Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction

Kjeld Schmiegelow, Stine N Nielsen, Thomas L Frandsen, Jacob Nersting, Kjeld Schmiegelow, Stine N Nielsen, Thomas L Frandsen, Jacob Nersting

Abstract

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Distribution of mean prescribed 6-mercaptopurine (m6MP) doses during maintenance therapy (protocol starting oral dose: 75 mg/m2/d) for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 registered drug doses and calculated by weighting each registered dose according to the time interval to the next measurement. The median m6MP dose for all patients is 59.4 mg/m2/d.
FIGURE 2
FIGURE 2
Distribution of mean white blood cell count (mWBC) and prescribed mean 6-mercaptopurine (m6MP) doses during maintenance therapy for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 registered drug doses and blood counts and calculated by weighting each registration according to the time interval to the next registration. The median m6MP (59.4 mg/m2/d) and median mWBC (3.3×109/L) are significantly correlated (rS=0.20; P<0.001).
FIGURE 3
FIGURE 3
Simplified draft of 6-mercaptopurine (6MP) metabolism and methotrexate (MTX)-6MP interactions. DNA-TG indicates thioguanine nucleotides incorporated into DNA; GDP, guanosine diphosphate; GMP, guanosine monophosphate; GMPS, guanosine monophosphate synthetase; GTP, guanosine triphosphate: HGPRT, hypoxanthine guanine phosphoribosyl transferase; IMP, inosine monophosphate; IMPDH, inosine monophosphate dehydrogenase; ITP, inosine triphosphate; ITPA, inosine triphosphate pyrophosphatases; M+DPK, monophosphate and diphosphate kinases; MP, mercaptopurine; PDNS, purine de novo synthesis; TDP, thymidine diphosphate; TMP, thymidine monophosphate; TPMT, thiopurine methyltransferase; TTP, thymidine triphosphate; U, uridine monophosphate; XO, xanthine oxidase.
FIGURE 4
FIGURE 4
A, Mean white blood cell (mWBC) and absolute neutrophil counts (mANC) for 538 patients included in the NOPHO ALL-92 maintenance therapy study. Means are based on a total of >28,000 blood counts and calculated by weighting each measurement according to the time interval to the next measurement. Each dot represents 1 patient. mWBC and mANC are highly correlated (rS=0.77; P<0.001). The target range for WBC was 1.5 to 3.5×109/L in the NOPHO ALL92 protocol from which the data were retrieved. B, Kaplan-Meier relapse risk plots for patients with a mean absolute neutrophil count (mANC) at the end of maintenance therapy above or below 2.0×109/L=median mANC for all patients (upper curve, N=248, relapse risk 23.5%±2.7%; lower curve, N=280, relapse risk 10.9%±1.9%; P<0.001). Mean absolute neutrophil counts during maintenance therapy are calculated by weighting each measurement according to the time interval to the next measurement.

References

    1. Farber S, Diamond LK, Mercer RD, et al. Temporary remissions in acute leukemia in children produced by folic acid antagonist 4-aminopteroylglutamic acid (aminopterin). N Engl J Med. 1948;238:787–793.
    1. 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;8:965–987.
    1. Thomas A. Joe Burchenal and the birth of combination chemotherapy. Br J Haematol. 2006;133:493–503.
    1. Frei E, III, Caron M, Levin RH, et al. The effectiveness of combinations of antileukemia agents in inducing and maintaining remission in children with acute leukemia. Blood. 1965;26:642–656.
    1. Simone JV. The treatment of acute lymphoblastic leukaemia. Br J Haematol. 1980;45:1–4.
    1. Holland JF, Glidewell O. Chemotherapy of acute lymphocytic leukemia of childhood. Cancer. 1972;30:1480–1487.
    1. Lonsdale D, Gehan EA, Fernbach DJ, et al. Interrupted vs. continued maintenance therapy in childhood acute leukemia. Cancer. 1975;36:341–352.
    1. Rivera GK, Pinkel D, Simone JV, et al. Treatment of acute lymphoblastic leukemia. 30 years’ experience at St. Jude Children’s Research Hospital. N Engl J Med. 1993;329:1289–1295.
    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;24:345–354.
    1. Conter V, Arico M, Basso G, et al. Long-term results of the Italian Association of Pediatric Hematology and Oncology (AIEOP) Studies 82, 87, 88, 91 and 95 for childhood acute lymphoblastic leukemia. Leukemia. 2010;24:255–264.
    1. Gaynon PS, Angiolillo AL, Carroll WL, et al. Long-term results of the children’s cancer group studies for childhood acute lymphoblastic leukemia 1983-2002: a Children’s Oncology Group Report. Leukemia. 2010;24:285–297.
    1. Kamps WA, van der Pal-de Bruin KM, Veerman AJ, et al. Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004. Leukemia. 2010;24:309–319.
    1. Salzer WL, Devidas M, Carroll WL, et al. Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984-2001: a report from the children’s oncology group. Leukemia. 2010;24:355–370.
    1. 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;24:265–284.
    1. Schrappe M, Nachman J, Hunger S, et al. Educational symposium on long-term results of large prospective clinical trials for childhood acute lymphoblastic leukemia (1985-2000). Leukemia. 2010;24:253–254.
