Skip to main content
SpringerLink
Log in

Safety and efficacy of arsenic trioxide and all-trans retinoic acid therapy in acute promyelocytic leukemia patients with a high risk for early death

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

Abstract

In this study, we investigated the safety and efficacy of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). The patients had been classified as unfit to receive anthracycline-based chemotherapy due to high-risk factors for early death. Twenty-five patients with APL receiving ATO/ATRA between 2007 and 2018 were divided into 3 groups as follows: elderly patients (age ≥ 70 years) with poor performance status (32%); patients with severe active infections at diagnosis (56%); and patients with multiple significant comorbidities (24%) who were unfit for conventional chemotherapy, regardless of age. Induction therapy comprised 0.15 mg/kg/day ATO combined with 45 mg/m2/day ATRA until patients attained complete remission (CR). Notably, only one patient (4.0%) died of septic shock 2 days after the ATO treatment had been initiated. The remaining 24 patients attained CR despite their serious and desperate conditions at diagnosis. In total, 44%, 28%, and 32% of the patients experienced neutropenia (grade 3 or 4), thrombocytopenia, and hepatopathy, respectively. Twenty-three of the 24 patients in CR proceeded to consolidation therapy and attained complete molecular remission with favorable overall survival (90.7%). This study demonstrates the safety and efficacy profile of ATO/ATRA first-line therapy for patients with APL and high-risk features for early death.

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

Similar content being viewed by others

Data availability

The data of the current study are available and can be requested from the corresponding author.

References

  1. Rahme R, Thomas X, Recher C, Vey N, Delaunay J, Deconinck E et al (2014) Early death in acute promyelocytic leukemia (APL) in French centers: a multicenter study in 399 patients. Leukemia 28(12):2422–2424. https://doi.org/10.1038/leu.2014.240

    Article  CAS  PubMed  Google Scholar 

  2. Park JH, Qiao B, Panageas KS, Schymura MJ, Jurcic JG, Rosenblat TL, Altman JK, Douer D, Rowe JM, Tallman MS (2011) Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid. Blood 118(5):1248–1254. https://doi.org/10.1182/blood-2011-04-346-437

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Montesinos P, Bergua JM, Vellenga E, Rayon C, Parody R, de la Serna J et al (2009) Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 113(4):775–783. https://doi.org/10.1182/blood-2008-07-168617

    Article  CAS  PubMed  Google Scholar 

  4. De Botton S, Dombret H, Sanz M, Miguel JS, Caillot D, Zittoun R et al (1998) Incidence, clinical features, and outcome of the all-trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 92(8):2712–2718

    Article  Google Scholar 

  5. Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, la Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D’Arco AM, di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F (2017) Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non–high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial. J Clin Oncol 35(6):605–612. https://doi.org/10.1200/jco.2016.67.1982

    Article  CAS  PubMed  Google Scholar 

  6. Burnett AK, Russell NH, Hills RK, Bowen D, Kell J, Knapper S, Morgan YG, Lok J, Grech A, Jones G, Khwaja A, Friis L, McMullin M, Hunter A, Clark RE, Grimwade D, UK National Cancer Research Institute Acute Myeloid Leukaemia Working Group (2015) Arsenic trioxide and all-trans retinoic acid treatment for acute promyelocytic leukemia in all risk groups (AML17): results of a randomized, controlled, phase 3 trial. Lancet Oncol 16(13):1295–1305. https://doi.org/10.1016/s1470-2045(15)00193-x

