Skip to main content
SpringerLink
Log in

The early addition of arsenic trioxide versus high-dose arabinoside is more effective and safe as consolidation chemotherapy for risk-tailored patients with acute promyelocytic leukemia: multicenter experience

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

The purpose of the study was to evaluate event-free survival (EFS), overall survival (OS) and safety for early addition of arsenic trioxide (As2O3) as frontline consolidation therapy compared to high-dose arabinoside (HiDAC) in adult patients with de novo acute promyelocytic leukemia (APL). 271 patients (aged 17–65 years) received consolidation therapy containing As2O3 (two 21-day courses) or HiDAC regimen. EFS at 5 years was 75% versus 54% (P < 0.001), and OS at 5 years was 83% versus 71% (P = 0.002) in As2O3 and HiDAC treatment arms. 139 patients treated with As2O3, EFS at 5 years reached 79% versus 56% (P = 0.014), but OS at 5 years was 77% versus 84% (P = 0.32) in low-risk (WBC ≤ 10 × 109/L) and high-risk (WBC > 10 × 109/L) cohorts. Further, patients treated with As2O3 rarely incurred agranulocytosis (1.4%, P < 0.001), or severe infection (0.7%, P < 0.001). It is still very well tolerated compared to HiDAC. We confirmed that As2O3 as a first-line consolidation regimen provided significant benefits of OS to patients with APL. The As2O3 regimen made low-risk patients gain more EFS benefits than high-risk group. The high-risk cohort receiving As2O3 overcame the negative impact, yielding OS similar to that for with the low-risk patients treated with As2O3.

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

Similar content being viewed by others

References

  1. Wang ZY, Chen Z. Acute promyelocytic leukemia: from highly fatal to highly curable. Blood. 2008;111:2505–15.

    Article  PubMed  CAS  Google Scholar 

  2. Hu J, Liu YF, Wu CF, Xu F, Shen ZX, Zhu YM, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci USA. 2009;106:3342–7.

    Article  PubMed  CAS  Google Scholar 

  3. Bernard J, Weil M, Boiron M, Jacquillat C, Flandrin G, Gemon MF. Acute promyelocytic leukemia: results of treatment by daunorubicin. Blood. 1973;41:489–96.

    PubMed  CAS  Google Scholar 

  4. Cunningham I, Gee TS, Reich LM, Kempin SJ, Naval AN, Clarkson BD. Acute promyelocytic leukemia: treatment results during a decade at Memorial Hospital. Blood. 1989;73:1116–22.

    PubMed  CAS  Google Scholar 

  5. Sanz MA, Jarque I, Martín G, Lorenzo I, Martínez J, Rafecas J, et al. Acute promyelocytic leukemia: therapy results and prognostic factors. Cancer. 1988;61:7–13.

    Article  PubMed  CAS  Google Scholar 

  6. Sanz MA, 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 Leukemia Net. Blood. 2009;113:1875–91.

    Article  PubMed  CAS  Google Scholar 

  7. Sanz MA, Lo-Coco F. Modern approaches to treating acute promyelocytic leukemia. J Clin Oncol. 2011;29:495–503.

    Article  PubMed  Google Scholar 

  8. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Woods WG, et al. All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol. Blood. 2002;100:4298–302.

    Article  PubMed  CAS  Google Scholar 

  9. Lengfelder E, Haferlach C, Saussele S, Haferlach T, Schultheis B, Schnittger S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia. 2009;23:2248–58.

    Article  PubMed  CAS  Google Scholar 

  10. Stone RM, O’Donnell MR, Sekeres MA. Acute myeloid leukemia. Hematology Am Soc Hematol Educ Program. 2004:98–117.

  11. Schlenk RF, Benner A, Hartmann F, del Valle F, Weber C, Pralle H, et al. Risk-adapted postremission therapy in acute myeloid leukemia: results of the German multicenter AML HD93 treatment trial. Leukemia. 2003;17:1521–8.

    Article  PubMed  CAS  Google Scholar 

  12. Fagundes EM, Rocha V, Glória AB, Clementino NC, Quintão JS, Guimarães JP, et al. De novo acute myeloid leukemia in adults younger than 60 years of age: socioeconomic aspects and treatment results in a Brazilian university center. Leuk Lymphoma. 2006;47:1557–64.

    Article  PubMed  Google Scholar 

  13. Böhm A, Piribauer M, Wimazal F, Geissler K, Gisslinger H, Knöbl P, et al. High dose intermittent ARA-C (HiDAC) for consolidation of patients with de novo AML: a single center experience. Leuk Res. 2005;29(6):609–15.

    Article  PubMed  Google Scholar 

  14. Zayed A, Couban S, Hayne O, Sparavalo N, Shawwa A, Sadek I, et al. Acute promyelocytic leukemia: a novel PML/RARalpha fusion that generates a frameshift in the RARalpha transcript and ATRA resistance. Leuk Lymphoma. 2007;48:489–96.

    Article  PubMed  CAS  Google Scholar 

  15. Tallman MS. What is the role of arsenic in newly diagnosed APL? Best Pract Res Clin Haematol. 2008;21:659–66.

    Article  PubMed  CAS  Google Scholar 

  16. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E, et al. United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol. 2001;19:3852–60.

    PubMed  CAS  Google Scholar 

  17. Au WY, Chim CS, Lie AK, Liang R, Kwong YL. Combined arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukaemia recurring from previous relapses successfully treated using arsenic trioxide. Br J Haematol. 2002;117:130–2.