    1. Sather H, Miller D, Nesbit M, et al. Differences in prognosis for boys and girls with acute lymphoblastic leukaemia. Lancet. 1981;1:739–743.
    1. Riehm H, Feickert HJ, Schrappe M, et al. Therapy results in five ALL-BFM studies since 1970: implications of risk factors for prognosis. Hamatol Bluttransfus. 1987;30:139–146.
    1. Chessells JM, Richards SM, Bailey CC, et al. Gender and treatment outcome in childhood lymphoblastic leukaemia: report from the MRC UKALL trials. Br J Haematol. 1995;89:364–372.
    1. Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Lancet. 1996;347:1783–1788.
    1. Pui CH, Boyett JM, Relling MV, et al. Sex differences in prognosis for children with acute lymphoblastic leukemia. J Clin Oncol. 1999;17:818–824.
    1. Tzoneva G, Perez-Garcia A, Carpenter Z, et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med. 2013;19:368–371.
    1. Meyer JA, Wang J, Hogan LE, et al. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013;45:290–294.
    1. Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest. 1985;76:907–912.
    1. Waters TR, Swann PF. Cytotoxic mechanism of 6-thioguanine: hMutSalpha, the human mismatch binding heterodimer, binds to DNA containing S6-methylthioguanine. Biochemistry. 1997;36:2501–2506.
    1. Kamen BA. Serendipity-methotrexate and 6-mercaptopurine for continuation therapy for patients with acute lymphoblastic leukemia: the leukemic stem cell and beyond? J Pediatr Hematol Oncol. 2009;31:383–384.
    1. Gale RP, Butturini A. Maintenance chemotherapy and cure of childhood acute lymphoblastic leukaemia. Lancet. 1991;338:1315–1318.
    1. Kumagai M, Manabe A, Pui CH, et al. Stroma-supported culture in childhood B-lineage acute lymphoblastic leukemia cells predicts treatment outcome. J Clin Invest. 1996;97:755–760.
    1. Campana D, Coustan-Smith E, Manabe A, et al. Human B-cell progenitors and bone marrow microenvironment. Hum Cell. 1996;9:317–322.
    1. Mudry RE, Fortney JE, York T, et al. Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood. 2000;96:1926–1932.
    1. Narendran A, Ganjavi H, Morson N, et al. Mutant p53 in bone marrow stromal cells increases VEGF expression and supports leukemia cell growth. Exp Hematol. 2003;31:693–701.
    1. Perez-Atayde AR, Sallan SE, Tedrow U, et al. Spectrum of tumor angiogenesis in the bone marrow of children with acute lymphoblastic leukemia. Am J Pathol. 1997;150:815–821.
    1. Keyhani A, Jendiroba DB, Freireich EJ. Angiogenesis and leukemia. Leuk Res. 2001;25:639–645.
    1. Schmiegelow K, Heyman M, Kristinsson J, et al. Oral methotrexate/6-mercaptopurine may be superior to a multidrug LSA2L2 Maintenance therapy for higher risk childhood acute lymphoblastic leukemia: results from the NOPHO ALL-92 study. J Pediatr Hematol Oncol. 2009;31:385–392.
    1. 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;24:715–720.
    1. Bohnstedt C, Levinsen M, Rosthoj S, et al. Physicians compliance during maintenance therapy in children with Down syndrome and acute lymphoblastic leukemia. Leukemia. 2013;27:866–870.
    1. Peeters M, Koren G, Jakubovicz D, et al. Physician compliance and relapse rates of acute lymphoblastic leukemia in children. Clin Pharmacol Ther. 1988;43:228–232.
    1. Schmiegelow K. Prognostic significance of methotrexate and 6-mercaptopurine dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1991;8:301–312.
    1. Relling MV, Hancock ML, Boyett JM, et al. Prognostic importance of 6-mercaptopurine dose intensity in acute lymphoblastic leukemia. Blood. 1999;93:2817–2823.
    1. Bhatia S, Landier W, Shangguan M, et al. Nonadherence to oral mercaptopurine and risk of relapse in Hispanic and non-Hispanic white children with acute lymphoblastic leukemia: a report from the children’s oncology group. J Clin Oncol. 2012;30:2094–2101.
    1. Pui CH, Mullighan CG, Evans WE, et al. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120:1165–1174.
    1. 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;113:6077–6084.
    1. Schmiegelow K, Levinsen MF, Attarbaschi A, et al. Second malignant neoplasms after treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 2013;31:2469–2476.
    1. 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;61:797–802.
    1. Riehm H, Gadner H, Henze G, et al. Results and significance of six randomised trials in four consecutive ALL-BFM studies. Hematol Blood Transf. 1990;33:439–450.
    1. Toyoda Y, Manabe A, Tsuchida M, et al. Six months of maintenance chemotherapy after intensified treatment for acute lymphoblastic leukemia of childhood. J Clin Oncol. 2000;18:1508–1516.
    1. Nyvold C, Madsen HO, Ryder LP, et al. Precise quantification of minimal residual disease at day 29 allows identification of children with acute lymphoblastic leukemia and an excellent outcome. Blood. 2002;99:1253–1258.