    Article  CAS  PubMed  Google Scholar 

  7. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, Ferrara F, Fazi P, Cicconi L, di Bona E, Specchia G, Sica S, Divona M, Levis A, Fiedler W, Cerqui E, Breccia M, Fioritoni G, Salih HR, Cazzola M, Melillo L, Carella AM, Brandts CH, Morra E, von Lilienfeld-Toal M, Hertenstein B, Wattad M, Lübbert M, Hänel M, Schmitz N, Link H, Kropp MG, Rambaldi A, la Nasa G, Luppi M, Ciceri F, Finizio O, Venditti A, Fabbiano F, Döhner K, Sauer M, Ganser A, Amadori S, Mandelli F, Döhner H, Ehninger G, Schlenk RF, Platzbecker U, Gruppo Italiano Malattie Ematologiche dell’Adulto, German-Austrian Acute Myeloid Leukemia Study Group, Study Alliance Leukemia (2013) Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 369(2):111–121. https://doi.org/10.1056/NEJMoa1300874

    Article  CAS  PubMed  Google Scholar 

  8. Lengfelder E, Lo-Coco F, Ades L, Montesinos P, Grimwade D, Kishore B, Ramadan SM, Pagoni M, Breccia M, Huerta AJ, Nloga AM, González-Sanmiguel JD, Schmidt A, Lambert JF, Lehmann S, di Bona E, Cassinat B, Hofmann WK, Görlich D, Sauerland MC, Fenaux P, Sanz M, European LeukemiaNet (2015) Arsenic trioxide-based therapy of relapsed acute promyelocytic leukemia: registry results from the European LeukemiaNet. Leukemia 29(5):1084–1091. https://doi.org/10.1038/leu.2015.12

    Article  CAS  PubMed  Google Scholar 

  9. Sanz MA, Lo Coco F, Martin G, Avvisati G, Rayon C, Barbui T et al (2000) Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups. Blood 96(4):1247–1253

    CAS  PubMed  Google Scholar 

  10. Lee S, Kim YJ, Eom KS, Min CK, Kim HJ, Cho SG, Lee JW, Min WS, Kim CC (2006) The significance of minimal residual disease kinetics in adults with newly diagnosed PML-RARalpha-positive acute promyelocytic leukemia: results of a prospective trial. Haematologica 91(5):671–674

    CAS  PubMed  Google Scholar 

  11. Estey E, Garcia-Manero G, Ferrajoli A, Faderl S, Verstovsek S, Jones D, Kantarjian H (2006) Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 107(9):3469–3473. https://doi.org/10.1182/blood-2005-10-4006

    Article  CAS  PubMed  Google Scholar 

  12. Sanz MA, Montesinos P, Vellenga E, Rayon C, de la Serna J, Parody R et al (2008) Risk-adapted treatment of acute promyelocytic leukemia with all-trans retinoic acid and anthracycline monochemotherapy: long-term outcome of the LPA 99 multicenter study by the PETHEMA Group. Blood 112(8):3130–3134. https://doi.org/10.1182/blood-2008-05-159632

    Article  CAS  PubMed  Google Scholar 

  13. Sanz MA, Martin G, Gonzalez M, Leon A, Rayon C, Rivas C et al (2004) Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 103(4):1237–1243. https://doi.org/10.1182/blood-2003-07-2462

    Article  CAS  PubMed  Google Scholar 

  14. Roboz GJ, Ritchie EK, Carlin RF, Samuel M, Gale L, Juliette L et al (2014) Prevalence, management, and clinical consequences of QT interval prolongation during treatment with arsenic trioxide. J Clin Oncol 33(32). https://doi.org/10.1200/JCO.2013.51.2913

  15. Paulson K, Serebrin A, Lambert P, Bergeron J, Everett J, Kew A, Jones D, Mahmud S, Meloche C, Sabloff M, Sharif I, Storring J, Turner D, Seftel MD (2014) Acute promyelocytic leukemia is characterized by stable incidence and improved survival that is restricted to patients managed in leukemia referral centers: a pan-Canadian epidemiological study. Br J Haematol 166(5):660–666. https://doi.org/10.1111/bjh.12931

    Article  PubMed  Google Scholar 

  16. Lehmann S, Ravn A, Carlsson L, Antunovic P, Deneberg S, Mollgard L et al (2011) Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry. Leukemia 25(7):1128–1134. https://doi.org/10.1038/leu.2011.78

