Skip to main content
SpringerLink
Log in

Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Antileukemic Drugs

  • Chapter
  • First Online:
Book cover Childhood Acute Lymphoblastic Leukemia

Abstract

At least 85% of children with acute lymphoblastic leukemia (ALL) can be cured by the best contemporary therapy, but it is uncertain which of the multiple effector mechanisms of the antileukemic agents that are responsible for the efficacy (Fig. 5.1 and Table 5.1). This contrasts the modern era of targeted therapy, where molecular mapping of chemoresistant cancer cells has led to development of drugs that specifically target aberrant pathways (see Chap. 9).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Schmiegelow K, Forestier E, Hellebostad M, et al. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010;24(2):345–54.

    Article  CAS  PubMed  Google Scholar 

  2. Pui CH, Yang JJ, Hunger SP, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(27):2938–48.

    Article  CAS  Google Scholar 

  3. Farber S, Diamond LK. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid. N Engl J Med. 1948;238(23):787–93.

    Article  CAS  PubMed  Google Scholar 

  4. Burchenal JH, Murphy ML, Ellison RR, et al. Clinical evaluation of a new antimetabolite, 6-mercaptopurine, in the treatment of leukemia and allied diseases. Blood. 1953;8(11):965–99.

    CAS  PubMed  Google Scholar 

  5. Simone J, Pinkel D. Rationale and results of combination chemotherapy and central nervous system irradiation in acute lymphocytic leukemia. Bibl Haematol. 1973;39:1068–73.

    CAS  PubMed  Google Scholar 

  6. Vora A, Andreano A, Pui CH, et al. Influence of cranial radiotherapy on outcome in children with acute lymphoblastic leukemia treated with contemporary therapy. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(9):919–26.

    Article  CAS  Google Scholar 

  7. Riehm H, Feickert HJ, Schrappe M, Henze G, Schellong G. Therapy results in five ALL-BFM studies since 1970: implications of risk factors for prognosis. Haematol Blood Transf. 1987;30:139–46.

    CAS  Google Scholar 

  8. Galpin AJ, Schuetz JD, Masson E, et al. Differences in folylpolyglutamate synthetase and dihydrofolate reductase expression in human B-lineage versus T-lineage leukemic lymphoblasts: mechanisms for lineage differences in methotrexate polyglutamylation and cytotoxicity. Mol Pharmacol. 1997;52(1):155–63.

    CAS  PubMed  Google Scholar 

  9. Coustan-Smith E, Behm FG, Sanchez J, et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet. 1998;351(9102):550–4.

    Article  CAS  PubMed  Google Scholar 

  10. Neale GA, Coustan-Smith E, Pan Q, et al. Tandem application of flow cytometry and polymerase chain reaction for comprehensive detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia. 1999;13(8):1221–6.

    Article  CAS  PubMed  Google Scholar 

  11. Nyvold C, Madsen HO, Ryder LP, et al. Competitive PCR for quantification of minimal residual disease in acute lymphoblastic leukaemia. J Immunol Methods. 2000;233(1–2):107–18.

    Article  CAS  PubMed  Google Scholar 

  12. Bruggemann M, Schrauder A, Raff T, et al. Standardized MRD quantification in European ALL trials: proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. Leukemia. 2010;24(3):521–35.

    Article  CAS  PubMed  Google Scholar 

  13. Pui CH, Pei D, Coustan-Smith E, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol. 2015;16(4):465–74.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Madhusoodhan PP, Carroll WL, Bhatla T. Progress and prospects in pediatric leukemia. Curr Probl Pediatr Adolesc Health Care. 2016;46(7):229–41.

    Article  PubMed  Google Scholar 

  15. Ronghe M, Burke GA, Lowis SP, Estlin EJ. Remission induction therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase and anthracyclines. Cancer Treat Rev. 2001;27(6):327–37.

    Article  CAS  PubMed  Google Scholar 

  16. Schmiegelow K, Nielsen SN, Frandsen TL, Nersting J. Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol. 2014;36(7):503–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmiegelow K, Nersting J, Nielsen SN, et al. Maintenance therapy of childhood acute lymphoblastic leukemia revisited – should drug doses be adjusted by white blood cell, neutrophil, or lymphocyte counts? Pediatr Blood Cancer. 2016;63:2104.

    Article  CAS  PubMed  Google Scholar 

  18. Meibohm B, Derendorf H. Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling. Int J Clin Pharmacol Ther. 1997;35(10):401–13.

    CAS  PubMed  Google Scholar 

  19. Evans WE, Rodman JH, Relling MV, et al. Concept of maximum tolerated systemic exposure and its application to phase I-II studies of anticancer drugs. Med Pediatr Oncol. 1991;19(3):153–9.

    Article  CAS  PubMed  Google Scholar 

  20. Schmiegelow K. Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol. 2009;146(5):489–503.

    Article  CAS  PubMed  Google Scholar 

  21. Boos J. Pharmacokinetics and drug monitoring of L-asparaginase treatment. Int J Clin Pharmacol Ther. 1997;35(3):96–8.

    CAS  PubMed  Google Scholar 

  22. Asselin B, Rizzari C. Asparaginase pharmacokinetics and implications of therapeutic drug monitoring. Leuk Lymphoma. 2015;56(8):2273–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Evans WE, Relling MV, Rodman JH, Crom WR, Boyett JM, Pui CH. Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N Engl J Med. 1998;338(8):499–505.

    Article  CAS  PubMed  Google Scholar 

  24. Schmiegelow K, Bjork O, Glomstein A, et al. Intensification of mercaptopurine/methotrexate maintenance chemotherapy may increase the risk of relapse for some children with acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(7):1332–9.

    Article  CAS  Google Scholar 

  25. Vrooman LM, Stevenson KE, Supko JG, et al. Postinduction dexamethasone and individualized dosing of Escherichia Coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study – Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(9):1202–10.

    Article  CAS  Google Scholar 

  26. Mosteller RD. Simplified calculation of body-surface area. N Engl J Med. 1987;317(17):1098.

    CAS  PubMed  Google Scholar 

  27. Canal P, Chatelut E, Guichard S. Practical treatment guide for dose individualisation in cancer chemotherapy. Drugs. 1998;56(6):1019–38.

    Article  CAS  PubMed  Google Scholar 

  28. Cheung NV, Heller G. Chemotherapy dose intensity correlates strongly with response, median survival, and median progression-free survival in metastatic neuroblastoma. J Clin Oncol Off J Am Soc Clin Oncol. 1991;9(6):1050–8.

    Article  CAS  Google Scholar 

  29. Davidsen ML, Dalhoff K, Schmiegelow K. Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30(11):831–49.

    Article  CAS  PubMed  Google Scholar 

  30. Dulucq S, Laverdiere C, Sinnett D, Krajinovic M. Pharmacogenetic considerations for acute lymphoblastic leukemia therapies. Expert Opin Drug Metab Toxicol. 2014;10(5):699–719.

