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Homoharringtonine is a safe and effective substitute for anthracyclines in children younger than 2 years old with acute myeloid leukemia

  • Xiaoxiao Chen
  • Yanjing Tang
  • Jing Chen
  • Ru Chen
  • Longjun Gu
  • Huiliang Xue
  • Ci Pan
  • Jingyan TangEmail author
  • Shuhong ShenEmail author
Research Article
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Abstract

Homoharringtonine (HHT), a plant alkaloid from Cephalotaxus harringtonia, exhibits a unique anticancer mechanism and has been widely used in China to treat patients with acute myeloid leukemia (AML) since the 1970s. Trial SCMC-AML-2009 presented herein was a randomized clinical study designed based on our previous findings that pediatric AML patients younger than two years old may benefit from HHT-containing chemotherapy regimens. Patients randomized to arm A were treated with a standard chemotherapy regimen comprising mainly of anthracyclines and cytarabine (Ara-C), whereas patients in arm B were treated with HHT-containing regimens in which anthracyclines in all but the initial induction therapy were replaced by HHT. From February 2009 to November 2015, 59 patients less than 2 years old with de novo AML (other than acute promyelocytic leukemia) were recruited. A total of 42 patients achieved a morphologic complete remission (CR) after the first course, with similar rates in both arms (70.6% vs.72.0%). At the end of the follow-up period, 40 patients remained in CR and 5 patients underwent hematopoietic stem cell transplantation in CR, which could not be considered as events but censors. The 5-year event-free survival (EFS) was 60.2%±9.6% for arm A and 88.0%±6.5% for arm B (P= 0.024). Patients in arm B experienced shorter durations of leukopenia, neutropenia, and thrombocytopenia and had a lower risk of infection during consolidation chemotherapy with high-dosage Ara-C. Consequently, the homoharringtonine-based regimen achieved excellent EFS and alleviated hematologic toxicity for children aged younger than 2 years with de novo AML compared with the anthracycline-based regimen.

Keywords

homoharringtonine acute myeloid leukemia pediatrics 

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Notes

Acknowledgements

This work was partially supported by the National Natural Science Foundation of China (No. 81270623), the Science and Technology Commission of Shanghai Municipality (No. 14411950600), and the Public Health 3-Year Project of Shanghai Children’s Medical Center (No. GWIV-25).