    Article  CAS  PubMed  Google Scholar 

  17. Montesinos P, Gonzalez JD, Gonzalez J, Rayon C, de Lisa E, Amigo ML et al (2010) Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic acid and anthracycline-based chemotherapy. J Clin Oncol 28(24):3872–3879. https://doi.org/10.1200/jco.2010.29.2268

    Article  CAS  PubMed  Google Scholar 

  18. Ades L, Guerci A, Raffoux E, Sanz M, Chevallier P, Lapusan S et al (2010) Very long-term outcome of acute promyelocytic leukemia after treatment with all-trans retinoic acid and chemotherapy: the European APL Group experience. Blood 115(9):1690–1696. https://doi.org/10.1182/blood-2009-07-233387

    Article  CAS  PubMed  Google Scholar 

  19. Ades L, Chevret S, De Botton S, Thomas X, Dombret H, Beve B et al (2005) Outcome of acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy in elderly patients: the European group experience. Leukemia 19(2):230–233. https://doi.org/10.1038/sj.leu.2403597

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study received financial support from the Catholic Medical Center Research Foundation in the program year of 2017.

Author information

Authors and Affiliations

  1. Department of Hematology, Leukemia Research Institute, Seoul St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, Banpo-daero 222, Seocho-Gu, Seoul, Republic of Korea

    Gi-June Min, Byung-Sik Cho, Sung-Soo Park, Silvia Park, Jae-Ho Yoon, Sung-Eun Lee, Ki-Seong Eom, Yoo-Jin Kim, Seok Lee, Chang-Ki Min, Seok-Goo Cho, Dong-Wook Kim, Jong Wook Lee & Hee-Je Kim

  2. Department of Hematology, Yeouido St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 10, 63-ro, Yeongdeungpo-gu, Seoul, Republic of Korea

    Young-Woo Jeon

  3. Department of Hematology, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 665-9 Bupyeong-dong, Bupyeong-gu, Incheon, Republic of Korea

    Seung-Ah Yahng

  4. Department of Hematology, Eunpyeong St. Mary’s Hematology Hospital, College of Medicine, The Catholic University of Korea, 1021, Tongil Ro, Eunpyeong-gu, Seoul, Republic of Korea

    Seung-Hawn Shin

Authors
  1. Gi-June Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Byung-Sik Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sung-Soo Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Young-Woo Jeon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Seung-Ah Yahng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Seung-Hawn Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jae-Ho Yoon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sung-Eun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ki-Seong Eom
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Yoo-Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Seok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Chang-Ki Min
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Seok-Goo Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Dong-Wook Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jong Wook Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Hee-Je Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

G-JM performed the molecular research, collected and analyzed data, and wrote the manuscript. S-HS, S-AY, J-HY, B-SC, and H-JK provided patients and materials and reviewed the manuscript. S-SP, S-EL, K-SE, and C-KM provided materials and reviewed the manuscript. Y-JK, SL, S-GC, D-WK, and J-WL reviewed the manuscript and analyzed data. B-SC designed and conducted the study, provided patients and materials, analyzed data, and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Byung-Sik Cho.

Ethics declarations

Ethics approval and consent to participate

This study protocol was approved according to the guidelines of the Institutional Review Board and Ethics Committee of the Catholic Medical Center, Republic of Korea.

Consent for publication

The consent for publication was not applicable for this study and was permitted by the Institutional Review Board and Ethics Committee guidelines of the Catholic Medical Center (KC15RISI0862).

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 314 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Min, GJ., Cho, BS., Park, SS. et al. Safety and efficacy of arsenic trioxide and all-trans retinoic acid therapy in acute promyelocytic leukemia patients with a high risk for early death. Ann Hematol 99, 973–982 (2020). https://doi.org/10.1007/s00277-020-04010-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-020-04010-9

Keywords

Search

Navigation