    Article  CAS  PubMed  Google Scholar 

  31. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120(6):1165–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Moriyama T, Relling MV, Yang JJ. Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 2015;125(26):3988–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Borst L, Wallerek S, Dalhoff K, et al. The impact of CYP3A5*3 on risk and prognosis in childhood acute lymphoblastic leukemia. Eur J Haematol. 2011;86(6):477–83.

    Article  CAS  PubMed  Google Scholar 

  34. Borst L, Buchard A, Rosthoj S, et al. Gene dose effects of GSTM1, GSTT1 and GSTP1 polymorphisms on outcome in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2012;34(1):38–42.

    Article  CAS  PubMed  Google Scholar 

  35. Wahlang B, Falkner KC, Cave MC, Prough RA. Role of cytochrome P450 monooxygenase in carcinogen and chemotherapeutic drug metabolism. Adv Pharmacol. 2015;74:1–33.

    Article  CAS  PubMed  Google Scholar 

  36. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst. 1999;91(23):2001–8.

    Article  CAS  PubMed  Google Scholar 

  37. Levinsen M, Rotevatn EO, Rosthoj S, et al. Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer. 2014;61(5):797–802.

    Article  CAS  PubMed  Google Scholar 

  38. Yang JJ, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA. 2009;301(4):393–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wesolowska-Andersen A, Borst L, Dalgaard MD, et al. Genomic profiling of thousands of candidate polymorphisms predicts risk of relapse in 778 Danish and German childhood acute lymphoblastic leukemia patients. Leukemia. 2015;29(2):297–303.

    Article  CAS  PubMed  Google Scholar 

  40. Beck T, Gollapudi S, Brunak S, et al. Knowledge engineering for health: a new discipline required to bridge the “ICT gap” between research and healthcare. Hum Mutat. 2012;33(5):797–802.

    Article  PubMed  Google Scholar 

  41. Schmiegelow K, Nyvold C, Seyfarth J, et al. Post-induction residual leukemia in childhood acute lymphoblastic leukemia quantified by PCR correlates with in vitro prednisolone resistance. Leukemia. 2001;15(7):1066–71.

    Article  CAS  PubMed  Google Scholar 

  42. Lonnerholm G, Thorn I, Sundstrom C, et al. In vitro cellular drug resistance adds prognostic information to other known risk-factors in childhood acute lymphoblastic leukemia. Leuk Res. 2011;35(4):472–8.

    Article  PubMed  CAS  Google Scholar 

  43. Moricke A, Zimmermann M, Reiter A, et al. Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000. Leukemia. 2010;24(2):265–84.

    Article  CAS  PubMed  Google Scholar 

  44. Conter V, Valsecchi MG, Silvestri D, et al. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007;369(9556):123–31.

    Article  CAS  PubMed  Google Scholar 

  45. Eden T, Pieters R, Richards S. Childhood acute lymphoblastic leukaemia collaborative G. Systematic review of the addition of vincristine plus steroid pulses in maintenance treatment for childhood acute lymphoblastic leukaemia – an individual patient data meta-analysis involving 5,659 children. Br J Haematol. 2010;149(5):722–33.

    Article  CAS  PubMed  Google Scholar 

  46. Mattano Jr LA, Devidas M, Nachman JB, et al. Effect of alternate-week versus continuous dexamethasone scheduling on the risk of osteonecrosis in paediatric patients with acute lymphoblastic leukaemia: results from the CCG-1961 randomised cohort trial. Lancet Oncol. 2012;13(9):906–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ramsey LB, Janke LJ, Payton MA, et al. Antileukemic efficacy of continuous vs discontinuous dexamethasone in murine models of acute lymphoblastic leukemia. PloS One. 2015;10(8):e0135134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Inaba H, Pui CH. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 2010;11(11):1096–106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Domenech C, Suciu S, De Moerloose B, et al. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014;99(7):1220–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Ito C, Evans WE, McNinch L, et al. Comparative cytotoxicity of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 1996;14(8):2370–6.

    Article  CAS  Google Scholar 

  51. Gaynon PS, Carrel AL. Glucocorticosteroid therapy in childhood acute lymphoblastic leukemia. Adv Exp Med Biol. 1999;457:593–605.

    Article  CAS  PubMed  Google Scholar 

  52. Moricke A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127(17):2101–12.

    Article  CAS  PubMed  Google Scholar 

  53. O’Connor D, Bate J, Wade R, et al. Infection-related mortality in children with acute lymphoblastic leukemia: an analysis of infectious deaths on UKALL2003. Blood. 2014;124(7):1056–61.

    Article  PubMed  Google Scholar 

  54. O’Connor D, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35(6):660–7. PMID: 28045622.

    Article  PubMed  Google Scholar 

  55. Distelhorst CW. Recent insights into the mechanism of glucocorticosteroid-induced apoptosis. Cell Death Differ. 2002;9(1):6–19.

    Google Scholar 

  56. Bindreither D, Ecker S, Gschirr B, Kofler A, Kofler R, Rainer J. The synthetic glucocorticoids prednisolone and dexamethasone regulate the same genes in acute lymphoblastic leukemia cells. BMC Genomics. 2014;15:662.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Jackson RK, Irving JA, Veal GJ. Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia. Br J Haematol. 2016;173(1):13–24.

    Article  PubMed  Google Scholar 

  58. Choonara I, Wheeldon J, Rayner P, Blackburn M, Lewis I. Pharmacokinetics of prednisolone in children with acute lymphoblastic leukaemia. Cancer Chemother Pharmacol. 1989;23(6):392–4.

    Article  CAS  PubMed  Google Scholar 

  59. Petersen KB, Jusko WJ, Rasmussen M, Schmiegelow K. Population pharmacokinetics of prednisolone in children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2003;51(6):465–73.

    CAS  PubMed  Google Scholar 

  60. Gambertoglio JG, Frey FJ, Holford NH, et al. Prednisone and prednisolone bioavailability in renal transplant patients. Kidney Int. 1982;21(4):621–6.

    Article  CAS  PubMed  Google Scholar 

  61. Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack DG. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 1987;5(2):202–7.

    Article  CAS  Google Scholar 

  62. Warris LT, van den Heuvel-Eibrink MM, Aarsen FK, et al. Hydrocortisone as an intervention for dexamethasone-induced adverse effects in pediatric patients with acute lymphoblastic leukemia: results of a double-blind, randomized controlled trial. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(19):2287–93.

    Article  Google Scholar 

  63. Rocha JC, Cheng C, Liu W, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005;105(12):4752–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lauten M, Matthias T, Stanulla M, Beger C, Welte K, Schrappe M. Association of initial response to prednisone treatment in childhood acute lymphoblastic leukaemia and polymorphisms within the tumour necrosis factor and the interleukin-10 genes. Leukemia. 2002;16(8):1437–42.

    Article  CAS  PubMed  Google Scholar 

  65. Meissner B, Stanulla M, Ludwig WD, et al. The GSTT1 deletion polymorphism is associated with initial response to glucocorticoids in childhood acute lymphoblastic leukemia. Leukemia. 2004;18(11):1920–3.