    1. Lauten M, Moricke A, Beier R, et al. Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia. Haematologica. 2012;97:1048–1056.
    1. Arico M, Baruchel A, Bertrand Y, et al. The seventh international childhood acute lymphoblastic leukemia workshop report: Palermo, Italy, January 29-30, 2005. Leukemia. 2005;19:1145–1152.
    1. Chessells JM, Leiper AD, Tiedemann K, et al. Oral methotrexate is as effective as intramuscular in maintenance therapy of acute lymphoblastic leukaemia. Arch Dis Child. 1987;62:172–176.
    1. Balis FM, Mirro JJ, Reaman GH, et al. Pharmacokinetics of subcutaneous methotrexate. J Clin Oncol. 1988;6:1882–1886.
    1. Chessells JM, Cox TC, Kendall B, et al. Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation. Arch Dis Child. 1990;65:416–422.
    1. Matloub Y, Bostrom BC, Hunger SP, et al. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood. 2011;118:243–251.
    1. Pinkel D, Hernandez K, Borella L, et al. Drug dosage and remission duration in childhood lymphocytic leukemia. Cancer. 1971;27:247–256.
    1. Zimm S, Collins JM, Riccardi R, et al. Variable bioavailability of oral mercaptopurine. Is maintenance chemotherapy in acute lymphoblastic leukemia being optimally delivered? N Engl J Med. 1983;308:1005–1009.
    1. Lafolie P, Hayder S, Bjork O, et al. Large interindividual variations in the pharmacokinetics of oral 6-mercaptopurine in maintenance therapy of children with acute leukaemia and non-Hodgkin lymphoma. Acta Paediatr Scand. 1986;75:797–803.
    1. Poplack DG, Balis FM, Zimm S. The pharmacology of orally administered chemotherapy. A reappraisal. Cancer. 1986;58:473–480.
    1. Teresi ME, Crom WR, Choi KE, et al. Methotrexate bioavailability after oral and intramuscular administration in children. J Pediatr. 1987;110:788–792.
    1. Koren G, Solh H, Klein J, et al. Disposition of oral methotrexate in children with acute lymphoblastic leukemia and its relation to 6-mercaptopurine pharmacokinetics. Med Pediatr Oncol. 1989;17:450–454.
    1. Dupuis LL, Koren G, Silverman ED, et al. Influence of food on the bioavailability of oral methotrexate in children. J Rheumatol. 1995;22:1570–1573.
    1. 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;92:3569–3577.
    1. 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. 2003;21:1332–1339.
    1. Pearson AD, Amineddine HA, Yule M, et al. The influence of serum methotrexate concentrations and drug dosage on outcome in childhood acute lymphoblastic leukaemia. Br J Cancer. 1991;64:169–173.
    1. 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;3:557–564.
    1. Hayder S, Lafolie P, Bjork O, et al. 6-mercaptopurine plasma levels in children with acute lymphoblastic leukemia: relation to relapse risk and myelotoxicity. Ther Drug Monit. 1989;11:617–622.
    1. Koren G, Ferrazini G, Sulh H, et al. Systemic exposure to mercaptopurine as a prognostic factor in acute lymphocytic leukemia in children. N Engl J Med. 1990;323:17–21.
    1. Lafolie P, Bjork O, Hayder S, et al. Variability of 6-mercaptopurine pharmacokinetics during oral maintenance therapy of children with acute leukemia. Med Oncol Tumor Pharmacother. 1989;6:259–265.
    1. Relling MV, Lin JS, Ayers GD, et al. Racial and gender differences in N-acetyltransferase, xanthine oxidase, and CYP1A2 activities. Clin Pharmacol Ther. 1992;52:643–658.
    1. Zimm S, Collins JM, O’Neill D, et al. Inhibition of first-pass metabolism in cancer chemotherapy: interaction of 6-mercaptopurine and allopurinol. Clin Pharmacol Ther. 1983;34:810–817.
    1. Roberts RL, Gearry RB, Barclay ML. Allopurinol-thiopurine combination therapy in inflammatory bowel disease: are there genetic clues to this puzzle? Pharmacogenomics. 2010;11:1505–1508.
    1. Blaker PA, Arenas-Hernandez M, Smith MA, et al. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol. 2013;86:539–547.
    1. Brackett J, Schafer ES, Leung DH, et al. Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism. Pediatr Blood Cancer. 2014;61:1114–1117.
    1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329–339.
    1. Swann PF, Waters TR, Moulton DC, et al. Role of postreplicative DNA mismatch repair in the cytotoxic action of thioguanine. Science. 1996;273:1109–1111.
    1. 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;66:485–491.
    1. Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8:24–36.
    1. 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;93:324–325.
    1. Stet EH, De Abreu RA, Bokkerink JP, et al. Reversal of 6-mercaptopurine and 6-methylmercaptopurine ribonucleoside cytotoxicity by amidoimidazole carboxamide ribonucleoside in Molt F4 human malignant T-lymphoblasts. Biochem Pharmacol. 1993;46:547–550.
    1. Bokkerink JP, Stet EH, De Abreu RA, et al. 6-Mercaptopurine: cytotoxicity and biochemical pharmacology in human malignant T-lymphoblasts. Biochem Pharmacol. 1993;45:1455–1463.
