Acute promyelocytic leukemia historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Shyam Patel [2] Sogand Goudarzi, MD [3] Grammar Reviewer: Natalie Harpenau, B.S.[4]


The first documentation of the successful treatment of acute promyelocytic leukemia occurred in the late 19th century, at which time physicians and scientists explored the role of arsenic as an anti-leukemic agent. Since that time, multiple advances have been made over the years. Specifically, the use of cytotoxic chemotherapy (anthracycline and cytarabine) has been explored extensively. The use of all-trans retinoic acid in the 20th century has revolutionized the treatment paradigm for acute promyelocytic leukemia. In the early 21st century, a landmark study showed that the combination of arsenic plus all-trans retinoic acid was superior to conventional chemotherapy for low-risk acute promyelocytic leukemia.

Historical perspective

  • In 1882, A.C. Doyle reported on the efficacy of arsenic in acute promyelocytic leukemia.[1]
  • In 1957, Leif Hillestad described acute promyelocytic leukemia as a distinct clinical condition for the first time. He noted the syndrome of low fibrinogen levels, fibrin degradation, and life-threatening hemorrhage.[2] It was noted that this condition carried a high mortality rate due to severe hemorrhage.[3]
  • In 1970, scientists in Harbin showed that arsenic trioxide and mercury chloride could treat acute and chronic leukemia.[4]
  • In 1973, Bernard and colleagues showed in clinical studies that therapeutic efficacy of daunorubicin, an chemotherapy agent of the anthracycline class. This medication was shown to induce remission in the majority of patients, with an increase in remission rate from 13% to 58%. The median duration of remission with daunorubicin was more than 2 years. Compared to 6-mercaptopurine, daunorubicin was shown to reduce mortality from bleeding after 5 days.[3]
  • In the early 1990s, it was noted that arsenic trioxide could induce remission in a high proportion of patients.[3][5]
  • In 1980, Breitman and colleagues showed that all-trans retinoic acid could lead to the differentiation of the HL-60 cell line of myeloid leukemia. This was the first demonstration that differentiation therapy could treat leukemia. This concept was based on the fact that most cancers are primitive and stem-like, which leads to aggressive and chemo-resistant cellular behavior. Blockade of stemness and induction of differentiation could lead to anti-cancer effect.[2][6]
  • In 1988, Huang and colleagues showed that all-trans retinoic acid could successfully treat acute promyelocytic leukemia in 24 patients. The complete remission rate was more tan 90%.[2]
  • In 1995, D. Head and colleagues showed that higher remission rates and higher survival rates could be achieved with higher doses of daunorubicin, with a survival rate of 61% after 9 years and a 0% relapse after 36 months.[7]
  • In 1997, scientists in Harbin and Shanghai showed that single-agent arsenic trioxide could induce response rates of 90% in patients who relapsed after receiving all-trans retinoic acid and chemotherapy.[2]
  • In 2000, the United States Food and Drug Administration approved arsenic trioxide for treatment of acute promyelocytic leukemia.[8]
  • In 2001, Soignet and colleagues showed that a single, 5-week course of arsenic trioxide carried a complete remission rate of 50%. It was shown that 2 cycles of arsenic trioxide could induce remission in 86% of patients.[9]
  • In 2013, LoCoco and colleagues showed that, in a randomized phase 3 multi-center clinical trial, a non-chemotherapy-based regimen was superior to a chemotherapy-based regimen for low-risk acute promyelocytic leukemia. Specifically, the combination of all-''trans'' retinoic acid and arsenic trioxide resulted in improved overall survival compared to the combination of all-trans retinoic acid plus chemotherapy. This landmark clinical trial, which was conducted by the Italian and German-Austrian Leukemia Study Groups, altered the treatment paradigm for low-risk acute promyelocytic leukemia.[10]


  1. Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM (2016). "The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy". Cancer. 122 (8): 1160–8. doi:10.1002/cncr.29852. PMC 5042140. PMID 26716387.
  2. 2.0 2.1 2.2 2.3 McCulloch D, Brown C, Iland H (2017). "Retinoic acid and arsenic trioxide in the treatment of acute promyelocytic leukemia: current perspectives". Onco Targets Ther. 10: 1585–1601. doi:10.2147/OTT.S100513. PMC 5359123. PMID 28352191.
  3. 3.0 3.1 3.2 Coombs CC, Tavakkoli M, Tallman MS (2015). "Acute promyelocytic leukemia: where did we start, where are we now, and the future". Blood Cancer J. 5: e304. doi:10.1038/bcj.2015.25. PMC 4450325. PMID 25885425.
  4. Chen, Sai-Juan; Zhou, Guang-Biao (2012). "Targeted therapy: The new lease on life for acute promyelocytic leukemia, and beyond". IUBMB Life. 64 (8): 671–675. doi:10.1002/iub.1055. ISSN 1521-6543.
  5. Park J, Jurcic JG, Rosenblat T, Tallman MS (2011). "Emerging new approaches for the treatment of acute promyelocytic leukemia". Ther Adv Hematol. 2 (5): 335–52. doi:10.1177/2040620711410773. PMC 3573416. PMID 23556100.
  6. Frank, Natasha Y.; Schatton, Tobias; Frank, Markus H. (2010). "The therapeutic promise of the cancer stem cell concept". Journal of Clinical Investigation. 120 (1): 41–50. doi:10.1172/JCI41004. ISSN 0021-9738.
  7. Head D, Kopecky KJ, Weick J, Files JC, Ryan D, Foucar K; et al. (1995). "Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia". Blood. 86 (5): 1717–28. PMID 7655004.
  8. Kumar S, Yedjou CG, Tchounwou PB (2014). "Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells". J Exp Clin Cancer Res. 33: 42. doi:10.1186/1756-9966-33-42. PMC 4049373. PMID 24887205.
  9. Soignet SL, Frankel SR, Douer D, Tallman MS, Kantarjian H, Calleja E; et al. (2001). "United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia". J Clin Oncol. 19 (18): 3852–60. doi:10.1200/JCO.2001.19.18.3852. PMID 11559723.
  10. Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S; et al. (2013). "Retinoic acid and arsenic trioxide for acute promyelocytic leukemia". N Engl J Med. 369 (2): 111–21. doi:10.1056/NEJMoa1300874. PMID 23841729.

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