    Article  CAS  PubMed  Google Scholar 

  66. Jordan MA, Wilson L. Microtubules as a target for anticancer drugs. Nat Rev Cancer. 2004;4(4):253–65.

    Article  CAS  PubMed  Google Scholar 

  67. Stefanou A, Dooley M. Simple method to eliminate the risk of inadvertent intrathecal vincristine administration. J Clin Oncol Off J Am Soc Clin Oncol. 2003;21(10):2044. author reply 244

    Article  Google Scholar 

  68. Dennison JB, Mohutsky MA, Barbuch RJ, Wrighton SA, Hall SD. Apparent high CYP3A5 expression is required for significant metabolism of vincristine by human cryopreserved hepatocytes. J Pharmacol Exp Ther. 2008;327(1):248–57.

    Article  CAS  PubMed  Google Scholar 

  69. Jackson Jr DV, Castle MC, Bender RA. Biliary excretion of vincristine. Clin Pharmacol Ther. 1978;24(1):101–7.

    Article  PubMed  Google Scholar 

  70. Villikka K, Kivisto KT, Maenpaa H, Joensuu H, Neuvonen PJ. Cytochrome P450-inducing antiepileptics increase the clearance of vincristine in patients with brain tumors. Clin Pharmacol Ther. 1999;66(6):589–93.

    CAS  PubMed  Google Scholar 

  71. Relling MV, Pui CH, Sandlund JT, et al. Adverse effect of anticonvulsants on efficacy of chemotherapy for acute lymphoblastic leukaemia. Lancet. 2000;356(9226):285–90.

    Article  CAS  PubMed  Google Scholar 

  72. Gidding CE, Meeuwsen-de Boer GJ, Koopmans P, Uges DR, Kamps WA, de Graaf SS. Vincristine pharmacokinetics after repetitive dosing in children. Cancer Chemother Pharmacol. 1999;44(3):203–9.

    Article  CAS  PubMed  Google Scholar 

  73. Groninger E, Meeuwsen-de Boer T, Koopmans P, et al. Vincristine pharmacokinetics and response to vincristine monotherapy in an up-front window study of the Dutch Childhood Leukaemia Study Group (DCLSG). Eur J Cancer. 2005;41(1):98–103.

    Article  CAS  PubMed  Google Scholar 

  74. Lonnerholm G, Frost BM, Abrahamsson J, et al. Vincristine pharmacokinetics is related to clinical outcome in children with standard risk acute lymphoblastic leukemia. Br J Haematol. 2008;142(4):616–21.

    Article  PubMed  CAS  Google Scholar 

  75. Shah NN, Merchant MS, Cole DE, et al. Vincristine sulfate liposomes injection (VSLI, Marqibo(R)): results from a phase i study in children, adolescents, and young adults with refractory solid tumors or leukemias. Pediatr Blood Cancer. 2016;63(6):997–1005.

    Article  CAS  PubMed  Google Scholar 

  76. Gidding CE, Kellie SJ, Kamps WA, de Graaf SS. Vincristine revisited. Crit Rev Oncol Hematol. 1999;29(3):267–87.

    Article  CAS  PubMed  Google Scholar 

  77. Diouf B, Crews KR, Lew G, et al. Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA. 2015;313(8):815–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Lavoie Smith EM, Li L, Hutchinson RJ, et al. Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia. Cancer Nurs. 2013;36(5):E49–60.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Nishikawa T, Kawakami K, Kumamoto T, et al. Severe neurotoxicities in a case of Charcot-Marie-Tooth disease type 2 caused by vincristine for acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30(7):519–21.

    Article  PubMed  Google Scholar 

  80. Egbelakin A, Ferguson MJ, MacGill EA, et al. Increased risk of vincristine neurotoxicity associated with low CYP3A5 expression genotype in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2011;56(3):361–7.

    Article  PubMed  Google Scholar 

  81. van Dalen EC, Raphael MF, Caron HN, Kremer LC. Treatment including anthracyclines versus treatment not including anthracyclines for childhood cancer. Cochrane Database Syst Rev. 2014;9:CD006647.

    Google Scholar 

  82. Kamps WA, Veerman AJ, van Wering ER, van Weerden JF, Slater R, van der Does-van den Berg A. Long-term follow-up of Dutch Childhood Leukemia Study Group (DCLSG) protocols for children with acute lymphoblastic leukemia, 1984–1991. Leukemia. 2000;14(12):2240–6.

    Article  CAS  PubMed  Google Scholar 

  83. Vora A, Goulden N, Wade R, et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013;14(3):199–209.

    Article  CAS  PubMed  Google Scholar 

  84. Eksborg S. Anthracycline pharmacokinetics. Limited sampling model for plasma level monitoring with special reference to epirubicin (Farmorubicin). Acta Oncol. 1990;29(3):339–42.

    Article  CAS  PubMed  Google Scholar 

  85. Frost BM, Eksborg S, Bjork O, et al. Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study. Med Pediatr Oncol. 2002;38(5):329–37.

    Article  PubMed  Google Scholar 

  86. Bellott R, Auvrignon A, Leblanc T, et al. Pharmacokinetics of liposomal daunorubicin (DaunoXome) during a phase I–II study in children with relapsed acute lymphoblastic leukaemia. Cancer Chemother Pharmacol. 2001;47(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  87. van Dalen EC, Michiels EM, Caron HN, Kremer LC. Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev. 2010;5:CD005006.

    Google Scholar 

  88. Galettis P, Boutagy J, Ma DD. Daunorubicin pharmacokinetics and the correlation with P-glycoprotein and response in patients with acute leukaemia. Br J Cancer. 1994;70(2):324–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Olson RD, Mushlin PS, Brenner DE, et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proc Natl Acad Sci U S A. 1988;85(10):3585–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Krajinovic M, Labuda D, Mathonnet G, et al. Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res: Off J Am Assoc Cancer Res. 2002;8(3):802–10.

    CAS  Google Scholar 

  91. Lipshultz SE, Miller TL, Lipsitz SR, et al. Continuous versus bolus infusion of doxorubicin in children with ALL: long-term cardiac outcomes. Pediatrics. 2012;130(6):1003–11.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Aminkeng F, Bhavsar AP, Visscher H, et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat Genet. 2015;47(9):1079–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Asselin BL, Whitin JC, Coppola DJ, Rupp IP, Sallan SE, Cohen HJ. Comparative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol Off J Am Soc Clin Oncol. 1993;11(9):1780–6.

    Article  CAS  Google Scholar 

  94. Albertsen BK, Schroder H, Ingerslev J, et al. Comparison of intramuscular therapy with Erwinia asparaginase and asparaginase Medac: pharmacokinetics, pharmacodynamics, formation of antibodies and influence on the coagulation system. Br J Haematol. 2001;115(4):983–90.

    Article  CAS  PubMed  Google Scholar 

  95. Riccardi R, Holcenberg JS, Glaubiger DL, Wood JH, Poplack DG. L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. Cancer Res. 1981;41(11 Pt 1):4554–8.