    1. 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;53:670–674.
    1. Jacobsen JH, Schmiegelow K, Nersting J. Liquid chromatography-tandem mass spectrometry quantification of 6-thioguanine in DNA using endogenous guanine as internal standard. J Chromatogr B Analyt Technol Biomed Life Sci. 2012;881-882:115–118.
    1. Erb N, Haverland U, Harms DO, et al. High-performance liquid chromatographic assay of metabolites of thioguanine and mercaptopurine in capillary blood. J Chromatogr B Analyt Technol Biomed Life Sci. 2003;796:87–94.
    1. 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;26:288–292.
    1. Bostrom B, Erdmann G. Cellular pharmacology of 6-mercaptopurine in acute lymphoblastic leukemia. Am J Pediatr Hematol Oncol. 1993;15:80–86.
    1. Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic leukaemia. Lancet. 1994;343:1188–1190.
    1. 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. 1995;13:345–351.
    1. Bergan S, Bentdal O, Sodal G, et al. Patterns of azathioprine metabolites in neutrophils, lymphocytes, reticulocytes, and erythrocytes: relevance to toxicity and monitoring in recipients of renal allografts. Ther Drug Monit. 1997;19:502–509.
    1. Lancaster D, Lennard L, Lilleyman JS. Profile of non-compliance in lymphoblastic leukaemia. Arch Dis Child. 1997;76:365–366.
    1. 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;42:266–272.
    1. Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine are associated with hepatotoxicity. Clin Pharmacol Ther. 2004;75:274–281.
    1. Smith MA, Blaker P, Marinaki AM, et al. Optimising outcome on thiopurines in inflammatory bowel disease by co-prescription of allopurinol. J Crohns Colitis. 2012;6:905–912.
    1. Shih DQ, Nguyen M, Zheng L, et al. Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism. Aliment Pharmacol Ther. 2012;36:449–458.
    1. Bell BA, Brockway GN, Shuster JJ, et al. A comparison of red blood cell thiopurine metabolites in children with acute lymphoblastic leukemia who received oral mercaptopurine twice daily or once daily: a Pediatric Oncology Group study (now The Children’s Oncology Group). Pediatr Blood Cancer. 2004;43:105–109.
    1. Fotoohi AK, Albertioni F. Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells. Leuk Lymphoma. 2008;49:410–426.
    1. Sorich MJ, Pottier N, Pei D, et al. In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile. PLoS Med. 2008;5:e83.
    1. 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;115:110–117.
    1. Schmiegelow K. Advances in individual prediction of methotrexate toxicity: a review. Br J Haematol. 2009;146:489–503.
    1. Belkov VM, Krynetski EY, Schuetz JD, et al. Reduced folate carrier expression in acute lymphoblastic leukemia: a mechanism for ploidy but not lineage differences in methotrexate accumulation. Blood. 1999;93:1643–1650.
    1. 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;52:155–163.
    1. Schroder H, Fogh K, Herlin T. In vivo decline of methotrexate and methotrexate polyglutamates in age-fractionated erythrocytes. Cancer Chemother Pharmacol. 1988;21:150–155.
    1. Schmiegelow K, Schroder H, Pulczynska MK, et al. Maintenance chemotherapy for childhood acute lymphoblastic leukemia: relation of bone-marrow and hepatotoxicity to the concentration of methotrexate in erythrocytes. Cancer Chemother Pharmacol. 1989;25:65–69.
    1. Schroder H. In vivo methotrexate kinetics and metabolism in human hematopoietic cells. Clinical significance of methotrexate concentrations in erythrocytes. Dan Med Bull. 1990;37:22–40.
    1. Schmiegelow K, Schroder H, Schmiegelow M. Methotrexate and 6-mercaptopurine maintenance therapy for childhood acute lymphoblastic leukemia: dose adjustments by white cell counts or by pharmacokinetic parameters? Cancer Chemother Pharmacol. 1994;34:209–215.
    1. Graham ML, Shuster JJ, Kamen BA, et al. Red blood cell methotrexate and folate levels in children with acute lymphoblastic leukemia undergoing therapy: a Pediatric Oncology Group pilot study. Cancer Chemother Pharmacol. 1992;31:217–222.
    1. Aplenc R, Lange B. Pharmacogenetic determinants of outcome in acute lymphoblastic leukaemia. Br J Haematol. 2004;125:421–434.
    1. Davidsen ML, Dalhoff K, Schmiegelow K. Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2008;30:831–849.
    1. Chang JG, Lee LS, Chen CM, et al. Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics. 2002;12:191–195.
    1. Lu HF, Shih MC, Hsueh SC, et al. Molecular analysis of the thiopurine S-methyltransferase alleles in Bolivians and Tibetans. J Clin Pharm Ther. 2005;30:491–496.
    1. Lu HF, Shih MC, Chang YS, et al. Molecular analysis of thiopurine S-methyltransferase alleles in Taiwan aborigines and Taiwanese. J Clin Pharm Ther. 2006;31:93–98.
    1. Toft N, Nygaard U, Gregers J, et al. Genetic analyses of thiopurine methyltransferase polymorphisms in Greenlandic and Danish populations. Acta Paediatr. 2006;95:1665–1667.
