Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Acute Leukemias

Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial

Leukemia volume 27, pages 843–851 (2013)Cite this article

Subjects

Abstract

Two hundred eighty-five patients, median age 42, with PML-RARα-positive acute promyelocytic leukaemia were randomised to Ara-C-containing ‘Medical Research Council (MRC) Chemotherapy’+ATRA (All-trans-retinoic acid) or anthracycline+ATRA (modified ‘Spanish’) therapy. MRC treatment comprised four courses with ATRA in courses 1–2. Spanish treatment comprised four anthracycline-based courses with ATRA in courses 1–3. In course 3 patients were randomised to gemtuzumab ozogamicin (GO) or not. The Spanish arm received 24-month maintenance. Patients were sequentially molecularly monitored. Quality of life was assessed at baseline, 3, 6, 9, 12, 24 months. Remission rates were similar in both arms (93%): cumulative incidence of haematological relapse (CIHR) was 6% at 5 years; 5 patients relapsed molecularly. Survival post relapse was 80%. There were more deaths in remission in the MRC arm (4% vs 10%: P=0.2). The overall 5-year relapse-free and overall survival was similar between arms (81% vs 82% and 84% vs 83%, respectively). More supportive care and hospitalisation (81.8 vs 63 days, P<0.0001) was required in the MRC arm. GO did not provide benefit. High white blood cell count (>10 × 109/l) was not prognostic overall, or within treatment arms. Both approaches deliver similar results with minor differences in quality of life. MRC treatment required more hospitalisation. This suggests that additional chemotherapy, Ara-C in particular, is not required.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Lo-Coco F, Avvisati G, Vignetti M, Breccia M, Gallo E, Rambaldi A et al. Front-line treatment of acute promyelocytic Leukemia with AIDA induction followed by risk-adapted consolidation: results of the AIDA-2000 Trial of the Italian GIMEMA Group. Blood 2010; 116: 3171–3179.

    Article  CAS  PubMed  Google Scholar 

  2. Sanz MA, Martin G, Rayon C, Esteve J, Gonzalez M, Diaz-Mediavilla J et al. A modified AIDA protocol with Anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARa- positive acute promyelocytic leukemia. Blood 1999; 94: 3015–3021.

    CAS  PubMed  Google Scholar 

  3. Fenaux P, Le Deley MC, Castaigne S, Archimbaud E, Chomienne C, Lisk H et al. Effect of all trans retinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 1993; 82: 3241–3249.

    CAS  PubMed  Google Scholar 

  4. Tallman MS, Anderson JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A et al. All- transretinoic acid in acute promyelocytic leukemia. New Engl J Med 1997; 337: 1021–1028.

    Article  CAS  PubMed  Google Scholar 

  5. Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH . Presenting white cell count and kinetics of molecular remission predict prognosis acute promyelocytic leukaemia treated with All-transretinoic acid: result of the randomised MRC Trial. Blood 1999; 93: 4131–4143.

    CAS  PubMed  Google Scholar 

  6. Fenaux P, Chastang C, Cherzet S, Sanz M, Dombret H, Archimbaud E et al. A randomized comparison of ATRA followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance treatment in APL. Blood 1999; 94: 1192–1200.

    CAS  PubMed  Google Scholar 

  7. Avvisati G, Lo-Coco F, Paoloni FP, Petti MC, Diverio D, Vignetti M et al. AIDA 0493 protocol for newly diagnosed acute promyelocytic leukemia: very long-term results and role of maintenance. Blood 2011; 117: 4716–4725.

    Article  CAS  PubMed  Google Scholar 

  8. Asou N, Kishimoto Y, Kiyoi H, Okada M, Kawai Y, Tsuzuki M et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood 2007; 110: 59–66.

    Article  CAS  PubMed  Google Scholar 

  9. Grimwade D, Jovanovic JV, Hills RK, Nugent EA, Patel Y, Flora R et al. Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy. J Clin Oncol 2009; 27: 3650–3658.