    CAS  PubMed  Google Scholar 

  96. Appel IM, Pinheiro JP, den Boer ML, et al. Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL. Leukemia. 2003;17(11):2254–6.

    Article  CAS  PubMed  Google Scholar 

  97. van der Sluis IM, Vrooman LM, Pieters R, et al. Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation. Haematologica. 2016;101(3):279–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Stams WA, den Boer ML, Holleman A, et al. Asparagine synthetase expression is linked with L-asparaginase resistance in TEL-AML1-negative but not TEL-AML1-positive pediatric acute lymphoblastic leukemia. Blood. 2005;105(11):4223–5.

    Article  CAS  PubMed  Google Scholar 

  99. Raja RA, Schmiegelow K, Frandsen TL. Asparaginase-associated pancreatitis in children. Br J Haematol. 2012;159(1):18–27.

    Article  CAS  PubMed  Google Scholar 

  100. Bhojwani D, Darbandi R, Pei D, et al. Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. Eur J Cancer. 2014;50(15):2685–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Tong WH, Pieters R, de Groot-Kruseman HA, et al. The toxicity of very prolonged courses of PEGasparaginase or Erwinia asparaginase in relation to asparaginase activity, with a special focus on dyslipidemia. Haematologica. 2014;99(11):1716–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Vrooman LM, Kirov II, Dreyer ZE, et al. Activity and toxicity of intravenous Erwinia asparaginase following allergy to E. coli-derived asparaginase in children and adolescents with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2016;63(2):228–33.

    Article  CAS  PubMed  Google Scholar 

  103. Liu C, Yang W, Devidas M, et al. Clinical and genetic risk factors for acute pancreatitis in patients with acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(18):2133–40.

    Article  Google Scholar 

  104. Fernandez CA, Smith C, Yang W, et al. Genome-wide analysis links NFATC2 with asparaginase hypersensitivity. Blood. 2015;126(1):69–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yang L, Panetta JC, Cai X, et al. Asparaginase may influence dexamethasone pharmacokinetics in acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(12):1932–9.

    Article  CAS  Google Scholar 

  106. Schmiegelow K, Attarbaschi A, Barzilai S, et al. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus. Lancet Oncol. 2016;17(6):e231–9.

    Article  PubMed  Google Scholar 

  107. Chen SH, Pei D, Yang W, et al. Genetic variations in GRIA1 on chromosome 5q33 related to asparaginase hypersensitivity. Clin Pharmacol Ther. 2010;88(2):191–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Fernandez CA, Smith C, Yang W, et al. HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood. 2014;124(8):1266–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sur P, Fernandes DJ, Kute TE, Capizzi RL. L-asparaginase-induced modulation of methotrexate polyglutamylation in murine leukemia L5178Y. Cancer Res. 1987;47(5):1313–8.

    CAS  PubMed  Google Scholar 

  110. Frandsen TL, Abrahamsson J, Lausen B, et al. Individualized toxicity-titrated 6-mercaptopurine increments during high-dose methotrexate consolidation treatment of lower risk childhood acute lymphoblastic leukaemia. A Nordic Society of Paediatric Haematology and Oncology (NOPHO) pilot study. Br J Haematol. 2011;155(2):244–7.

    Article  CAS  PubMed  Google Scholar 

  111. Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8(1):24–36.

    Article  CAS  PubMed  Google Scholar 

  112. Lowe ES, Kitchen BJ, Erdmann G, et al. Plasma pharmacokinetics and cerebrospinal fluid penetration of thioguanine in children with acute lymphoblastic leukemia: a collaborative Pediatric Oncology Branch, NCI, and Children’s Cancer Group study. Cancer Chemother Pharmacol. 2001;47(3):199–205.

    Article  CAS  PubMed  Google Scholar 

  113. Vora A, Mitchell CD, Lennard L, et al. Toxicity and efficacy of 6-thioguanine versus 6-mercaptopurine in childhood lymphoblastic leukaemia: a randomised trial. Lancet. 2006;368(9544):1339–48.

    Article  CAS  PubMed  Google Scholar 

  114. Escherich G, Richards S, Stork LC, Vora AJ. Childhood acute lymphoblastic leukaemia collaborative G. Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia. Leukemia. 2011;25(6):953–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Lennard L, Richards S, Cartwright CS, et al. The thiopurine methyltransferase genetic polymorphism is associated with thioguanine-related veno-occlusive disease of the liver in children with acute lymphoblastic leukemia. Clin Pharmacol Ther. 2006;80(4):375–83.

    Article  CAS  PubMed  Google Scholar 

  116. Lafolie P, Hayder S, Bjork O, Peterson C. Intraindividual variation in 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute lymphoblastic leukaemia. Eur J Clin Pharmacol. 1991;40(6):599–601.

    CAS  PubMed  Google Scholar 

  117. Balis FM, Holcenberg JS, Poplack DG, et al. Pharmacokinetics and pharmacodynamics of oral methotrexate and mercaptopurine in children with lower risk acute lymphoblastic leukemia: a joint children’s cancer group and pediatric oncology branch study. Blood. 1998;92(10):3569–77.

    CAS  PubMed  Google Scholar 

  118. Erb N, Harms DO, Janka-Schaub G. Pharmacokinetics and metabolism of thiopurines in children with acute lymphoblastic leukemia receiving 6-thioguanine versus 6-mercaptopurine. Cancer Chemother Pharmacol. 1998;42(4):266–72.

    Article  CAS  PubMed  Google Scholar 

  119. Dervieux T, Brenner TL, Hon YY, et al. De novo purine synthesis inhibition and antileukemic effects of mercaptopurine alone or in combination with methotrexate in vivo. Blood. 2002;100(4):1240–7.

    Article  CAS  PubMed  Google Scholar 

  120. Hedeland RL, Hvidt K, Nersting J, et al. DNA incorporation of 6-thioguanine nucleotides during maintenance therapy of childhood acute lymphoblastic leukaemia and non-Hodgkin lymphoma. Cancer Chemother Pharmacol. 2010;66(3):485–91.

    Article  CAS  PubMed  Google Scholar 

  121. Ebbesen MS, Nersting J, Jacobsen JH, et al. Incorporation of 6-thioguanine nucleotides into DNA during maintenance therapy of childhood acute lymphoblastic leukemia-the influence of thiopurine methyltransferase genotypes. J Clin Pharmacol. 2013;53(6):670–4.

    Article  CAS  PubMed  Google Scholar 

  122. Nielsen SN, Grell K, Nersting J, Frandsen TL, Hjalgrim LL, Schmiegelow K. Measures of 6-mercaptopurine and methotrexate maintenance therapy intensity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol 2016; 78:983–94.