    1. Kim H, Kang HJ, Kim HJ, et al. Pharmacogenetic analysis of pediatric patients with acute lymphoblastic leukemia: a possible association between survival rate and ITPA polymorphism. PLoS One. 2012;7:e45558.
    1. Lennard L, Lewis IJ, Michelagnoli M, et al. Thiopurine methyltransferase deficiency in childhood lymphoblastic leukaemia: 6-mercaptopurine dosage strategies. Med Pediatr Oncol. 1997;29:252–255.
    1. Andersen JB, Szumlanski C, Weinshilboum RM, et al. Pharmacokinetics, dose adjustments, and 6-mercaptopurine/methotrexate drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr. 1998;87:108–111.
    1. Relling MV, Hancock ML, Rivera GK, et al. Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus [see comments]. J Natl Cancer Inst. 1999;91:2001–2008.
    1. Lennard L, Lilleyman JS, Van Loon J, et al. Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukaemia. Lancet. 1990;336:225–229.
    1. Relling MV, Rubnitz JE, Rivera GK, et al. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354:34–39.
    1. Thomsen JB, Schroder H, Kristinsson J, et al. Possible carcinogenic effect of 6-mercaptopurine on bone marrow stem cells: relation to thiopurine metabolism. Cancer. 1999;86:1080–1086.
    1. 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;114:1314–1318.
    1. Lennard L, Chew TS, Lilleyman JS. Human thiopurine methyltransferase activity varies with red blood cell age. Br J Clin Pharmacol. 2001;52:539–546.
    1. Stocco G, Cheok MH, Crews KR, et al. Genetic polymorphism of inosine triphosphate pyrophosphatase is a determinant of mercaptopurine metabolism and toxicity during treatment for acute lymphoblastic leukemia. Clin Pharmacol Ther. 2009;85:164–172.
    1. Adam-de BT, Jacqz-Aigrain E. Pharmacogenetic determinants of mercaptopurine disposition in children with acute lymphoblastic leukemia. Eur J Clin Pharmacol. 2012;68:1233–1242.
    1. Tanaka Y, Manabe A, Nakadate H, et al. The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. Leuk Res. 2012;36:560–564.
    1. Wan Rosalina WR, Teh LK, Mohamad N, et al. Polymorphism of ITPA 94C>A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther. 2012;37:237–241.
    1. Zelinkova Z, Derijks LJ, Stokkers PC, et al. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Clin Gastroenterol Hepatol. 2006;4:44–49.
    1. Adam de BT, Fakhoury M, Medard Y, et al. Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy. Br J Clin Pharmacol. 2011;71:575–584.
    1. Marsh S, King CR, Ahluwalia R, et al. Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet. 2004;49:579–581.
    1. Lennard L, Hale JP, Lilleyman JS. Red blood cell hypoxanthine phosphoribosyltransferase activity measured using 6-mercaptopurine as a substrate: a population study in children with acute lymphoblastic leukaemia. Br J Clin Pharmacol. 1993;36:277–284.
    1. Pieters R, Huismans DR, Loonen AH, et al. Hypoxanthine-guanine phosphoribosyl-transferase in childhood leukemia: relation with immunophenotype, in vitro drug resistance and clinical prognosis. Int J Cancer. 1992;51:213–217.
    1. Dulucq S, St-Onge G, Gagne V, et al. DNA variants in the dihydrofolate reductase gene and outcome in childhood ALL. Blood. 2008;111:3692–3700.
    1. Krajinovic M, Costea I, Primeau M, et al. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J. 2005;5:374–380.
    1. Rocha JC, Cheng C, Liu W, et al. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood. 2005;105:4752–4758.
    1. 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;115:4671–4677.
    1. Krajinovic M, Lemieux-Blanchard E, Chiasson S, et al. Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2004;4:66–72.
    1. Krajinovic M, Moghrabi A. Pharmacogenetics of methotrexate. Pharmacogenomics. 2004;5:819–834.
    1. Kager L, Evans WE. Pharmacogenomics of acute lymphoblastic leukemia. Curr Opin Hematol. 2006;13:260–265.
    1. Ranganathan P. An update on methotrexate pharmacogenetics in rheumatoid arthritis. Pharmacogenomics. 2008;9:439–451.
    1. Schmiegelow K. Maintenance chemotherapy of acute lymphoblastic leukemia in children. Dan Med Bull. 1998;45:510–532.
    1. van Eys J, Berry D, Crist W, et al. Treatment intensity and outcome for children with acute lymphocytic leukemia of standard risk. A Pediatric Oncology Group Study. Cancer. 1989;63:1466–1471.
    1. Lennard L, Rees CA, Lilleyman JS, et al. Childhood leukaemia: a relationship between intracellular 6-mercaptopurine metabolites and neutropenia. Br J Clin Pharmacol. 1983;16:359–363.
    1. Schmiegelow K, Pulczynska MK, Seip M. White cell count during maintenance chemotherapy for standard-risk childhood acute lymphoblastic leukemia: relation to relapse rate. Pediatr Hematol Oncol. 1988;5:259–267.
