The absorption of 6MP is rapid, and the elimination half-life is short (1 to 2 h). Even though small studies (somewhat surprisingly) have been able to associate plasma 6MP concentrations to relapse rates,64,65 such measurements cannot be used for 6MP dose adjustments, due to very large (up to 70-fold) interindividual and intraindividual variations in bioavailability.54,60,66
Second, 6MP is a prodrug that through a multistep process, involving hypoxanthine guanine phophoribosyl transferase mediated coupling of 6MP with phosphoribosyl pyrophosphate, base modification, and further phosphorylation to form 6TGN (Fig. 3). The deoxy form of 6TGN is then incorporated into DNA (DNA-TG) in nucleated cells,72–74 which may activate postreplication mismatch repair systems that lead to DNA strand breaks and apoptosis.24,75
A third metabolic pathway is thiomethylation of 6MP and some of its metabolites catalyzed by TPMT, thus reducing 6TGN formation76 (Fig. 3). Previously, methylated 6MP metabolites were considered largely insignificant for 6MP pharmacodynamics. However, some methylated metabolites, not least methylthioinosine monophosphates (MeMP), are strong inhibitors of purine de novo synthesis.77 As the purine salvage pathway is low in lymphoblasts that primarily depend on purine de novo synthesis,78 the reduced levels of endogenous nucleotides and the resulting enhanced DNA-TG incorporation in the presence of MeMP is likely to play a clinical role.74,79 Still, the impact of these pharmacodynamic interactions on relapse rates and toxicities remains undetermined, partly as a sufficiently sensitive and reliable assay for routine measurements of DNA-TG in nucleated blood has only recently become available.80
After a few weeks of oral 6MP therapy a steady state level in Ery-6TGN level is obtained.81,82 Early studies showed Ery-6TGN levels to be associated with both myelotoxicity and remission duration,83–85 even though the 6MP metabolite profiles differ widely between red blood cells and neutrophils.86 However, more recent studies have failed to confirm a significant association between Ery-6TGN and risk of relapse.38,61 Ery-6TGN levels reflect adherence to therapy87 and TPMT activity,63 but are only weakly, although statistically significantly, related to DNA-TG levels.74,79 Furthermore, 6MP dose increments to achieve higher Ery-6TGN levels primarily increase the methylated metabolite levels,88 which may enhance hepatotoxicity.89 There is a lack of large, prospective studies that explore whether monitoring of Ery-6TGN, Ery-MeMP, and DNA-TG adds dose adjustments advantages compared with adjustments by only myelotoxicity and hepatotoxicity.
As dose increments of 6MP increase the methylated metabolites and their associated toxicities far more than Ery-6TGN, several alternative treatment strategies have been efficacious in improving the 6TGN/MeMP ratio, including coadministration of allopurinol70,71,90 and splitting the daily 6MP dose in a morning and an evening dose,91,92 but it remains to be determined whether such approaches increase DNA-TG levels, ease 6MP dose adjustments to obtain target WBC/absolute neutrophil counts (ANC) levels, or reduce relapse rates of childhood ALL.
Although MTX disposition and pharmacodynamics have been well mapped in cancer cell lines,23,93,94 far less is known on how to implement such data into maintenance therapy strategies. The folate pathway gene expression profiles vary widely among subsets of ALL, which affects treatment efficacy of MTX.95 However, current guidelines for MTX dosing do not take into account the diversity of different leukemia subtypes’ sensitivity to MTX.