    Article  CAS  PubMed  Google Scholar 

  123. Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther. 2013;93(4):324–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Schmiegelow K, Schroder H, Gustafsson G, et al. Risk of relapse in childhood acute lymphoblastic leukemia is related to RBC methotrexate and mercaptopurine metabolites during maintenance chemotherapy. Nordic Society for Pediatric Hematology and Oncology. J Clin Oncol Off J Am Soc Clin Oncol. 1995;13(2):345–51.

    Article  CAS  Google Scholar 

  125. Bhatia S, Landier W, Hageman L, et al. Systemic exposure to thiopurines and risk of relapse in children with acute lymphoblastic leukemia: a Children’s Oncology Group Study. JAMA Oncol. 2015;1(3):287–95.

    Article  PubMed  PubMed Central  Google Scholar 

  126. Relling MV, Pui CH, Cheng C, Evans WE. Thiopurine methyltransferase in acute lymphoblastic leukemia. Blood. 2006;107(2):843–4.

    Article  CAS  PubMed  Google Scholar 

  127. Schmiegelow K, Forestier E, Kristinsson J, et al. Thiopurine methyltransferase activity is related to the risk of relapse of childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Leukemia. 2009;23(3):557–64.

    Article  CAS  PubMed  Google Scholar 

  128. Lennard L, Cartwright CS, Wade R, Vora A. Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics. Br J Haematol. 2015;169(2):228–40.

    Article  CAS  PubMed  Google Scholar 

  129. Appell ML, Berg J, Duley J, et al. Nomenclature for alleles of the thiopurine methyltransferase gene. Pharmacogenet Genomics. 2013;23(4):242–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus – implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3(1):89–98.

    Article  CAS  PubMed  Google Scholar 

  131. Stanulla M, Schaeffeler E, Flohr T, et al. Thiopurine methyltransferase (TPMT) genotype and early treatment response to mercaptopurine in childhood acute lymphoblastic leukemia. JAMA. 2005;293(12):1485–9.

    Article  CAS  PubMed  Google Scholar 

  132. Lennard L, Cartwright CS, Wade R, Vora A. Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003. Br J Haematol. 2015;170(4):550–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Nielsen SN, Grell K, Nersting J, Abrahamson J, Lund B, Kanerva J, Jónsson OG, Vaitkeviciene G, Pruunsild K, Hjalgrim LL, Schmiegelow K. Population-based, prospective analysis of DNA thioguanine nucleotide levels during maintenance therapy of childhood acute lymphoblastic leukemia. Lancet Oncol (In press).

    Google Scholar 

  134. Yang JJ, Landier W, Yang W, et al. Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2015;33(11):1235–42.

    Article  CAS  Google Scholar 

  135. Moriyama T, Nishii R, Perez-Andreu V, et al. NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity. Nat Genet. 2016;48(4):367–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Schmiegelow K, Bruunshuus I. 6-Thioguanine nucleotide accumulation in red blood cells during maintenance chemotherapy for childhood acute lymphoblastic leukemia, and its relation to leukopenia. Cancer Chemother Pharmacol. 1990;26(4):288–92.

    Article  CAS  PubMed  Google Scholar 

  137. Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther. 2004;75(4):274–81.

    Article  CAS  PubMed  Google Scholar 

  138. Rivard GE, Infante-Rivard C, Hoyoux C, Champagne J. Maintenance chemotherapy for childhood acute lymphoblastic leukaemia: better in the evening. Lancet. 1985;2(8467):1264–6.

    Article  CAS  PubMed  Google Scholar 

  139. Schmiegelow K, Glomstein A, Kristinsson J, Salmi T, Schroder H, Bjork O. Impact of morning versus evening schedule for oral methotrexate and 6-mercaptopurine on relapse risk for children with acute lymphoblastic leukemia. Nordic Society for Pediatric Hematology and Oncology (NOPHO). J Pediatr Hematol Oncol. 1997;19(2):102–9.

    Article  CAS  PubMed  Google Scholar 

  140. Koren G, Langevin AM, Olivieri N, Giesbrecht E, Zipursky A, Greenberg M. Diurnal variation in the pharmacokinetics and myelotoxicity of mercaptopurine in children with acute lymphocytic leukemia. Am J Dis Child. 1990;144(10):1135–7.

    CAS  PubMed  Google Scholar 

  141. Koren G, Ferrazzini G, Sohl H, Robieux I, Johnson D, Giesbrecht E. Chronopharmacology of methotrexate pharmacokinetics in childhood leukemia. Chronobiol Int. 1992;9(6):434–8.

    Article  CAS  PubMed  Google Scholar 

  142. Clemmensen KK, Christensen RH, Shabaneh DN, et al. The circadian schedule for childhood acute lymphoblastic leukemia maintenance therapy does not influence event-free survival in the NOPHO ALL92 protocol. Pediatr Blood Cancer. 2014;61(4):653–8.

    Article  CAS  PubMed  Google Scholar 

  143. Schmiegelow K, Levinsen MF, Attarbaschi A, et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(19):2469–76.

    Article  CAS  Google Scholar 

  144. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354(9172):34–9.

    Article  CAS  PubMed  Google Scholar 

  145. Schmiegelow K, Al-Modhwahi I, Andersen MK, et al. Methotrexate/6-mercaptopurine maintenance therapy influences the risk of a second malignant neoplasm after childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. Blood. 2009;113(24):6077–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Stanulla M, Schaeffeler E, Moricke A, et al. Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Munster protocols. Blood. 2009;114(7):1314–8.

    Article  CAS  PubMed  Google Scholar 

  147. Mikkelsen TS, Thorn CF, Yang JJ, et al. PharmGKB summary: methotrexate pathway. Pharmacogenet Genomics. 2011;21(10):679–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Cronstein BN, Merrill JT. Mechanisms of the effects of methotrexate. Bull Rheum Dis. 1996;45(5):6–8.

    CAS  PubMed  Google Scholar 

  149. Goldman ID, Matherly LH. The cellular pharmacology of methotrexate. Pharmacol Ther. 1985;28(1):77–102.

    Article  CAS  PubMed  Google Scholar 

  150. Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest. 1985;76(3):907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Schroder H, Clausen N, Ostergaard E, Pressler T. Pharmacokinetics of erythrocyte methotrexate in children with acute lymphoblastic leukemia during maintenance treatment. Cancer Chemother Pharmacol. 1986;16(2):190–3.

    Article  CAS  PubMed  Google Scholar 

  152. Schroder H. Methotrexate pharmacokinetics in age-fractionated erythrocytes. Cancer Chemother Pharmacol. 1986;18(3):203–7.

    Article  CAS  PubMed  Google Scholar 

  153. Schroder H. Methotrexate kinetics in myeloid bone marrow cells and peripheral neutrophils. Cancer Chemother Pharmacol. 1987;19(1):42–6.