    1. Dolan G, Lilleyman JS, Richards SM. Prognostic importance of myelosuppression during maintenance treatment of lymphoblastic leukaemia. Leukaemia in Childhood Working Party of the Medical Research Council. Arch Dis Child. 1989;64:1231–1234.
    1. Gobrecht O, Gobel U, Graubner U, et al. Effect of dose intensity and therapy-induced leukocytopenia in intensive therapy on the prognosis of acute lymphatic leukemia in childhood. Results in 213 patients of the COALL-85 study. Klin Padiatr. 1992;204:230–235.
    1. Hayder S, Bjork O, Nilsson B. Relapse factors during maintenance therapy of acute lymphoblastic leukemia in children. Pediatr Hematol Oncol. 1992;9:21–27.
    1. Lucas K, Gula MJ, Blatt J. Relapse in acute lymphoblastic leukemia as a function of white blood cell and absolute neutrophil counts during maintenance chemotherapy. Pediatr Hematol Oncol. 1992;9:91–97.
    1. Chessells JM, Harrison G, Lilleyman JS, et al. Continuing (maintenance) therapy in lymphoblastic leukaemia: lessons from MRC UKALL X. Medical Research Council Working Party in Childhood Leukaemia. Br J Haematol. 1997;98:945–951.
    1. Schmiegelow K, Pulczynska MK. White-cell counts in childhood acute lymphoblastic leukemia. Eur J Haematol. 1990;44:72–74.
    1. Schmiegelow K, Ifversen M. Myelotoxicity, pharmacokinetics, and relapse rate with methotrexate/6-mercaptopurine maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1996;13:433–441.
    1. Harms DO, Gobel U, Spaar HJ, et al. Thioguanine offers no advantage over mercaptopurine in maintenance treatment of childhood ALL: results of the randomized trial COALL-92. Blood. 2003;102:2736–2740.
    1. Satti MB, Weinbren K, Gordon-Smith EC. 6-thioguanine as a cause of toxic veno-occlusive disease of the liver. J Clin Pathol. 1982;35:1086–1091.
    1. Broxson EH, Dole M, Wong R, et al. Portal hypertension develops in a subset of children with standard risk acute lymphoblastic leukemia treated with oral 6-thioguanine during maintenance therapy. Pediatr Blood Cancer. 2005;44:226–231.
    1. Escherich G, Horstmann MA, Zimmermann M, et al. Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97. Leukemia. 2010;24:298–308.
    1. Heegaard ED, Kerndrup GB, Carlsen NT, et al. [Thrombocytopenia caused by Parvovirus B19 infection in a child with acute lymphatic leukemia]. Ugeskr Laeger. 1999;161:6501–6502.
    1. Topley JM, Benson J, Squier MV, et al. Hepatotoxicity in the treatment of acute lymphoblastic leukaemia. Med Pediatr Oncol. 1979;7:393–399.
    1. Bessho F, Kinumaki H, Yokota S, et al. Liver function studies in children with acute lymphocytic leukemia after cessation of therapy. Med Pediatr Oncol. 1994;23:111–115.
    1. Farrow AC, Buchanan GR, Zwiener RJ, et al. Serum aminotransferase elevation during and following treatment of childhood acute lymphoblastic leukemia. J Clin Oncol. 1997;15:1560–1566.
    1. 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;15:74–79.
    1. Halonen P, Mattila J, Makipernaa A, et al. Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine and methotrexate do not predict liver changes in children treated for acute lymphoblastic leukemia. Pediatr Blood Cancer. 2006;46:762–766.
    1. Halonen P, Salo MK, Makipernaa A. Fasting hypoglycemia is common during maintenance therapy for childhood acute lymphoblastic leukemia. J Pediatr. 2001;138:428–431.
    1. Bay A, Oner AF, Cesur Y, et al. Symptomatic hypoglycemia: an unusual side effect of oral purine analogues for treatment of ALL. Pediatr Blood Cancer. 2006;47:330–331.
    1. El-Bitar MK, Muwakkit SA, Dabbagh O. Severe hypoglycemic seizures in a child receiving 6-mercaptopurine. J Pediatr Hematol Oncol. 2011;33:e75–e76.
    1. Trelinska J, Fendler W, Szadkowska A, et al. Hypoglycemia and glycemic variability among children with acute lymphoblastic leukemia during maintenance therapy. Leuk Lymphoma. 2011;52:1704–1710.
    1. Melachuri S, Gandrud L, Bostrom B. The association between fasting hypoglycemia and methylated mercaptopurine metabolites in children with acute lymphoblastic leukemia. Pediatr Blood Cancer. 2014;61:1003–1006.
    1. Halonen P, Mattila J, Suominen P, et al. Iron overload in children who are treated for acute lymphoblastic leukemia estimated by liver siderosis and serum iron parameters. Pediatrics. 2003;111:91–96.
    1. Halonen P, Mattila J, Ruuska T, et al. Liver histology after current intensified therapy for childhood acute lymphoblastic leukemia: microvesicular fatty change and siderosis are the main findings. Med Pediatr Oncol. 2003;40:148–154.
    1. Halonen P, Salo MK, Schmiegelow K, et al. Investigation of the mechanisms of therapy-related hypoglycaemia in children with acute lymphoblastic leukaemia. Acta Paediatr. 2003;92:37–42.