Bioavailability of low dose oral MTX is generally >90%, but is significantly reduced at doses >40 mg/m2.57 Similar to natural folates, MTX is converted into MTX polyglutamates (MTXPG, with 2 to 7 glutamyl residues) by the enzyme folylpolyglytamyl transferase, which enhances intracellular retention, inhibition of the target enzymes in purine and pyrimidine de novo synthesis, and treatment efficacy (Fig. 3).96 The propensity for MTX to undergo polyglutamation is higher for B-cell precursor ALL subtypes (not least the high-hyperdiploid cases) than for T-cell ALL.95,97,98 Accordingly, many groups offer high-dose MTX at doses of 5 g/m2/24 h during consolidation therapy to cure T-cell ALL. MTXPG bind tightly to and inhibit dihydrofolate reductase, the enzyme responsible for reducing folates to their bioactive tetrahydrofolate form.23 During weekly low-dose oral MTX therapy, MTXPG accumulates in red blood cell precursors in the bone marrow, and MTXPG with longer glutamyl chains are then retained in the erythrocytes (Ery-MTXPG) throughout their life span.99 Steady-state Ery-MTXPG is achieved after 4 to 8 weeks.100,101 High Ery-MTXPG levels have been associated with increased risk of myelotoxicity,100,102 but only a single Nordic study has found Ery-MTXPG levels significantly related to remission duration,102 and this association could not be confirmed in later studies,61,103 potentially due to more intensive use of intravenous MTX in these studies. No study has explored the impact on relapse rates of various Ery-MTX polyglutamate chain lengths. At steady state, Ery-MTXPG is both interindividually and intraindividually related to the dose of oral MTX and may thus be used for monitoring treatment adherence.34,100
Single nucleotide polymorphisms in genes that affect the disposition of anticancer agents influence the outcome of childhood ALL.104,105 However, so far only TPMT variants have influenced drug dosing,76,96 and it is poorly explored which host genome variants that ultimately determine the complex metabolism and efficacy of thiopurines and MTX, how this influences the toxicity profiles across ethnic groups,106–110 and how such data should be applied for dose adjustments.
The normal substrate for TPMT is not known, and, in the absence of thiopurines, TPMT-deficient individuals are clinically and biochemically normal. In white individuals, the most common variants are *3A,*3B, and *3C all involving G460A and/or A719G and accounting for at least 90% of low-activity alleles among white individuals of North European decent.63,76 Approximately 5% to 10% are TPMT heterozygous carrying 1 wild-type and 1 low-activity allele, and 1 in 300 is TPMT deficient and at risk of life-threatening myelosuppression at standard 6MP doses.111,112 Although thiopurine dosing according to the TPMT genotype has been implemented by a few ALL study groups,48,79,113 the benefits of this strategy remain uncertain. Compared with TPMT wild-type patients, heterozygous patients experience higher intracellular 6TGN levels, more myelotoxicity, higher cure rates,63,113,114 but probably also a higher risk of second cancers.41,115,116 The German BFM group that administered lower starting doses of 6MP (50 mg/m2) failed to confirm the association with second cancers.117 It is noteworthy that, a recent study indicated that reduction of oral 6MP starting doses from 75 to 50 mg/m2/d, reflecting these BFM data, did reduce the risk of second cancers among TPMT heterozygous patients, but at the same time lead to an increased risk of relapse.43
Measuring TPMT activity in erythrocytes is an alternative to genotyping and may also identify rare low-activity variants missed by routine allele testing. However, as TPMT activity is inversely related to the erythrocyte age,118 the TPMT activity will in general be increased during maintenance therapy when the erythrocyte life span is shortened, and be low at diagnosis of ALL due to reduced erythropoiesis, hampering reliable discrimination of heterozygous and wild-type TPMT phenotypes.
Low-activity alleles of ITPA, the enzyme that dephosphorylates thioinosine triphosphate (Fig. 3), may increase methylated thiopurine metabolite levels,119,120 the risk of hepatotoxicity121,122 and of bone marrow toxicity123 with febrile neutropenia,119,124 and potentially also the risk of relapse.110 The frequency of ITPA low-activity alleles show wide interethnic variability being 1% to 2% among Hispanics, but almost 20% in Asian populations, which may influence tolerance to thiopurine therapy.125
Other 6MP metabolizing enzymes, such as xanthine oxidase and hypoxanthine guanine phosphoribosyl transferase (HGPRT) may vary among individuals,67,126 in part determined by genetic polymorphisms, and at least low HGPRT in B-cell precursor ALL has been associated with an inferior cure rate, although this association was not related to increased in vitro thiopurine resistance.127
Several groups have demonstrated that MTX treatment efficacy is associated with polymorphisms in dihydrofolate reductase,128 thymidylate synthetase,129,130 reduced folate carrier,131 5,10-methylenetetrahydrofolate reductase, and methylenetetrahydrofolate dehydrogenase132 (for reviews on childhood ALL and rheumatoid arthritis, see Davidsen and colleagues105,133–135). However, the results of these studies are often contradictory with some studies demonstrating improved cure rates for a specific genetic polymorphism, whereas others demonstrate the opposite, many of the studies are small, most only address 1 or a few of the many genetic polymorphisms involved in the disposition of MTX, and in general they address responses to high-dose MTX rather than low-dose MTX maintenance therapy. Furthermore, it is impossible to evaluate whether a specific polymorphism exert its modifying effect on relapse rate and/or toxicities directly through changed MTX disposition or indirectly by modifying endogenous folate levels. So far no groups have adjusted their MTX treatment strategies based on polymorphisms in the MTX/folate pathway.