    Article  CAS  PubMed  Google Scholar 

  154. Fotoohi AK, Albertioni F. Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leuk Lymphoma. 2008;49(3):410–26.

    Article  CAS  PubMed  Google Scholar 

  155. Panetta JC, Sparreboom A, Pui CH, Relling MV, Evans WE. Modeling mechanisms of in vivo variability in methotrexate accumulation and folate pathway inhibition in acute lymphoblastic leukemia cells. PLoS Comput Biol. 2010;6(12):e1001019.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Borsi JD, Wesenberg F, Stokland T, Moe PJ. How much is too much? Folinic acid rescue dose in children with acute lymphoblastic leukaemia. Eur J Cancer. 1991;27(8):1006–9.

    Article  CAS  PubMed  Google Scholar 

  157. Skarby TV, Anderson H, Heldrup J, et al. High leucovorin doses during high-dose methotrexate treatment may reduce the cure rate in childhood acute lymphoblastic leukemia. Leukemia. 2006;20(11):1955–62.

    Article  PubMed  CAS  Google Scholar 

  158. Bertino JR. “Rescue” techniques in cancer chemotherapy: use of leucovorin and other rescue agents after methotrexate treatment. Semin Oncol. 1977;4(2):203–16.

    CAS  PubMed  Google Scholar 

  159. Wolfrom C, Hartmann R, Fengler R, Bruhmuller S, Ingwersen A, Henze G. Randomized comparison of 36-hour intermediate-dose versus 4-hour high-dose methotrexate infusions for remission induction in relapsed childhood acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 1993;11(5):827–33.

    Article  CAS  Google Scholar 

  160. von Stackelberg A, Hartmann R, Buhrer C, et al. High-dose compared with intermediate-dose methotrexate in children with a first relapse of acute lymphoblastic leukemia. Blood. 2008;111(5):2573–80.

    Article  CAS  Google Scholar 

  161. Borsi JD, Moe PJ. Systemic clearance of methotrexate in the prognosis of acute lymphoblastic leukemia in children. Cancer. 1987;60(12):3020–4.

    Article  CAS  PubMed  Google Scholar 

  162. Csordas K, Hegyi M, Eipel OT, Muller J, Erdelyi DJ, Kovacs GT. Comparison of pharmacokinetics and toxicity after high-dose methotrexate treatments in children with acute lymphoblastic leukemia. Anti-Cancer Drugs. 2013;24(2):189–97.

    Article  CAS  PubMed  Google Scholar 

  163. Yarlagadda SG, Perazella MA. Drug-induced crystal nephropathy: an update. Expert Opin Drug Saf. 2008;7(2):147–58.

    Article  CAS  PubMed  Google Scholar 

  164. Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19:453–6.

    Google Scholar 

  165. Garneau AP, Riopel J, Isenring P. Acute Methotrexate-Induced Crystal Nephropathy. The New England journal of medicine. 2015;373:2691–3.

    Google Scholar 

  166. Skarby T, Jonsson P, Hjorth L, et al. High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother Pharmacol. 2003;51(4):311–20.

    CAS  PubMed  Google Scholar 

  167. Rasmussen MM, Christensen RH, Gregers J, Heldrup J, Nersting J, Schmiegelow K. Can SLC19A1 80G>A polymorphisms predict risk of extremely delayed MTX excretion after high dose of methotrexate? J Pediatr Hematol Oncol. 2013;35(5):417–8.

    Article  PubMed  Google Scholar 

  168. Widemann BC, Schwartz S, Jayaprakash N, et al. Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. Pharmacotherapy. 2014;34(5):427–39.

    Article  CAS  PubMed  Google Scholar 

  169. Svahn T, Mellgren K, Harila-Saari A, Åsberg A, Kanerva J, Jónsson O, Vaitkeviciene G, Mikkelssen TS, Schmiegelow K, Heldrup J. Delayed elimination of high dose methotrexate and use of Carboxypeptidase G2 in pediatric patients during treatment for acute lymphoblastic leukemia. Ped Blood Cancer 2017.

    Google Scholar 

  170. Chessells JM, Leiper AD, Tiedemann K, Hardisty RM, Richards S. Oral methotrexate is as effective as intramuscular in maintenance therapy of acute lymphoblastic leukaemia. Arch Dis Child. 1987;62(2):172–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Whittle SL, Hughes RA. Folate supplementation and methotrexate treatment in rheumatoid arthritis: a review. Rheumatology (Oxford). 2004;43(3):267–71.

    Article  CAS  Google Scholar 

  172. Schroder H, Clausen N, Ostergard E, Pressler T. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1986;3(3):241–7.

    Article  CAS  PubMed  Google Scholar 

  173. Richards S, Pui CH, Gayon P. Childhood acute lymphoblastic leukemia collaborative G. Systematic review and meta-analysis of randomized trials of central nervous system directed therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60(2):185–95.

    Article  PubMed  Google Scholar 

  174. Kager L, Cheok M, Yang W, et al. Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest. 2005;115(1):110–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013;121(6):898–904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Radtke S, Zolk O, Renner B, et al. Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia. Blood. 2013;121(26):5145–53.

    Article  CAS  PubMed  Google Scholar 

  177. Baslund B, Gregers J, Nielsen CH. Reduced folate carrier polymorphism determines methotrexate uptake by B cells and CD4+ T cells. Rheumatology (Oxford). 2008;47(4):451–3.

    Article  CAS  Google Scholar 

  178. Gregers J, Christensen IJ, Dalhoff K, et al. The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number. Blood. 2010;115(23):4671–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Campbell JM, Bateman E, Stephenson MD, Bowen JM, Keefe DM, Peters MD. Methotrexate-induced toxicity pharmacogenetics: an umbrella review of systematic reviews and meta-analyses. Cancer Chemother Pharmacol. 2016;78(1):27–39.

    Article  CAS  PubMed  Google Scholar 

  180. Aplenc R, Thompson J, Han P, et al. Methylenetetrahydrofolate reductase polymorphisms and therapy response in pediatric acute lymphoblastic leukemia. Cancer Res. 2005;65(6):2482–7.

    Article  CAS  PubMed  Google Scholar 

  181. Schroder H, Agger KE, Rosthoj S, Carlsen NT, Schmiegelow K. Antibacterial prophylaxis with trimethoprim-sulfamethoxazole during induction treatment for acute lymphoblastic leukemia. Dan Med Bull. 2001;48(4):275–7.

    CAS  PubMed  Google Scholar 

  182. Poulsen A, Demeny AK, Bang Plum C, Gjerum Nielsen K, Schmiegelow K. Pneumocystis carinii pneumonia during maintenance treatment of childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 2001;37(1):20–3.

    Article  CAS  PubMed  Google Scholar 

  183. Beach BJ, Woods WG, Howell SB. Influence of co-trimoxazole on methotrexate pharmacokinetics in children with acute lymphoblastic leukemia. Am J Pediatr Hematol/Oncol. 1981;3(2):115–9.

    Article  CAS  Google Scholar 

  184. Watts CS, Sciasci JN, Pauley JL, et al. Prophylactic trimethoprim-sulfamethoxazole does not affect pharmacokinetics or pharmacodynamics of methotrexate. J Pediatr Hematol Oncol. 2016;38:449.