    1. Bodey GP, Brodovsky HS, Isassi AA, et al. Studies of combination 6-mercaptopurine (NSC-755) and 6-methylmercaptopurine riboside (NSC-40774) in patients with acute leukemia and metastatic cancer. Cancer Chemother Rep. 1968;52:315–320.
    1. Hewlett JS, Bodey GP, Wilson HE, et al. Combination 6-mercaptopurine and 6-methylmercaptopurine riboside in the treatment of adult acute leukemia: a Southwest Oncology Group study. Cancer Treat Rep. 1979;63:156–158.
    1. Dubinsky MC, Lamothe S, Yang HY, et al. Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease. Gastroenterology. 2000;118:705–713.
    1. Rulyak SJ, Saunders MD, Lee SD. Hepatotoxicity associated with 6-thioguanine therapy for Crohn’s disease. J Clin Gastroenterol. 2003;36:234–237.
    1. Berkovitch M, Matsui D, Zipursky A, et al. Hepatotoxicity of 6-mercaptopurine in childhood acute lymphocytic leukemia: pharmacokinetic characteristics. Med Pediatr Oncol. 1996;26:85–89.
    1. Schmiegelow K, Pulczynska M. Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic leukaemia. Br J Cancer. 1990;61:767–772.
    1. Bokkerink JP, Damen FJ, Hulscher MW, et al. Biochemical evidence for synergistic combination treatment with methotrexate and 6-mercaptopurine in acute lymphoblastic leukemia. Haematol Blood Transfus. 1990;33:110–117.
    1. Balis FM, Holcenberg JS, Zimm S, et al. The effect of methotrexate on the bioavailability of oral 6-mercaptopurine. Clin Pharmacol Ther. 1987;41:384–387.
    1. Dervieux T, Hancock M, Evans W, et al. Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine. Leukemia. 2002;16:209–212.
    1. Escherich G, Richards S, Stork LC, et al. Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia. Leukemia. 2011;25:953–959.
    1. Lancaster DL, Lennard L, Rowland K, et al. Thioguanine versus mercaptopurine for therapy of childhood lymphoblastic leukaemia: a comparison of haematological toxicity and drug metabolite concentrations. Br J Haematol. 1998;102:439–443.
    1. 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;368:1339–1348.
    1. 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;80:375–383.
    1. Jacobs SS, Stork LC, Bostrom BC, et al. Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: a collaborative Children’s Oncology Group/National Cancer Institute pilot trial (CCG-1942). Pediatr Blood Cancer. 2007;49:250–255.
    1. Breitkreutz J, Buckman J, Fischer R, et al. Comparative in vitro studies on different 6-mercaptopurine formulations for use in children. Paediatr Perinat Drug Ther. 2007;8:31–39.
    1. Mulla H, Leary A, White P, et al. A step toward more accurate dosing for mercaptopurine in childhood acute lymphoblastic leukemia. J Clin Pharmacol. 2012;52:161–163.
    1. Lennard L, Welch J, Lilleyman JS. Intracellular metabolites of mercaptopurine in children with lymphoblastic leukaemia: a possible indicator of non-compliance? Br J Cancer. 1995;72:1004–1006.
    1. Lau RC, Matsui D, Greenberg M, et al. Electronic measurement of compliance with mercaptopurine in pediatric patients with acute lymphoblastic leukemia. Med Pediatr Oncol. 1998;30:85–90.
    1. Pritchard MT, Butow PN, Stevens MM, et al. Understanding medication adherence in pediatric acute lymphoblastic leukemia: a review. J Pediatr Hematol Oncol. 2006;28:816–823.
    1. Hanghoj S, Boisen KA. Self-reported barriers to medication adherence among chronically ill adolescents: a systematic review. J Adolesc Health. 2014;54:121–138.
    1. Brandalise SR, Pinheiro VR, Aguiar SS, et al. Benefits of the intermittent use of 6-mercaptopurine and methotrexate in maintenance treatment for low-risk acute lymphoblastic leukemia in children: randomized trial from the Brazilian Childhood Cooperative Group—protocol ALL-99. J Clin Oncol. 2010;28:1911–1918.
    1. Hrushesky WJ, Bjarnason GA. Circadian cancer therapy. J Clin Oncol. 1993;11:1403–1417.
    1. Rivard GE, Infante-Rivard C, Hoyoux C, et al. Maintenance chemotherapy for childhood acute lymphoblastic leukaemia: better in the evening. Lancet. 1985;2:1264–1266.
    1. Schmiegelow K, Glomstein A, Kristinsson J, et al. 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;19:102–109.
    1. Ramot B, Brok-Simoni F, Chweidan E, et al. Blood leucocyte enzymes. III. Diurnal rhythm of activity in isolated lymphocytes of normal subjects and chronic lymphatic leukaemia patients. Br J Haematol. 1976;34:79–85.
    1. Sletvold O, Smaaland R, Laerum OD. Cytometry and time-dependent variations in peripheral blood and bone marrow cells: a literature review and relevance to the chronotherapy of cancer. Chronobiol Int. 1991;8:235–250.
    1. 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. 2013;61:653–658.
