Abstract
The purpose of this study was to assess the feasibility and efficacy of a treatment regimen for pediatric acute myelogenous leukemia (AML) that uses four rotating drug pairs and adjusts dosages of etoposide and cytarabine to target specific plasma concentrations. Thirty-one girls and 27 boys (median age, 9.7 years) with de novo AML were treated on the protocol. Six cycles of chemotherapy were planned. Cycles 1 to 4 comprised the drug combinations cytarabine plus etoposide, cytarabine plus daunomycin, etoposide plus amsacrine, and etoposide plus azacitidine, respectively. For cycles 5 and 6, the first two combinations were repeated. Dosages were adjusted to achieve plasma concentrations of 1.0 μM ± 0.1 μM cytarabine μ 30μM ± 0.3 μM etoposide. Forty-four patients (76%) entered complete remission. Of those, 24 have had relapses; 23 remain alive in first or subsequent remission. The 5-year event-free survival (EFS) estimate was 31.0% ± 5.9%; the 5-year survival estimate was 41.4% ± 6.3%. Six patients (10%) died of the toxic effects of therapy. Severe neutropenia occurred in all cycles. Long-term complications of therapy included hepatitis C, cardiac insufficiency, and hearing loss. Adjustment of cytarabine and etoposide dosage was feasible for achieving targeted plasma drug concentrations; however, the potential clinical efficacy of this approach was offset by substantial acute and long-term toxicity.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Pui CH . Acute leukemia in children Curr Opin Hematol 1996 3: 249–258
Woods WG, Kobrinsky N, Buckley JD, Lee JW, Sanders J, Neudorf S, Gold S, Barnard DR, DeSwarte J, Dusenbery K, Kalousek D, Arthur DC, Lange BJ . Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group Blood 1996 87: 4979–4989
Stevens RF, Hann IM, Wheatley K, Gray RG . Marked improvements in outcome with chemotherapy alone in paediatric acute myeloid leukaemia: results of the United Kingdom Medical Research Council's 10th AML trial. MRC Childhood Leukaemia Working Party Br J Haematol 1998 101: 130–140
Mayer RJ, Davis RB, Schiffer CA, Berg DT, Powell BL, Schulman P, Omura GA, Moore JO, McIntyre OR, Frei E III . Intensive postremission chemotherapy in adults with acute myeloid leukemia. Cancer and Leukemia Group B New Engl J Med 1994 331: 896–903
Rees JK, Gray RG, Wheatley K . Dose intensification in acute myeloid leukaemia: greater effectiveness at lower cost. Principal report of the Medical Research Council's AML9 study. MRC Leukaemia in Adults Working Party Br J Haematol 1996 94: 89–98
Bishop JF, Lowenthal RM, Joshua D, Matthews JP, Todd D, Cobcroft R, Whiteside MG, Kronenberg H, Ma D, Dodds A . Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group Blood 1990 75: 27–32
Weick JK, Kopecky KJ, Appelbaum FR, Head DR, Kingsbury LL, Balcerzak SP, Bickers JN, Hynes HE, Welborn JL, Simon SR, Grever M . A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study Blood 1996 88: 2841–2851
Evans WE, Sinkule JA, Crom WR, Dow L, Look AT, Rivera G . Pharmacokinetics of teniposide (VM26) and etoposide (VP16–213) in children with cancer Cancer Chemother Pharmacol 1982 7: 147–150
Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH . Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia New Engl J Med 1998 338: 499–505
Behm FG . Diagnosis of childhood acute myeloid leukemia Clin Lab Med 1999 19: 187–237
Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C . Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French–American–British Cooperative Group Ann Intern Med 1985 103: 620–625
Pui CH, Mahmoud HH, Rivera GK, Hancock ML, Sandlund JT, Behm FG, Head DR, Relling MV, Ribeiro RC, Rubnitz JE, Kun LE, Evans WE . Early intensification of intrathecal chemotherapy virtually eliminates central nervous system relapse in children with acute lymphoblastic leukemia Blood 1998 92: 411–415
Sinkule JA, Evans WE . High-performance liquid chromatographic assay for cytosine arabinoside, uracil arabinoside and some related nucleosides J Chromatogr 1983 274: 87–93
Sinkule JA, Evans WE . High-performance liquid chromatographic analysis of the semisynthetic epipodophyllotoxins teniposide and etoposide using electrochemical detection J Pharm Sci 1984 73: 164–168
Liliemark JO, Paul CY, Gahrton CG, Peterson CO . Pharmacokinetics of 1-beta-D-arabinofuranosylcytosine 5′-triphosphate in leukemic cells after intravenous and subcutaneous administration of 1-beta-Darabinofuranosylcytosine Cancer Res 1985 45: 2373–2375