Dose adjustments guided by toxicity assumes that the individual variations in 6MP/MTX pharmacokinetics and/or pharmacodynamics affect leukemic and normal cells in parallel.136 For maintenance therapy, 6MP/MTX dosage is targeted to a preset degree of myelosuppression, generally a WBC of 1.5 to 3.0 (or 3.5)×109/L,48 but randomized studies demonstrating benefits hereof are lacking.137 Most observational studies have shown low WBC and/or ANC during maintenance therapy to be related to red blood cell levels of cytotoxic 6MP/MTX metabolites and/or to a reduced relapse rate.38,61,82,100,138–144 However, ANC correlates so closely with WBC, that it is virtually impossible to determine which of these 2 parameters is superior as guidance for dose adjustment (Fig. 4A). In the Nordic Society for Paediatric Haematology and Oncology (NOPHO) ALL92 maintenance therapy study,61 patients with an average ANC <2.0×109/L during maintenance therapy had a significantly better relapse-free survival than patients with higher ANC levels (Fig. 4B), and ANC was somewhat more strongly associated with relapse rates than WBC level, although the latter was the dose adjustment target in that protocol. Nevertheless, several factors challenge 6MP/MTX dose adjustments by the leukocyte counts.
First, physicians may be more inclined to decrease 6MP/MTX drug doses in case of toxicity than to escalate doses in patients insufficiently myelosuppressed,36 requiring different strategies for 6MP dose adjustments, if the 6MP starting dose is 50 versus 75 mg/m2.
Second, the WBC levels reflect both treatment intensity and the child’s normal WBC level, which varies both between and within age groups, and by ethnicity. Thus, patients with lower WBC levels during therapy also have low WBC after cessation of therapy (rS=0.76; P<0.00001),145 and even more important, the best predictor of the rise in WBC after cessation of therapy is not the WBC level during maintenance therapy, but Ery-6TGN and Ery-MTXPG.102 Thus, an average WBC during therapy of 3.5×109/L could reflect more intensive treatment than an average WBC of 3.2×109/L, if the patients’ off-therapy WBC levels were 8.5 and 4.5×109/L, respectively. In support hereof, the red blood cell 6MP/MTX metabolite levels are overall higher in the former patient, and the rise in WBC following cessation of maintenance therapy is a stronger predictor of relapse than the average WBC level during maintenance therapy, associating a high rise in WBC with a reduced relapse rate after cessation of maintenance therapy.146
Third, often it is not possible to suppress WBC levels to a target range of 1.5 to 3.0×109/L by dose intensification without unacceptable extramedullary toxicity, including hepatotoxicity (see below).
Finally, an aggressive approach with higher 6MP doses and higher treatment intensity to achieve low WBC levels may be counteracted by treatment interruptions,61 or lead to an increased risk of second cancers.41,42 Other not yet understood mechanisms such as induction of dormant leukemic stem cells61 due to inhibition of purine de novo synthesis could also increase the risk of relapse for the dose-intensified patients.