    1. Pinkerton CR, Welshman SG, Glasgow JF, et al. Can food influence the absorption of methotrexate in children with acute lymphoblastic leukaemia? Lancet. 1980;2:944–946.
    1. Riccardi R, Balis FM, Ferrara P, et al. Influence of food intake on bioavailability of oral 6-mercaptopurine in children with acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1986;3:319–324.
    1. Lonnerholm G, Kreuger A, Lindstrom B, et al. Oral mercaptopurine in childhood leukemia: influence of food intake on bioavailability. Pediatr Hematol Oncol. 1989;6:105–112.
    1. Kozloski GD, De Vito JM, Kisicki JC, et al. The effect of food on the absorption of methotrexate sodium tablets in healthy volunteers. Arthritis Rheum. 1992;35:761–764.
    1. Hamilton RA, Kremer JM. The effects of food on methotrexate absorption. J Rheumatol. 1995;22:630–632.
    1. de Lemos ML, Hamata L, Jennings S, et al. Interaction between mercaptopurine and milk. J Oncol Pharm Pract. 2007;13:237–240.
    1. Pinkel D. Intravenous mercaptopurine: life begins at 40. J Clin Oncol. 1993;11:1826–1831.
    1. Bostrom BC, Sensel MR, Sather HN, et al. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children’s Cancer Group. Blood. 2003;101:3809–3817.
    1. 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;369:123–131.
    1. Eden T, Pieters R, Richards S. 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 5659 children. Br J Haematol. 2010;149:722–733.
    1. Adam de Beaumais T, Dervieux T, Fakhoury M, et al. The impact of high-dose methotrexate on intracellular 6-mercaptopurine disposition during interval therapy of childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2010;66:653–658.
    1. Nygaard U, Schmiegelow K. Dose reduction of coadministered 6-mercaptopurine decreases myelotoxicity following high-dose methotrexate in childhood leukemia. Leukemia. 2003;17:1344–1348.
    1. 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;81:391–398.
    1. De MB, Suciu S, Bertrand Y, et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010;116:36–44.
    1. Bleyer WA, Sather HN, Nickerson HJ, et al. Monthly pulses of vincristine and prednisone prevent bone marrow and testicular relapse in low-risk childhood acute lymphoblastic leukemia: a report of the CCG-161 study by the Childrens Cancer Study Group. J Clin Oncol. 1991;9:1012–1021.
    1. Felice MS, Rossi JG, Gallego MS, et al. No advantage of a rotational continuation phase in acute lymphoblastic leukemia in childhood treated with a BFM back-bone therapy. Pediatr Blood Cancer. 2011;57:47–55.
    1. Shea B, Swinden MV, Tanjong GE, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;5:CD000951.
    1. Robien K, Schubert MM, Yasui Y, et al. Folic acid supplementation during methotrexate immunosuppression is not associated with early toxicity, risk of acute graft-versus-host disease or relapse following hematopoietic transplantation. Bone Marrow Transplant. 2006;37:687–692.
    1. Lennard L, Lilleyman JS, Maddocks JL. The effect of folate supplements on 6-mercaptopurine remission maintenance therapy in childhood leukaemia. Br J Cancer. 1986;53:115–119.
    1. Schroder H, Clausen N, Ostergard E, et al. Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1986;3:241–247.
    1. Poulsen A, Demeny AK, Bang PC, et al. Pneumocystis carinii pneumonia during maintenance treatment of childhood acute lymphoblastic leukemia. Med Pediatr Oncol. 2001;37:20–23.
    1. Ferrazzini G, Klein J, Sulh H, et al. Interaction between trimethoprim-sulfamethoxazole and methotrexate in children with leukemia. J Pediatr. 1990;117:823–826.
    1. Rees CA, Lennard L, Lilleyman JS, et al. Disturbance of 6-mercaptopurine metabolism by cotrimoxazole in childhood lymphoblastic leukaemia. Cancer Chemother Pharmacol. 1984;12:87–89.
    1. 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;88:78–86.
    1. Schrappe M, Valsecchi MG, Bartram CR, et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood. 2011;118:2077–2084.
    1. Vaitkeviciene G, Heyman M, Jonsson OG, et al. Early morbidity and mortality in childhood acute lymphoblastic leukemia with very high white blood cell count. Leukemia. 2013;27:2259–2262.
    1. Rubnitz JE, Camitta BM, Mahmoud H, et al. Childhood acute lymphoblastic leukemia with the MLL-ENL fusion and t(11;19)(q23;p13.3) translocation. J Clin Oncol. 1999;17:191–196.
    1. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110:1112–1115.
    1. Forestier E, Johansson B, Gustafsson G, et al. Prognostic impact of karyotypic findings in childhood acute lymphoblastic leukaemia: a Nordic series comparing two treatment periods. For the Nordic Society of Paediatric Haematology and Oncology (NOPHO) Leukaemia Cytogenetic Study Group. Br J Haematol. 2000;110:147–153.
    1. Schmiegelow K, Pulczynska MK. Maintenance chemotherapy for childhood acute lymphoblastic leukemia: should dosage be guided by white blood cell counts? Am J Pediatr Hematol Oncol. 1990;12:462–467.

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