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References

  1. 1.
    Kaspers GJ. Pediatric acute myeloid leukemia. Expert Rev Anticancer Ther 2012; 12(3): 405–413CrossRefGoogle Scholar
  2. 2.
    de Rooij JD, Zwaan CM, van den Heuvel-Eibrink M. Pediatric AML: from biology to clinical management. J Clin Med 2015; 4(1): 127–149CrossRefGoogle Scholar
  3. 3.
    Taga T, Tomizawa D, Takahashi H, Adachi S. Acute myeloid leukemia in children: current status and future directions. Pediatr Int 2016; 58(2): 71–80CrossRefGoogle Scholar
  4. 4.
    Luo CY, Tang JY, Wang YP. Homoharringtonine: a new treatment option for myeloid leukemia. Hematology 2004; 9(4): 259–270CrossRefGoogle Scholar
  5. 5.
    Lü S, Wang J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. J Hematol Oncol 2014; 7(1): 2CrossRefGoogle Scholar
  6. 6.
    Jin J, Jiang DZ, Mai WY, Meng HT, Qian WB, Tong HY, Huang J, Mao LP, Tong Y, Wang L, Chen ZM, Xu WL. Homoharringtonine in combination with cytarabine and aclarubicin resulted in high complete remission rate after the first induction therapy in patients with de novo acute myeloid leukemia. Leukemia 2006; 20(8): 1361–1367CrossRefGoogle Scholar
  7. 7.
    Kantarjian HM, Talpaz M, Santini V, Murgo A, Cheson B, O’Brien SM. Homoharringtonine: history, current research, and future direction. Cancer 2001; 92(6): 1591–1605CrossRefGoogle Scholar
  8. 8.
    Tong H, Ren Y, Zhang F, Jin J. Homoharringtonine affects the JAK2-STAT5 signal pathway through alteration of protein tyrosine kinase phosphorylation in acute myeloid leukemia cells. Eur J Haematol 2008; 81(4): 259–266CrossRefGoogle Scholar
  9. 9.
    Feldman E, Arlin Z, Ahmed T, Mittelman A, Puccio C, Chun H, Cook P, Baskind P. Homoharringtonine is safe and effective for patients with acute myelogenous leukemia. Leukemia 1992; 6(11): 1185–1188Google Scholar
  10. 10.
    Tang J, Liu Y, Chen J, Xue H, Pan C, Gu L. Homoharringtonine as a backbone drug for the treatment of newly diagnosed pediatric acute myeloid leukemia: a report from a single institution in China. Int J Hematol 2011; 93(5): 610–617CrossRefGoogle Scholar
  11. 11.
    Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, Schiffer CA, Doehner H, Tallman MS, Lister TA, Lo-Coco F, Willemze R, Biondi A, Hiddemann W, Larson RA, Löwenberg B, Sanz MA, Head DR, Ohno R, Bloomfield CD; International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. 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(24): 4642–4649CrossRefGoogle Scholar
  12. 12.
    Lehrnbecher T, Varwig D, Kaiser J, Reinhardt D, Klingebiel T, Creutzig U. Infectious complications in pediatric acute myeloid leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia 2004; 18(1): 72–77CrossRefGoogle Scholar
  13. 13.
    Bochennek K, Hassler A, Perner C, Gilfert J, Schöning S, Klingebiel T, Reinhardt D, Creutzig U, Lehrnbecher T. Infectious complications in children with acute myeloid leukemia: decreased mortality in multicenter trial AML-BFM 2004. Blood Cancer J 2016; 6(1): e382CrossRefGoogle Scholar
  14. 14.
    Wisplinghoff H, Seifert H, Wenzel RP, Edmond MB. Current trends in the epidemiology of nosocomial bloodstream infections in patients with hematological malignancies and solid neoplasms in hospitals in the United States. Clin Infect Dis 2003; 36(9): 1103–1110CrossRefGoogle Scholar
  15. 15.
    Powell RG, Weisleder D, Smith CR Jr, Rohwedder WK. Structures of harringtonine, isoharringtonine, and homoharringtonine. Tetrahedron Lett 1970; 11(11): 815–818CrossRefGoogle Scholar
  16. 16.
    Gu LF, Zhang WG, Wang FX, Cao XM, Chen YX, He AL, Liu J, Ma XR. Low dose of homoharringtonine and cytarabine combined with granulocyte colony-stimulating factor priming on the outcome of relapsed or refractory acute myeloid leukemia. J Cancer Res Clin Oncol 2011; 137(6): 997–1003CrossRefGoogle Scholar
  17. 17.
    Yu W, Mao L, Qian J, Qian W, Meng H, Mai W, Tong H, Tong Y, Jin J. Homoharringtonine in combination with cytarabine and aclarubicin in the treatment of refractory/relapsed acute myeloid leukemia: a single-center experience. Ann Hematol 2013; 92(8): 1091–1100CrossRefGoogle Scholar
  18. 18.
    Tan CT, Luks E, Bacha DM, Steinherz P, Steinherz L, Mondora A. Phase I trial of homoharringtonine in children with refractory leukemia. Cancer Treat Rep 1987; 71(12): 1245–1248Google Scholar