    Article  PubMed  CAS  Google Scholar 

  18. Grigg A, Kimber R, Szer J. Prolonged molecular remission after arsenic trioxide and all-trans retinoic acid for acute promyelocytic leukemia relapsed after allogeneic stem cell transplantation. Leukemia. 2003;17:1916–7.

    Article  PubMed  CAS  Google Scholar 

  19. Shen ZX, Chen GQ, Ni JH, et al. Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood. 1997;89:3354–60.

    PubMed  CAS  Google Scholar 

  20. Shigeno K, Naito K, Sahara N, et al. Arsenic trioxide therapy in relapsed or refractory Japanese patients with acute promyelocytic leukemia: updated outcomes of the phase II study and postremission therapies. Int J Hematol. 2005;82:224–9.

    Article  PubMed  CAS  Google Scholar 

  21. Ranganathan A, Powell BL. Risk-adapted approaches to therapy for high-risk acute promyelocytic leukemia. Clin Lymphoma Myeloma Leuk. 2010;10:135–8.

    Article  Google Scholar 

  22. Sanz MA, Montesinos P. Risk-adapted treatment for low- and intermediate-risk acute promyelocytic leukemia. Clin Lymphoma Myeloma Leuk. 2010;10:130–4.

    Article  Google Scholar 

  23. Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010;116:3751–7.

    Article  PubMed  CAS  Google Scholar 

  24. Cheson BD, Bennett JM, Kopecky KJ, et al. 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. 2003;21:4642–9.

    Article  PubMed  Google Scholar 

  25. van den Heuvel-Eibrink MM, van der Holt B, Marry M, et al. CD34-related coexpression of MDR1 and BCRP indicates a clinically resistant phenotype in patients with acute myeloid leukemia (AML) of older age. Ann Hematol. 2007;86:329–37.

    Article  PubMed  Google Scholar 

  26. Mandelli F, Vignetti M, Suciu S, Stasi R, Petti MC, Meloni G, et al. Daunorubicin versus mitoxantrone versus idarubicin as induction and consolidation chemotherapy for adults with acute myeloid leukemia: the EORTC and GIMEMA Groups Study AML-10. J Clin Oncol. 2009;27:5397–403.

    Article  PubMed  CAS  Google Scholar 

  27. Sanz MA, Martín G, González M, León A, Rayón C, Rivas C, et al. Risk-adapted treatment of acute promyelocytic leukemia with alltrans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood. 2004;103:1237–43.

    Article  PubMed  CAS  Google Scholar 

  28. Adès L, Sanz MA, Chevret S, Montesinos P, Chevallier P, Raffoux E, et al. Treatment of newly diagnosed acute promyelocytic leukemia (APL): a comparison of French-Belgian-Swiss and PETHEMA results. Blood. 2008;111:1078–84.

    Article  PubMed  Google Scholar 

  29. Tallman MS. Treatment of relapsed or refractory acute promyelocytic leukemia. Best Pract Res Clin Haematol. 2007;20:57–65.

    Article  PubMed  Google Scholar 

  30. 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;101:5328–35.

    Article  PubMed  CAS  Google Scholar 

  31. Chen Y, Gu L, Zhou C, Wu X, Gao J, Li Q, et al. Relapsed APL patient with variant NPM-RARalpha fusion responded to arsenic trioxide-based therapy and achieved long-term survival. Int J Hematol. 2010;91:708–10.

    Article  PubMed  Google Scholar 

  32. Gore SD, Gojo I, Sekeres MA, Morris L, Devetten M, Jamieson K, et al. Single cycle of arsenic trioxide-based consolidation chemotherapy spares anthracycline exposure in the primary management of acute promyelocytic leukemia. J Clin Oncol. 2010;28:1047–53.

    Article  PubMed  CAS  Google Scholar 

  33. Ramirez LY, Huestis SE, Yap TY, Zyzanski S, Drotar D, Kodish E. Potential chemotherapy side effects: what do oncologists tell parents? Pediatr Blood Cancer. 2009;52:497–502.

    Article  PubMed  Google Scholar 

  34. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol. 2003;21:3609–15.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank all the patients and the clinicians from the participating sites. This work was supported by grants from the Natural Science Foundation of Inner Mongolia (200711020952). All authors discussed the results and commented on the manuscript.

Conflict of interest

I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed.

Author information

Authors and Affiliations

  1. Department of Hematology, The Affiliated Hospital of Inner Mongolia Medical College, 1 TongDao Avenue North, Hohhot, 010059, People’s Republic of China

    Bin-Tao Huang & Zhen Xiao

  2. Department of Medicine, The Affiliated Hospital of Guangdong Medical College, Zhanjiang, 524001, People’s Republic of China

    Qing-Chun Zeng

  3. Department of Bioengineering, University of Colorado Denver, Aurora, CO, 80045, USA

    Arati Gurung

  4. Department of Gastroenterology, The Affiliated Hospital of Inner Mongolia Medical College, Hohhot, 010059, People’s Republic of China

    Wei-Hong Zhao

  5. Huizhou Medicine Institute, Huizhou, 516003, People’s Republic of China

    Bing-Sheng Li

Authors
  1. Bin-Tao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qing-Chun Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arati Gurung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wei-Hong Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhen Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bing-Sheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhen Xiao.

Additional information

Bin-Tao Huang, Qing-Chun Zeng equally contributed to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huang, BT., Zeng, QC., Gurung, A. et al. The early addition of arsenic trioxide versus high-dose arabinoside is more effective and safe as consolidation chemotherapy for risk-tailored patients with acute promyelocytic leukemia: multicenter experience. Med Oncol 29, 2088–2094 (2012). https://doi.org/10.1007/s12032-011-0099-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12032-011-0099-2

Keywords

Search

Navigation