    Article  CAS  PubMed  Google Scholar 

  10. Cheson BD, Bennett JM, Kopecky KJ, Buchner T, Wilman CL, Estey EH et al. Revised recommendation of the International Working Group for diagnosis standardisation, of response criteria treatment outcomes and reporting standards for therapeutic trials in acute myeloid leukaemia. J Clin Oncol 2003; 21: 4642–4649.

    Article  PubMed  Google Scholar 

  11. Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116: 3751–3757.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 2011; 118: 1248–1254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. McClellan JS, Kohrt HE, Coutre S, Gotlib JR, Majeti R, Alizadeh AA et al. Treatment advances have not improved the early death rate in acute promyelocytic leukemia. Haematologica 2012; 97: 133–136.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sanz M, Grimwade D, Tallman MS, Lowenberg B, Fenaux P, Estey EH et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113: 1875–1891.

    Article  CAS  PubMed  Google Scholar 

  15. Ades L, Chevret S, Raffoux E, Botton Sde, Guerci A, Pigneux A et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006; 24: 5703–5710.

    Article  CAS  PubMed  Google Scholar 

  16. Shen ZX, Shi ZZ, Fang J, Gu BW, Li JM, Zhu YM et al. All-trans retinoic acid/As2O3 combination yields a high quality remission and survival in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA 2004; 101: 5328–5335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Mathews V, George B, Lakshmi KM, Viswabandya A, Bajel A, Balasubramanian P et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: durable remissions with minimal toxicity. Blood 2006; 107: 2627–2632.

    Article  CAS  PubMed  Google Scholar 

  18. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 3469–3473.

    Article  CAS  PubMed  Google Scholar 

  19. Ravandi F, Estey E, Jones D, Faderl S, O'Brien S, Fiorentino J et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27: 504–510.

    Article  CAS  PubMed  Google Scholar 

  20. Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 2225–2229.

    CAS  PubMed  Google Scholar 

  21. Esteve J, Escoda L, Martin G, Rubio V, az-Mediavilla J, Gonzalez M et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 2007; 21: 446–452.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the physicians, nurses and pharmacists who contributed to this study; Wyeth Research for the provision of gemtuzumab ozogamicin and to the Birmingham Clinical Trials Unit for supporting the trial, to the UK Medical Research Council for providing research support, and to Leukaemia & Lymphoma Research for supporting molecular diagnostics and MRD monitoring.

Author information

Authors and Affiliations

  1. Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK

    A K Burnett & R K Hills

  2. Department of Medical and Molecular Genetics, King’s College Medical School, London, UK

    D Grimwade & J V Jovanovic

  3. Department of Haematology, Addenbrooke’s Hospital, Cambridge, UK

    J Craig

  4. Department of Haematology, Belfast City Hospital, Belfast, UK

    M F McMullin

  5. Department of Haematology, University Hospital of Wales, Cardiff, UK

    J Kell

  6. CRUK Clinical Trials Unit, University of Birmingham, Birmingham, UK

    K Wheatley

  7. Department of Haematology, Manchester Royal Infirmary, Manchester, UK

    J A L Yin

  8. Department of Haematology, Leicester Royal Infirmary, Leicester, UK

    A Hunter

  9. Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK

    D Milligan

  10. Department of Haematology, Nottingham University Hospital NHS Trust, Nottingham, UK

    N H Russell

Authors
  1. A K Burnett
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R K Hills
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Grimwade
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J V Jovanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J Craig
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M F McMullin
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Kell
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. K Wheatley
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J A L Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. A Hunter
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Milligan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. N H Russell
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

on behalf of the United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup

Corresponding author

Correspondence to A K Burnett.

Ethics declarations

Competing interests

A K Burnett has received trial funding from Pfizer and has served on Advisory Boards for Pfizer.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burnett, A., Hills, R., Grimwade, D. et al. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia 27, 843–851 (2013). https://doi.org/10.1038/leu.2012.360

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.360

Keywords

This article is cited by

Search

Advanced search

Quick links