Kaplan EL, Meier P . Nonparametric estimation from incomplete observations J Am Stat Assoc 1999 53: 457–481
Plunkett W, Iacoboni S, Keating MJ . Cellularpharmacology and optimal therapeutic concentrations of 1-beta-D-arabinofuranosylcytosine 5′-triphosphate in leukemic blasts during treatment of refractory leukemia with high-dose 1-beta-D-arabinofuranosylcytosine Scand JHaematol Suppl 1986 44: 51–59
Plunkett W, Heinemann V, Estey E, Keating M . Pharmacologically directed design of leukemia therapy Hamatol Bluttransfus 1990 33: 610–613
Ross DD, Thompson BW, Joneckis CC, Akman SA, Schiffer CA . Metabolism of ara-C by blast cells from patients with ANLL Blood 1986 68: 76–82
Hande KR, Wedlund PJ, Noone RM, Wilkinson GR, Greco FA, Wolff SN . Pharmacokinetics of high-dose etoposide (VP-16–213) administered to cancer patients Cancer Res 1984 44: 379–382
Johnson DH, Hande KR, Porter LL, Hainsworth JD, Wolff SN, Greco FA . High-dose pilot studies in extensive-stage small-cell lung cancer Semin Oncol 1986 13: 37–39
Bishop JF, Matthews JP, Young GA, Szer J, Gillett A, Joshua D, Bradstock K, Enno A, Wolf MM, Fox R . A randomized study of high-dose cytarabine in induction in acute myeloid leukemia Blood 1996 87: 1710–1717
Lampkin BC, Nagao T, Mauer AM . Synchronization of the mitotic cycle in acute leukaemia Nature 1969 222: 1274–1275
Goldie JH, Coldman AJ, Gudauskas GA . Rationale for the use of alternating non-cross-resistant chemotherapy Cancer Treat Rep 1982 66: 439–449
Kalwinsky D, Mirro J Jr, Schell M, Behm F, Mason C, Dahl GV . Early intensification of chemotherapy for childhood acute nonlymphoblastic leukemia: improved remission induction with a five- drug regimen including etoposide J Clin Oncol 1988 6: 1134–1143
Creutzig U, Ritter J, Schellong G . Identification of two risk groups in childhood acute myelogenous leukemia after therapy intensification in study AML-BFM-83 as compared with study AML-BFM-78. AML-BFM Study Group Blood 1990 75: 1932–1940
Ochs J, Rivera GK, Pollock BH, Buchanan G, Crist W, Freeman AI . Teniposide (VM-26) and continuous infusion cytosine arabinoside for initial induction failure in childhood acute lymphoblastic leukemia. A Pediatric Oncology Group pilot study Cancer 1990 66: 1671–1677
Donehower RC, Karp JE, Burke PJ . Pharmacology and toxicity of high-dose cytarabine by 72-hour continuous infusion Cancer Treat Rep 1986 70: 1059–1065
Creutzig U, Ritter J, Zimmermann M, Schellong G . Does cranial irradiation reduce the risk for bone marrow relapse in acute myelogenous leukemia? Unexpected results of the Childhood Acute Myelogenous Leukemia Study BFM-87 J Clin Oncol 1993 11: 279–286
Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ . Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group New Engl J Med 1996 334: 1428–1434
Robinson N, Sullivan KM . Complications of allogeneic bone marrow transplantation Curr Opin Hematol 1994 1: 406–411
Didi M, Didcock E, Davies HA, Ogilvy-Stuart AL, Wales JK, Shalet SM . High incidence of obesity in young adults after treatment of acute lymphoblastic leukemia in childhood J Pediatr 1995 127: 63–67
Creutzig U, Zimmermann M, Ritter J, Henze G, Graf N, Loffler H, Schellong G . Definition of a standard-risk group in children with AML Br J Haematol 1999 104: 630–639
Acknowledgements
This work was supported in part by NCI Cancer Center Core Grants P30-CA-21765 and PO1-CA-20180 and by the American Lebanese Syrian Associated Charities (ALSAC). The authors extend special thanks to Sharon Naron for editorial assistance.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Arnaout, M., Radomski, K., Srivastava, D. et al. Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: short- and long-term effects. Leukemia 14, 1736–1742 (2000). https://doi.org/10.1038/sj.leu.2401906
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2401906
Keywords
This article is cited by
-
The miR-125a-3p Inhibits TIM-3 Expression in AML Cell Line HL-60 In Vitro
Indian Journal of Hematology and Blood Transfusion (2017)
-
Successive clinical trials for childhood acute myeloid leukemia at St Jude Children's Research Hospital, from 1980 to 2000
Leukemia (2005)
-
Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action
British Journal of Pharmacology (2004)
-
Clinical significance of central nervous system involvement at diagnosis of pediatric acute myeloid leukemia: a single institution's experience
Leukemia (2003)
-
Characteristics and outcome of t(8;21)-positive childhood acute myeloid leukemia: a single institution's experience
Leukemia (2002)