  19. 19.
    Bell BA, Chang MN, Weinstein HJ. A phase II study of homoharringtonine for the treatment of children with refractory or recurrent acute myelogenous leukemia: a pediatric oncology group study. Med Pediatr Oncol 2001; 37(2): 103–107CrossRefGoogle Scholar
  20. 20.
    Tang J, Xue H, Pan C, Chen J, Gu L, Zhao H. A homoharringtoninebased regimen for childhood acute myelogenous leukemia. Med Pediatr Oncol 2003; 41(1): 70–72CrossRefGoogle Scholar
  21. 21.
    Gruber TA, Downing JR. The biology of pediatric acute megakaryoblastic leukemia. Blood 2015; 126(8): 943–949CrossRefGoogle Scholar
  22. 22.
    de Rooij JD, Branstetter C, Ma J, Li Y, Walsh MP, Cheng J, Obulkasim A, Dang J, Easton J, Verboon LJ, Mulder HL, Zimmermann M, Koss C, Gupta P, Edmonson M, Rusch M, Lim JY, Reinhardt K, Pigazzi M, Song G, Yeoh AE, Shih LY, Liang DC, Halene S, Krause DS, Zhang J, Downing JR, Locatelli F, Reinhardt D, van den Heuvel-Eibrink MM, Zwaan CM, Fornerod M, Gruber TA. Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nat Genet 2017; 49(3): 451–456CrossRefGoogle Scholar
  23. 23.
    Hara Y, Shiba N, Ohki K, Tabuchi K, Yamato G, Park MJ, Tomizawa D, Kinoshita A, Shimada A, Arakawa H, Saito AM, Kiyokawa N, Tawa A, Horibe K, Taga T, Adachi S, Taki T, Hayashi Y. Prognostic impact of specific molecular profiles in pediatric acute megakaryoblastic leukemia in non-Down syndrome. Genes Chromosomes Cancer 2017; 56(5): 394–404CrossRefGoogle Scholar
  24. 24.
    Simon A. Risk factors for and prevention of bloodstream infection in pediatric AML—the debate continues. Pediatr Blood Cancer 2017; 64(3): e26300CrossRefGoogle Scholar
  25. 25.
    Rogers AE, Eisenman KM, Dolan SA, Belderson KM, Zauche JR, Tong S, Gralla J, Hilden JM, Wang M, Maloney KW, Dominguez SR. Risk factors for bacteremia and central line-associated blood stream infections in children with acute myelogenous leukemia: a single-institution report. Pediatr Blood Cancer 2017; 64(3): e26254CrossRefGoogle Scholar
  26. 26.
    Mertens AC, Liu Q, Neglia JP, Wasilewski K, Leisenring W, Armstrong GT, Robison LL, Yasui Y. Cause-specific late mortality among 5-year survivors of childhood cancer: the Childhood Cancer Survivor Study. J Natl Cancer Inst 2008; 100(19): 1368–1379CrossRefGoogle Scholar
  27. 27.
    Jarfelt M, Andersen NH, Hasle H. Is it possible to cure childhood acute myeloid leukaemia without significant cardiotoxicity? Br J Haematol 2016; 175(4): 577–587CrossRefGoogle Scholar
  28. 28.
    Leung W, Hudson MM, Strickland DK, Phipps S, Srivastava DK, Ribeiro RC, Rubnitz JE, Sandlund JT, Kun LE, Bowman LC, Razzouk BI, Mathew P, Shearer P, Evans WE, Pui CH. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000; 18(18): 3273–3279CrossRefGoogle Scholar
  29. 29.
    Temming P, Qureshi A, Hardt J, Leiper AD, Levitt G, Ancliff PJ, Webb DKH. Prevalence and predictors of anthracycline cardiotoxicity in children treated for acute myeloid leukaemia: retrospective cohort study in a single centre in the United Kingdom. Pediatr Blood Cancer 2011; 56(4): 625–630CrossRefGoogle Scholar
  30. 30.
    Jarfelt M, Andersen NH, Glosli H, Jahnukainen K, Jónmundsson GK, Malmros J, Nysom K, Hasle H; Nordic Society of Pediatric Hematology and Oncology (NOPHO). Cardiac function in survivors of childhood acute myeloid leukemia treated with chemotherapy only: a NOPHO-AML study. Eur J Haematol 2016; 57(7): 55–62CrossRefGoogle Scholar
  31. 31.
    Wang Y, Lin D, Wei H, Li W, Liu B, Zhou C, Liu K, Mi Y, Wang J. Long-term follow-up of homoharringtonine plus all-trans retinoic acid-based induction and consolidation therapy in newly diagnosed acute promyelocytic leukemia. Int J Hematol 2015; 101(3): 279–285CrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Xiaoxiao Chen
    • 1
  • Yanjing Tang
    • 1
  • Jing Chen
    • 1
  • Ru Chen
    • 1
  • Longjun Gu
    • 1
  • Huiliang Xue
    • 1
  • Ci Pan
    • 1
  • Jingyan Tang
    • 1
    Email author
  • Shuhong Shen
    • 1
    Email author
  1. 1.Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Department of Hematology and Oncology, Pediatric Translational Medicine Institute, Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghaiChina

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