maintenance by reduced monthly TAD or TAD-HAM-TAD and one course of intensive consolidation by sequential HAM in adult patients at all ages with de novo acute myeloid leukemia (AML): a randomized trial of the German AML Cooperative Group. J Clin Oncol 21:4496–4504

    Article  PubMed  Google Scholar 

  28. Büchner T, Berdel WE, Schoch C et al (2006) Double induction containing either two courses or one course of high-dose cytarabine plus mitoxantrone and postremission therapy by either autologous stem-cell transplantation or by prolonged maintenance for acute myeloid leukemia. J Clin Oncol 24:2480–2489

    Article  PubMed  Google Scholar 

  29. Rai KR, Holland JF, Glidewell OJ et al (1981) Treatment of acute myelocytic leukemia: a study by cancer and leukemia group B. Blood 58:1203–1212

    CAS  PubMed  Google Scholar 

  30. Sanz MA, Grimwade D, Tallman MS et al (2009) Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European Leukemia Net. Blood 113:1875–1891

    Article  CAS  PubMed  Google Scholar 

  31. Altucci L, Rossin A, Hirsch O et al (2005) Rexinoid-triggered differentiation and tumor-selective apoptosis of acute myeloid leukemia by protein kinase A-mediated desubordination of retinoid X receptor. Cancer Res 65:8754–8765

    Article  CAS  PubMed  Google Scholar 

  32. Schenk T, Chen WC, Göllner S et al (2012) Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia. Nat Med 18:605–611

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Morosetti R, Koeffler HP (1996) Differentiation therapy in myelodysplastic syndromes. Semin Hematol 33:236–245

    CAS  PubMed  Google Scholar 

  34. Ferrero D, Carlesso N, Bresso P et al (1997) Suppression of in vitro maintenance of non-promyelocytic myeloid leukemia clonogenic cells by all-trans retinoic acid: modulating effects of dihydroxylated vitamin D3, alpha interferon and “stem cell factor”. Leuk Res 21:51–58

    Article  CAS  PubMed  Google Scholar 

  35. Ferrero D, Carlesso N, Pregno P et al (1992) Self-renewal inhibition of acute myeloid leukemia clonogenic cells by biological inducers of differentiation. Leukemia 6:100–106

    CAS  PubMed  Google Scholar 

  36. Waxman S (2000) Differentiation therapy in acute myelogenous leukemia (non-APL). Leukemia 14:491–496

    Article  CAS  PubMed  Google Scholar 

  37. Bruserud O, Gjertsen BT (2000) New strategies for the treatment of acute myelogenous leukemia: differentiation induction—present use and future possibilities. Stem Cells 18:157–165

    Article  CAS  PubMed  Google Scholar 

  38. Schlenk RF, Fröhling S, Hartmann F et al (2004) Phase III study of all-trans retinoic acid in previously untreated patients 61 years or older with acute myeloid leukemia. Leukemia 18:1798–1803

    Article  CAS  PubMed  Google Scholar 

  39. Venditti A, Tamburini A, Buccisano F et al (2000) A phase-II trial of all trans retinoic acid and low-dose cytosine arabinoside for the treatment of high-risk myelodysplastic syndromes. Ann Hematol 79:138–142

    Article  CAS  PubMed  Google Scholar 

  40. Ferrero D, Bruno B, Pregno P et al (1996) Combined differentiating therapy for myelodysplastic syndromes: a phase II study. Leuk Res 20:867–876

    Article  CAS  PubMed  Google Scholar 

  41. Ferrero D, Foli C, Campa E, Pileri A (1999) A combination of 13-cis retinoic acid + dihydroxylated vitamin d3 +/- low-dose chemotherapy as a treatment for myelodysplastic syndromes (abstract). Blood 94:307a

    Google Scholar 

  42. Ferrero D, Campa E, Dellacasa C et al (2004) Differentiating agents + low-dose chemotherapy in the management of old/poor prognosis patients with acute myeloid leukemia or myelodysplastic syndrome. Haematologica 89:619–620

    CAS  PubMed  Google Scholar 

  43. Greenberg P, Cox C, LeBeau MM et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89:2079–2088

    CAS  PubMed  Google Scholar 

  44. Grimwade D (2012) The changing paradigm of prognostic factors in acute myeloid leukaemia. Best Pract Res Clin Haematol 25:419–425

    Article  PubMed  Google Scholar 

  45. Cilloni D, Renneville A, Hermitte F et al (2009) Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European Leukemia Net study. J Clin Oncol 27:5195–5201

    Article  CAS  PubMed  Google Scholar 

  46. Van Dongen JJ, Macintyre EA, Gabert JA et al (1999) Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Report of the BIOMED-1 concerted action: investigation of minimal residual disease in acute leukemia. Leukemia 13:1901–1928

    Article  PubMed  Google Scholar 

  47. Gabert J, Beillard E, van der Velden VHJ et al (2003) Standardization and quality control studies of “real-time” quantitative reverse transcriptase polymerase chain reaction of fusion gene transcripts for residual disease detection in leukemia—a Europe Against Cancer program. Leukemia 17:2318–2357

    Article  CAS  PubMed  Google Scholar 

  48. Beillard E, Pallisgaard N, van der Velden VHJ et al (2003) Evaluation of candidate control genes for diagnosis and residual disease detection in leukemic patients using “real-time” quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR)—a Europe Against Cancer program. Leukemia 17:2474–2486

    Article  CAS  PubMed  Google Scholar 

  49. Boumber Y, Kantarjian H, Jorgensen J et al (2012) A randomized study of decitabine versus conventional care for maintenance therapy in patients with acute myeloid leukemia in complete remission. Leukemia 26:2428–2431

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have no conflict of interest to disclose.

Author contributions

DF designed the study, treated patients and wrote the paper; EC collected and analyzed data,treated patients and wrote the paper;* FM, EA, CF, VG, BB treated patients and reviewed the paper; TG e MF collected data; TG also helped in manuscript preparation; RP performed statistical analysis; LR performed molecular analysis; MB and BB supervised the research and provided funds.

Author information

Authors and Affiliations

  1. Section of Hematology, Department of Molecular Biotechnology and Health Sciences, University of Turin, via Genova, 3, 10126, Turin, Italy

    Dario Ferrero, Elena Crisà, Valentina Giai, Tiziana Gatti, Moreno Festuccia, Benedetto Bruno & Mario Boccadoro

  2. Section of Pathology, Center for Experimental Research and Medical Studies (CeRMS), Turin, Italy

    Ludovica Riera

  3. Hematology Division, Azienda Ospedaliera Città della Salute e della Scienza, Turin, Italy

    Filippo Marmont, Ernesta Audisio & Chiara Frairia

  4. Nuclear Medicine Division, University of Turin, Turin, Italy

    Roberto Passera

Authors
  1. Dario Ferrero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elena Crisà
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Filippo Marmont
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ernesta Audisio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chiara Frairia
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Valentina Giai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tiziana Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Moreno Festuccia
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Benedetto Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ludovica Riera
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Roberto Passera
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Mario Boccadoro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dario Ferrero.

Additional information

Dario Ferrero and Elena Crisà equally contributed to the clinical study and to paper preparation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ferrero, D., Crisà, E., Marmont, F. et al. Survival improvement of poor-prognosis AML/MDS patients by maintenance treatment with low-dose chemotherapy and differentiating agents. Ann Hematol 93, 1391–1400 (2014). https://doi.org/10.1007/s00277-014-2047-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-014-2047-7

Keywords

Search

Navigation