    Article  CAS  PubMed  Google Scholar 

  185. Levinsen M, Shabaneh D, Bohnstedt C, et al. Pneumocystis jiroveci pneumonia prophylaxis during maintenance therapy influences methotrexate/6-mercaptopurine dosing but not event-free survival for childhood acute lymphoblastic leukemia. Eur J Haematol. 2012;88(1):78–86.

    Article  CAS  PubMed  Google Scholar 

  186. Schmiegelow K, Bretton-Meyer U. 6-mercaptopurine dosage and pharmacokinetics influence the degree of bone marrow toxicity following high-dose methotrexate in children with acute lymphoblastic leukemia. Leukemia. 2001;15(1):74–9.

    Article  CAS  PubMed  Google Scholar 

  187. van Kooten Niekerk PB, Schmiegelow K, Schroeder H. Influence of methylene tetrahydrofolate reductase polymorphisms and coadministration of antimetabolites on toxicity after high dose methotrexate. Eur J Haematol. 2008;81(5):391–8.

    PubMed  Google Scholar 

  188. Balis FM, Holcenberg JS, Zimm S, et al. The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther. 1987;41(4):384–7.

    Article  CAS  PubMed  Google Scholar 

  189. Innocenti F, Danesi R, Di Paolo A, et al. Clinical and experimental pharmacokinetic interaction between 6-mercaptopurine and methotrexate. Cancer Chemother Pharmacol. 1996;37(5):409–14.

    Article  CAS  PubMed  Google Scholar 

  190. Nygaard U, Schmiegelow K. Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia. Leukemia. 2003;17(7):1344–8.

    Article  CAS  PubMed  Google Scholar 

  191. Jordheim LP, Dumontet C. Review of recent studies on resistance to cytotoxic deoxynucleoside analogues. Biochim Biophys Acta. 2007;1776(2):138–59.

    CAS  PubMed  Google Scholar 

  192. Veerman AJ, Hogeman PH, van Zantwijk CH, Bezemer PD. Prognostic value of 5'nucleotidase in acute lymphoblastic leukemia with the common-ALL phenotype. Leuk Res. 1985;9(10):1227–9.

    Article  CAS  PubMed  Google Scholar 

  193. Estlin EJ, Ronghe M, Burke GA, Yule SM. The clinical and cellular pharmacology of vincristine, corticosteroids, L-asparaginase, anthracyclines and cyclophosphamide in relation to childhood acute lymphoblastic leukaemia. Br J Haematol. 2000;110(4):780–90.

    Article  CAS  PubMed  Google Scholar 

  194. Ratain MJ, Mick R, Schilsky RL, Vogelzang NJ, Berezin F. Pharmacologically based dosing of etoposide: a means of safely increasing dose intensity. J Clin Oncol Off J Am Soc Clin Oncol. 1991;9(8):1480–6.

    Article  CAS  Google Scholar 

  195. Stewart CF, Arbuck SG, Fleming RA, Evans WE. Relation of systemic exposure to unbound etoposide and hematologic toxicity. Clin Pharmacol Ther. 1991;50(4):385–93.

    Article  CAS  PubMed  Google Scholar 

  196. Evans WE, Rodman JH, Relling MV, et al. Differences in teniposide disposition and pharmacodynamics in patients with newly diagnosed and relapsed acute lymphocytic leukemia. J Pharmacol Exp Ther. 1992;260(1):71–7.

    CAS  PubMed  Google Scholar 

  197. Rodman JH, Abromowitch M, Sinkule JA, Hayes FA, Rivera GK, Evans WE. Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J Clin Oncol Off J Am Soc Clin Oncol. 1987;5(7):1007–14.

    Article  CAS  Google Scholar 

  198. Clark PI, Slevin ML. The clinical pharmacology of etoposide and teniposide. Clin Pharmacokinet. 1987;12(4):223–52.

    Article  CAS  PubMed  Google Scholar 

  199. Relling MV, Mahmoud HH, Pui CH, et al. Etoposide achieves potentially cytotoxic concentrations in CSF of children with acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 1996;14(2):399–404.

    Article  CAS  Google Scholar 

  200. Levinsen M, Marquart HV, Groth-Pedersen L, et al. Leukemic blasts are present at low levels in spinal fluid in one third of childhood acute lymphoblastic leukemia cases. Pediatr Blood Cancer. 2016;63:1935.

    Article  CAS  PubMed  Google Scholar 

  201. Taskinen M, Oskarsson T, Levinsen M, et al. The effect of central nervous system involvement and irradiation in childhood ALL: lessons from the NOPHO ALL-92 and ALL-2000 protocols. Br J Haematol. 2016. doi:10.1002/pbc.26191.

  202. Pui CH, Howard SC. Current management and challenges of malignant disease in the CNS in paediatric leukaemia. Lancet Oncol. 2008;9(3):257–68.

    Article  PubMed  Google Scholar 

  203. Kose F, Abali H, Sezer A, Mertsoylu H, Disel U, Ozyilkan O. Little dose, huge toxicity: profound hematological toxicity of intrathecal methotrexate. Leuk Lymphoma. 2009;50(2):282–3.

    Article  PubMed  Google Scholar 

  204. Peyrl A, Sauermann R, Traunmueller F, et al. Pharmacokinetics and safety of intrathecal liposomal cytarabine in children aged <3 years. Clin Pharmacokinet. 2009;48(4):265–71.

    Article  CAS  PubMed  Google Scholar 

  205. Levinsen M, Harila-Saari A, Grell K, et al. Efficacy and toxicity of intrathecal liposomal cytarabine in first-line therapy of childhood acute lymphoblastic leukemia. J Pediat Hematol Onc. 2016;38(8):602–609.

    Google Scholar 

  206. Bohnstedt C, Levinsen M, Rosthoj S, et al. Physicians compliance during maintenance therapy in children with down syndrome and acute lymphoblastic leukemia. Leukemia. 2013;27(4):866–70.

    Article  CAS  PubMed  Google Scholar 

  207. Thompson PA, Murry DJ, Rosner GL, et al. Methotrexate pharmacokinetics in infants with acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2007;59(6):847–53.

    Article  CAS  PubMed  Google Scholar 

  208. Lonnerholm G, Valsecchi MG, De Lorenzo P, et al. Pharmacokinetics of high-dose methotrexate in infants treated for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2009;52(5):596–601.

    Article  PubMed  Google Scholar 

  209. Lucchesi M, Guidi M, Fonte C, et al. Pharmacokinetics of high-dose methotrexate in infants aged less than 12 months treated for aggressive brain tumors. Cancer Chemother Pharmacol. 2016;77(4):857–64.

    Article  CAS  PubMed  Google Scholar 

  210. Lonnerholm G, Frost BM, Soderhall S, de Graaf SS. Vincristine pharmacokinetics in children with down syndrome. Pediatr Blood Cancer. 2009;52(1):123–5.

    Article  PubMed  Google Scholar 

  211. Hempel G, Relling MV, de Rossi G, et al. Pharmacokinetics of daunorubicin and daunorubicinol in infants with leukemia treated in the interfant 99 protocol. Pediatr Blood Cancer. 2010;54(3):355–60.

