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

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

References

[1] Kaspers GJ. Pediatric acute myeloid leukemia. Expert Rev Anticancer Ther 2012; 12(3): 405–413

[2] de Rooij JD, Zwaan CM, van den Heuvel-Eibrink M. Pediatric AML: from biology to clinical management. J Clin Med 2015; 4(1): 127–149

[3] Taga T, Tomizawa D, Takahashi H, Adachi S. Acute myeloid leukemia in children: current status and future directions. Pediatr Int 2016; 58(2): 71–80

[4] Luo CY, Tang JY, Wang YP. Homoharringtonine: a new treatment option for myeloid leukemia. Hematology 2004; 9(4): 259–270

[5] Lü S, Wang J. Homoharringtonine and omacetaxine for myeloid hematological malignancies. J Hematol Oncol 2014; 7(1): 2

[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): 1361–1367

[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): 1591–1605

[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): 259–266

[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): 1185–1188

[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): 610–617

[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): 4642–4649

[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): 72–77

[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): e382

[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): 1103–1110

[15] Powell RG, Weisleder D, Smith CR Jr, Rohwedder WK. Structures of harringtonine, isoharringtonine, and homoharringtonine. Tetrahedron Lett 1970; 11(11): 815–818

[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): 997–1003

[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): 1091–1100

[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): 1245–1248

[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): 103–107

[20] Tang J, Xue H, Pan C, Chen J, Gu L, Zhao H. A homoharringtonine-based regimen for childhood acute myelogenous leukemia. Med Pediatr Oncol 2003; 41(1): 70–72

[21] Gruber TA, Downing JR. The biology of pediatric acute megakaryoblastic leukemia. Blood 2015; 126(8): 943–949

[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): 451–456

[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): 394–404

[24] Simon A. Risk factors for and prevention of bloodstream infection in pediatric AML—the debate continues. Pediatr Blood Cancer 2017; 64(3): e26300

[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): e26254

[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): 1368–1379

[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): 577–587

[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): 3273–3279

[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): 625–630

[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): 55–62 doi:10.1111/ejh.12683 PMID:26383901

[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): 279–285

RIGHTS & PERMISSIONS

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