6MP and MTX are hepatotoxic and 2-fold elevations or more of serum aminotransferases are frequent,100,146,152–156 but usually normalize within a few weeks after discontinuation of maintenance therapy.146,153 Hypoglycemic episodes during fasting157–160 have been associated with high levels of methylated 6MP metabolites.161 It can be counteracted by evening meals with slowly absorbed carbohydrates, by administration of rapidly absorbed carbohydrates (eg, apple juice) in case of symptoms, or by shifting to morning dosage. The latter reduces Ery-MeMP levels but the impact on relapse rate is unknown.161 Few patients develop symptoms of hypoglycemia such as severe nausea, itching, or malaise to a degree that requires dose reductions. A moderate rise in bilirubin or reduced levels of coagulation factors is common, but the risk of serious and/or permanent liver damage seems low.162–164 Accordingly, most study groups do not recommend dose reductions in case of high aminotransferase levels48 unless accompanied by biochemical evidence of severe hepatic dysfunction, that is, bilirubin 3 times above the upper normal limit and/or coagulation factor II-VII-X <0.50 IU/L. Such patients should be explored for other causes, including hepatotropic vira (eg, B or C virus153,154), veno-occlusive syndrome (VOD), or Gilbert syndrome with reduced glucuronyltransferase activity and elevated unconjugated bilirubin.
In accordance with the high incidence of hepatotoxicity seen with methylmercaptopurine riboside therapy,165,166 and the low rate of hepatotoxicity in patients with low TPMT activity,38,89 most cases of high aminotransferase levels can be related to high levels of methylated 6MP metabolites,89,167 but have also more rarely been proposed to be associated with high Ery-6TGN168 or Ery-MTXpg,100 or to accumulation of 6MP in the liver.169
A small Danish study from the 1980s linked increased aminotransferases levels during maintenance therapy with a reduced relapse rate.170 This could reflect reduced first-pass effect on oral 6MP with higher systemic 6MP exposure among developing hepatotoxicity, or higher levels of methylthioinosine monophosphate causing both liver toxicity and inhibition of purine de novo synthesis in leukemic cells,78,171 which could have increased the incorporation of 6TGN into DNA.74,79 Alternatively, elevated aminotransferases and reduced relapse risks could merely reflect that the patients were adherent to maintenance therapy. Importantly, patients who continued therapy despite an increase in aminotransferases had a lower relapse rates than patients with treatment interruptions due to hepatotoxicity.37
In 3 randomized studies by the US CCG, the German COALL, and the British UKALL groups that all compared 6MP with 6TG as the maintenance therapy thiopurine, only males below 10 years of age seemed to have reduced relapse rates with 6TG (OR=0.70; 95% confidence interval, 0.58-0.84), although with no significant difference in overall survival.174 The lack of MeMP and the associated inhibition of purine de novo synthesis for patients on 6TG may explain why this thiopurine failed to improve EFS, even though children receiving 6TG had several-fold higher Ery-6TGN levels.88,147,174,175 More worrying is that, 10% to 15% of patients on 6TG developed VOD, a few of which were sufficiently severe to require liver transplantation.148,176–178 It is noteworthy that, the German COALL study147 did not report 6TG-associated VOD, the only major difference from the other 2 studies being the absence of vincristine/glucocorticosteroid reinductions during maintenance therapy in the German trial. However, the biology behind this association remains uncertain.
With the complexity of multiple factors influencing therapy (physician compliance, patient adherence, drug disposition, toxicity), there are many potential layers of failure to optimize maintenance therapy. Toxicity-guided dosing relies heavily on physicians’ willingness to comply with the protocol guidelines, their experience with maintenance therapy, and their ability to explain the pharmacology, the biology of toxicities, and the importance of treatment adherence to patients and parents. Patient adherence will on the contrary reflect the patient’s/family’s willingness to accept burdensome toxicities of 6MP and MTX and frequent hospital visits to cure a disease that no longer can be detected. For very young children, not least infants, treatment adherence has been jeopardized by the commercially available 6MP tablets having been developed for adult-sized patients,179 and not until recently has a liquid formulation of 6MP been marketed (although still not formally tested) in children.180
The randomized Brazilian ALL99 study indicated that intermittent oral high-dose 6MP with IV MTX 200 mg/m2/6 h not only improved adherence but also gave better pEFS than oral 6MP (50 mg/m2/d) with IM MTX 25 mg/m2/wk, although only for boys.185 However, the extent of patient adherence in the oral 6MP arm is difficult to assess, as 6MP/MTX metabolite measurements were not done, and it is also unclear whether the difference in 6MP and/or MTX dosing in the 2 treatment arms caused the difference in EFS.
The circadian schedule has a strong impact on efficacy and toxicity of a number of anticancer agents.186 Two maintenance therapy studies from the 1980s and 1990s found that the risk of relapse was several-fold higher for patients who reported taking 6MP and MTX in the morning compared with patients on evening schedule.187,188 It was speculated that differences in biological activity between malignant lymphoid cells and normal bone marrow cells determined these chronochemotherapeutical findings,189,190 but whatever the biological mechanism, changing patients from morning to evening schedule seemed a simple procedure to improve outcome, and this has become the general standard.48 However, a recent large study of 526 children on maintenance therapy with almost 10,000 E-6TGN/MTXpg measurements, found no association between relapse rates and the cumulative duration of evening dosage for the individual patient, when adjusting for 6MP and MTX doses, WBC levels during maintenance therapy, and Ery-6TGN and Ery-MTXPG levels.191
During the last decades more attention has been paid to dose titration by myelotoxicity, and some groups even monitor 6MP and MTX metabolites to reveal poor treatment adherence. However, until it has been determined that such therapeutic drug monitoring eases dose adjustments, improves cure rates, and/or reduce toxicity, maintenance therapy should be adjusted according to the WBC, and lack of myelotoxicity and hepatotoxicity regarded as a surrogate marker for nonadherence. Future research should address the applicability of DNA-TG monitoring, extensive host single nucleotide polymorphism profiling, screening methods for resistant leukemic subclones, and alternative thiopurine dosing regimens to improve maintenance therapy for the individual patient.
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.
2. 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.
3. Thomas A. Joe Burchenal and the birth of combination chemotherapy. Br J Haematol. 2006;133:493–503.
4. 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.
5. Simone JV. The treatment of acute lymphoblastic
leukaemia. Br J Haematol. 1980;45:1–4.
6. Holland JF, Glidewell O. Chemotherapy of acute
of childhood. Cancer. 1972;30:1480–1487.
7. Lonsdale D, Gehan EA, Fernbach DJ, et al.. Interrupted vs. continued maintenance therapy
in childhood acute leukemia
. Cancer. 1975;36:341–352.
8. 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.
9. Schmiegelow K, Forestier E, Hellebostad M, et al.. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia
10. 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
11. 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
12. 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
13. 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
14. 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
15. Schrappe M, Nachman J, Hunger S, et al.. Educational symposium on long-term results of large prospective clinical trials for childhood acute lymphoblastic leukemia
16. Sather H, Miller D, Nesbit M, et al.. Differences in prognosis for boys and girls with acute lymphoblastic
leukaemia. Lancet. 1981;1:739–743.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. Meyer JA, Wang J, Hogan LE, et al.. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia
. Nat Genet. 2013;45:290–294.
23. Chabner BA, Allegra CJ, Curt GA, et al.. Polyglutamation of methotrexate
. Is methotrexate
a prodrug? J Clin Invest. 1985;76:907–912.
24. 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.
25. Kamen BA. Serendipity-methotrexate
for continuation therapy for patients with acute lymphoblastic leukemia
: the leukemic stem cell and beyond? J Pediatr Hematol Oncol. 2009;31:383–384.
26. Gale RP, Butturini A. Maintenance chemotherapy and cure of childhood acute lymphoblastic
leukaemia. Lancet. 1991;338:1315–1318.
27. 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.
28. Campana D, Coustan-Smith E, Manabe A, et al.. Human B-cell progenitors and bone marrow microenvironment. Hum Cell. 1996;9:317–322.
29. Mudry RE, Fortney JE, York T, et al.. Stromal cells regulate survival of B-lineage leukemic cells during chemotherapy. Blood. 2000;96:1926–1932.
30. 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.
31. 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.
32. Keyhani A, Jendiroba DB, Freireich EJ. Angiogenesis and leukemia
. Leuk Res. 2001;25:639–645.
33. Schmiegelow K, Heyman M, Kristinsson J, et al.. Oral methotrexate
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.
34. 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
35. Bohnstedt C, Levinsen M, Rosthoj S, et al.. Physicians compliance during maintenance therapy
in children with Down syndrome and acute lymphoblastic leukemia
36. 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.
37. Schmiegelow K. Prognostic significance of methotrexate
dosage during maintenance chemotherapy for childhood acute lymphoblastic leukemia
. Pediatr Hematol Oncol. 1991;8:301–312.
38. Relling MV, Hancock ML, Boyett JM, et al.. Prognostic importance of 6-mercaptopurine
dose intensity in acute lymphoblastic leukemia
. Blood. 1999;93:2817–2823.
39. 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.
40. 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.
41. 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.
42. 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.
43. 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.
44. 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.
45. 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.
46. 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.
47. 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.
48. Arico M, Baruchel A, Bertrand Y, et al.. The seventh international childhood acute lymphoblastic leukemia
workshop report: Palermo, Italy, January 29-30, 2005. Leukemia
49. 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.
50. Balis FM, Mirro JJ, Reaman GH, et al.. Pharmacokinetics
of subcutaneous methotrexate
. J Clin Oncol. 1988;6:1882–1886.
51. 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.
52. 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.
53. Pinkel D, Hernandez K, Borella L, et al.. Drug dosage and remission duration in childhood lymphocytic leukemia
. Cancer. 1971;27:247–256.
54. 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.
55. 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.
56. Poplack DG, Balis FM, Zimm S. The pharmacology
of orally administered chemotherapy. A reappraisal. Cancer. 1986;58:473–480.
57. Teresi ME, Crom WR, Choi KE, et al.. Methotrexate
bioavailability after oral and intramuscular administration in children. J Pediatr. 1987;110:788–792.
58. 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.
59. 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.
60. 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.
61. 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.
62. 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.
63. 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
64. 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.
65. Koren G, Ferrazini G, Sulh H, et al.. Systemic exposure to mercaptopurine as a prognostic factor in acute
in children. N Engl J Med. 1990;323:17–21.
66. 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.
67. 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.
68. 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.
69. 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.
70. Blaker PA, Arenas-Hernandez M, Smith MA, et al.. Mechanism of allopurinol induced TPMT inhibition. Biochem Pharmacol. 2013;86:539–547.
71. 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.
72. Lennard L. The clinical pharmacology
. Eur J Clin Pharmacol. 1992;43:329–339.
73. 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.
74. 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.
75. Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8:24–36.
76. 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.
77. 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.
78. 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.
79. 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.
80. 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.
81. 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.
82. 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.
83. Bostrom B, Erdmann G. Cellular pharmacology
in acute lymphoblastic leukemia
. Am J Pediatr Hematol Oncol. 1993;15:80–86.
84. Lilleyman JS, Lennard L. Mercaptopurine metabolism and risk of relapse in childhood lymphoblastic
leukaemia. Lancet. 1994;343:1188–1190.
85. 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.
86. 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.
87. Lancaster D, Lennard L, Lilleyman JS. Profile of non-compliance in lymphoblastic
leukaemia. Arch Dis Child. 1997;76:365–366.
88. 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.
89. Nygaard U, Toft N, Schmiegelow K. Methylated metabolites of 6-mercaptopurine
are associated with hepatotoxicity. Clin Pharmacol Ther. 2004;75:274–281.
90. 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.
91. 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.
92. 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.
93. Fotoohi AK, Albertioni F. Mechanisms of antifolate resistance and methotrexate
efficacy in leukemia
cells. Leuk Lymphoma. 2008;49:410–426.
94. 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.
95. 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.
96. Schmiegelow K. Advances in individual prediction of methotrexate
toxicity: a review. Br J Haematol. 2009;146:489–503.
97. 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.
98. 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.
99. Schroder H, Fogh K, Herlin T. In vivo decline of methotrexate
polyglutamates in age-fractionated erythrocytes. Cancer Chemother Pharmacol. 1988;21:150–155.
100. 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.
101. 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.
102. 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.
103. 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.
104. Aplenc R, Lange B. Pharmacogenetic determinants of outcome in acute lymphoblastic
leukaemia. Br J Haematol. 2004;125:421–434.
105. Davidsen ML, Dalhoff K, Schmiegelow K. Pharmacogenetics influence treatment efficacy in childhood acute lymphoblastic leukemia
. J Pediatr Hematol Oncol. 2008;30:831–849.
106. 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.
107. 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.
108. 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.
109. 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.
110. 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.
111. Lennard L, Lewis IJ, Michelagnoli M, et al.. Thiopurine methyltransferase deficiency in childhood lymphoblastic
dosage strategies. Med Pediatr Oncol. 1997;29:252–255.
112. Andersen JB, Szumlanski C, Weinshilboum RM, et al.. Pharmacokinetics
, dose adjustments, and 6-mercaptopurine
drug interactions in two patients with thiopurine methyltransferase deficiency. Acta Paediatr. 1998;87:108–111.
113. 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.
114. 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.
115. Relling MV, Rubnitz JE, Rivera GK, et al.. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet. 1999;354:34–39.
116. 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.
117. 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.
118. Lennard L, Chew TS, Lilleyman JS. Human thiopurine methyltransferase activity varies with red blood cell age. Br J Clin Pharmacol. 2001;52:539–546.
119. 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.
120. 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.
121. 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.
122. 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.
123. 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.
124. 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.
125. Marsh S, King CR, Ahluwalia R, et al.. Distribution of ITPA P32T alleles in multiple world populations. J Hum Genet. 2004;49:579–581.
126. 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.
127. 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.
128. 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.
129. Krajinovic M, Costea I, Primeau M, et al.. Combining several polymorphisms of thymidylate synthase gene for pharmacogenetic analysis. Pharmacogenomics J. 2005;5:374–380.
130. Rocha JC, Cheng C, Liu W, et al.. Pharmacogenetics of outcome in children with acute lymphoblastic leukemia
. Blood. 2005;105:4752–4758.
131. 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.
132. 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.
133. Krajinovic M, Moghrabi A. Pharmacogenetics of methotrexate
. Pharmacogenomics. 2004;5:819–834.
134. Kager L, Evans WE. Pharmacogenomics of acute lymphoblastic leukemia
. Curr Opin Hematol. 2006;13:260–265.
135. Ranganathan P. An update on methotrexate
pharmacogenetics in rheumatoid arthritis. Pharmacogenomics. 2008;9:439–451.
136. Schmiegelow K. Maintenance chemotherapy of acute lymphoblastic leukemia
in children. Dan Med Bull. 1998;45:510–532.
137. van Eys J, Berry D, Crist W, et al.. Treatment intensity and outcome for children with acute
of standard risk. A Pediatric Oncology Group Study. Cancer. 1989;63:1466–1471.
138. 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.
139. 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.
140. 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.
141. Gobrecht O, Gobel U, Graubner U, et al.. Effect of dose intensity and therapy-induced leukocytopenia in intensive therapy on the prognosis of acute
in childhood. Results in 213 patients of the COALL-85 study. Klin Padiatr. 1992;204:230–235.
142. Hayder S, Bjork O, Nilsson B. Relapse factors during maintenance therapy
of acute lymphoblastic leukemia
in children. Pediatr Hematol Oncol. 1992;9:21–27.
143. 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.
144. 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.
145. Schmiegelow K, Pulczynska MK. White-cell counts in childhood acute lymphoblastic leukemia
. Eur J Haematol. 1990;44:72–74.
146. 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.
147. 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.
148. 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.
149. 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.
150. 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
151. Heegaard ED, Kerndrup GB, Carlsen NT, et al.. [Thrombocytopenia caused by Parvovirus B19 infection in a child with acute
]. Ugeskr Laeger. 1999;161:6501–6502.
152. Topley JM, Benson J, Squier MV, et al.. Hepatotoxicity in the treatment of acute lymphoblastic
leukaemia. Med Pediatr Oncol. 1979;7:393–399.
153. Bessho F, Kinumaki H, Yokota S, et al.. Liver function studies in children with acute
after cessation of therapy. Med Pediatr Oncol. 1994;23:111–115.
154. 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.
155. 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
156. Halonen P, Mattila J, Makipernaa A, et al.. Erythrocyte concentrations of metabolites or cumulative doses of 6-mercaptopurine
do not predict liver changes in children treated for acute lymphoblastic leukemia
. Pediatr Blood Cancer. 2006;46:762–766.
157. Halonen P, Salo MK, Makipernaa A. Fasting hypoglycemia is common during maintenance therapy
for childhood acute lymphoblastic leukemia
. J Pediatr. 2001;138:428–431.
158. 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.
159. El-Bitar MK, Muwakkit SA, Dabbagh O. Severe hypoglycemic seizures in a child receiving 6-mercaptopurine
. J Pediatr Hematol Oncol. 2011;33:e75–e76.
160. 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.
161. 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.
162. 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.
163. 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.
164. 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.
165. 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.
166. 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.
167. 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.
168. Rulyak SJ, Saunders MD, Lee SD. Hepatotoxicity associated with 6-thioguanine therapy for Crohn’s disease. J Clin Gastroenterol. 2003;36:234–237.
169. Berkovitch M, Matsui D, Zipursky A, et al.. Hepatotoxicity of 6-mercaptopurine
in childhood acute
: pharmacokinetic characteristics. Med Pediatr Oncol. 1996;26:85–89.
170. Schmiegelow K, Pulczynska M. Prognostic significance of hepatotoxicity during maintenance chemotherapy for childhood acute lymphoblastic
leukaemia. Br J Cancer. 1990;61:767–772.
171. Bokkerink JP, Damen FJ, Hulscher MW, et al.. Biochemical evidence for synergistic combination treatment with methotrexate
in acute lymphoblastic leukemia
. Haematol Blood Transfus. 1990;33:110–117.
172. 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.
173. 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
174. Escherich G, Richards S, Stork LC, et al.. Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic
175. 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.
176. 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.
177. 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.
178. 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.
179. 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.
180. 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.
181. 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.
182. 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.
183. 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.
184. Hanghoj S, Boisen KA. Self-reported barriers to medication adherence
among chronically ill adolescents: a systematic review. J Adolesc Health. 2014;54:121–138.
185. Brandalise SR, Pinheiro VR, Aguiar SS, et al.. Benefits of the intermittent use of 6-mercaptopurine
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.
186. Hrushesky WJ, Bjarnason GA. Circadian cancer therapy. J Clin Oncol. 1993;11:1403–1417.
187. 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.
188. Schmiegelow K, Glomstein A, Kristinsson J, et al.. Impact of morning versus evening schedule for oral methotrexate
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.
189. 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.
190. 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.
191. 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.
192. 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.
193. 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.
194. 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.
195. 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.
196. Hamilton RA, Kremer JM. The effects of food on methotrexate
absorption. J Rheumatol. 1995;22:630–632.
197. de Lemos ML, Hamata L, Jennings S, et al.. Interaction between mercaptopurine and milk. J Oncol Pharm Pract. 2007;13:237–240.
198. Pinkel D. Intravenous mercaptopurine: life begins at 40. J Clin Oncol. 1993;11:1826–1831.
199. 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.
200. 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.
201. 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.
202. 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.
203. Nygaard U, Schmiegelow K. Dose reduction of coadministered 6-mercaptopurine
decreases myelotoxicity following high-dose methotrexate
in childhood leukemia
204. 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.
205. 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.
206. 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.
207. 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.
208. 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.
209. 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.
210. 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.
211. 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.
212. 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.
213. Ferrazzini G, Klein J, Sulh H, et al.. Interaction between trimethoprim-sulfamethoxazole and methotrexate
in children with leukemia
. J Pediatr. 1990;117:823–826.
214. 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.
215. Levinsen M, Shabaneh D, Bohnstedt C, et al.. Pneumocystis jiroveci pneumonia prophylaxis during maintenance therapy
dosing but not event-free survival for childhood acute lymphoblastic leukemia
. Eur J Haematol. 2012;88:78–86.
216. 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.
217. 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
218. 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.
219. Nachman JB, Heerema NA, Sather H, et al.. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia
. Blood. 2007;110:1112–1115.
220. 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.
221. 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.