    Article  PubMed  Google Scholar 

  212. van der Sluis I, Moricke A, Escherich G, et al. Pediatric acute lymphoblastic leukemia: efficacy and safety of recombinant E. coli-asparaginase in infants (less than one year of age) with acute lymphoblastic leukemia. Haematologica. 2013;98(11):1697–701.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Pui CH, Pei D, Campana D, et al. Improved prognosis for older adolescents with acute lymphoblastic leukemia. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(4):386–91.

    Article  Google Scholar 

  214. Hough R, Rowntree C, Goulden N, et al. Efficacy and toxicity of a paediatric protocol in teenagers and young adults with Philadelphia chromosome negative acute lymphoblastic leukaemia: results from UKALL 2003. Br J Haematol. 2016;172(3):439–51.

    Article  CAS  PubMed  Google Scholar 

  215. Knoester PD, Underberg WJ, Beijnen JH. Clinical pharmacokinetics and pharmacodynamics of anticancer agents in pediatric patients (review). Anticancer Res. 1993;13(5C):1795–808.

    CAS  PubMed  Google Scholar 

  216. Frost BM, Lonnerholm G, Koopmans P, et al. Vincristine in childhood leukaemia: no pharmacokinetic rationale for dose reduction in adolescents. Acta Paediatr. 2003;92(5):551–7.

    Article  CAS  PubMed  Google Scholar 

  217. Silverman LB, Supko JG, Stevenson KE, et al. Intravenous PEG-asparaginase during remission induction in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Blood. 2010;115(7):1351–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Peyrl A, Sauermann R, Chocholous M, et al. Pharmacokinetics and toxicity of intrathecal liposomal cytarabine in children and adolescents following age-adapted dosing. Clin Pharmacokinet. 2014;53(2):165–73.

    Article  CAS  PubMed  Google Scholar 

  219. Donelli MG, Zucchetti M, Robatto A, et al. Pharmacokinetics of HD-MTX in infants, children, and adolescents with non-B acute lymphoblastic leukemia. Med Pediatr Oncol. 1995;24(3):154–9.

    Article  CAS  PubMed  Google Scholar 

  220. Toft N, Birgens H, Abrahamsson J, et al. Risk group assignment differs for children and adults 1–45 yr with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol. Eur J Haematol. 2013;90(5):404–12.

    Article  PubMed  Google Scholar 

  221. Frandsen TL, Heyman M, Abrahamsson J, et al. Complying with the European Clinical Trials directive while surviving the administrative pressure – an alternative approach to toxicity registration in a cancer trial. Eur J Cancer. 2014;50(2):251–9.

    Article  PubMed  Google Scholar 

  222. Toft N, Birgens H, Abrahamsson J, et al. Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia. Eur J Haematol. 2016;96(2):160–9.

    Article  CAS  PubMed  Google Scholar 

  223. Schmiegelow K, Heyman M, Gustafsson G, et al. The degree of myelosuppression during maintenance therapy of adolescents with B-lineage intermediate risk acute lymphoblastic leukemia predicts risk of relapse. Leukemia. 2010;24(4):715–20.

    Article  CAS  PubMed  Google Scholar 

  224. Hijiya N, Panetta JC, Zhou Y, et al. Body mass index does not influence pharmacokinetics or outcome of treatment in children with acute lymphoblastic leukemia. Blood. 2006;108(13):3997–4002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Orgel E, Genkinger JM, Aggarwal D, Sung L, Nieder M, Ladas EJ. Association of body mass index and survival in pediatric leukemia: a meta-analysis. Am J Clin Nutr. 2016;103(3):808–17.

    Article  CAS  PubMed  Google Scholar 

  226. Kendrick JG, Carr RR, Ensom MH. Pediatric obesity: pharmacokinetics and implications for drug dosing. Clin Ther. 2015;37(9):1897–923.

    Article  CAS  PubMed  Google Scholar 

  227. Griggs JJ, Mangu PB, Anderson H, et al. Appropriate chemotherapy dosing for obese adult patients with cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30(13):1553–61.

    Article  Google Scholar 

  228. Schmiegelow K. Treatment-related toxicities in children with acute lymphoblastic leukaemia predisposition syndromes. Eur J Med Genet. 2016; doi:10.1016/j.ejmg.2016.02.006.

    PubMed  Google Scholar 

  229. Lee P, Bhansali R, Izraeli S, Hijiya N, Crispino JD. The biology, pathogenesis and clinical aspects of acute lymphoblastic leukemia in children with down syndrome. Leukemia. 2016;30:1816.

    Article  CAS  PubMed  Google Scholar 

  230. Hefti E, Blanco JG. Pharmacokinetics of chemotherapeutic drugs in pediatric patients with down syndrome and leukemia. J Pediatr Hematol Oncol. 2016;38(4):283–7.

    Article  CAS  PubMed  Google Scholar 

  231. Buitenkamp TD, Mathot RA, de Haas V, Pieters R, Zwaan CM. Methotrexate-induced side effects are not due to differences in pharmacokinetics in children with down syndrome and acute lymphoblastic leukemia. Haematologica. 2010;95(7):1106–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Bienemann K, Burkhardt B, Modlich S, et al. Promising therapy results for lymphoid malignancies in children with chromosomal breakage syndromes (Ataxia teleangiectasia or Nijmegen-breakage syndrome): a retrospective survey. Br J Haematol. 2011;155(4):468–76.

    Article  CAS  PubMed  Google Scholar 

  233. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet. 2013;45(3):242–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark

    Kjeld Schmiegelow MD, DrMedSci.

  2. Institute of Clinical Medicine, University of Copenhagen, København, Denmark

    Kjeld Schmiegelow MD, DrMedSci.

  3. Department of Pediatrics and Adolescent Medicine, JMC-4072, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Kjeld Schmiegelow MD, DrMedSci.

  4. Department of Pediatric Hematology-Oncology, Erasmus Medical Center – Sophia Children’s Hospital, Rotterdam, The Netherlands

    Inge van der Sluis MD, PhD

  5. The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Inge van der Sluis MD, PhD

Authors
  1. Kjeld Schmiegelow MD, DrMedSci.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Inge van der Sluis MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kjeld Schmiegelow MD, DrMedSci. .

Editor information

Editors and Affiliations

  1. Department of Paediatric Haemotology, Sheffield Children’s Hospital NHS Trust, University of Sheffield, Sheffield, South Yorkshire, United Kingdom

    Ajay Vora

Rights and permissions

Reprints and permissions

Copyright information

© 2017 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Schmiegelow, K., van der Sluis, I. (2017). Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Antileukemic Drugs. In: Vora, A. (eds) Childhood Acute Lymphoblastic Leukemia. Springer, Cham. https://doi.org/10.1007/978-3-319-39708-5_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-39708-5_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-39707-8

  • Online ISBN: 978-3-319-39708-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation