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.
Thrombocyte counts during and after cessation of maintenance therapy are significantly correlated (rS=0.74, P<0.0001),102 but thrombocytopenia is rarely a dose-limiting factor during 6MP/MTX maintenance therapy. However, if 6MP is substituted with the alternative thiopurine, thioguanine (6TG), Ery-6TGN levels become 7-fold higher and severe thrombocytopenia becomes 5- to 10-fold more common.147 Furthermore, 10% to 15% of 6TG-treated patients develop sinusoidal occlusive disease and/or portal hypertension, which often is accompanied by thrombocytopenia.148–150 Patients on 6MP with unexplained thrombocytopenia should be explored for hypersplenism and persistent Parvovirus B19 infection.151
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
Several groups have reported poor treatment adherence to maintenance therapy in a significant proportion of childhood ALL patients.39,87,181,182 The reasons for poor medication adherence can be biological, psychological, and social, and they vary across age groups and by ethnicity.183,184 Various approaches to address this challenge have been proposed, including routine measurements of Ery-6TGN/MeMP/MTXPG, but such analyses are only available in a few centers. If 6MP/MTX metabolite measurements are unavailable, nonadherence should be suspected in TPMT heterozygous patients with persistent WBC >3.0 to 3.5×109/L despite prescribed 6MP dose increments, and in patients with a TPMT wild-type genotype/phenotype, if dose increments do not lead to a rise in aminotransferases.
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
It is unproven that alternative or additive components of maintenance therapy such as intravenous 6MP,198,199 6TG, allopurinol, high-dose MTX,9 vincristine/glucocorticoid,200,201 or more intensive reinductions19 significantly reduce relapse rates with contemporary ALL therapy, although they can add to the burden of myelotoxicity202 and hepatotoxicity, which may necessitate 6MP and MTX dose reductions.155,203,204 Specifically, vincristine/glucocorticoid pulses during 6MP/MTX have been applied by many groups, but so far most, although not all,205 randomized studies have failed to demonstrate benefits of such pulses.200,201,206,207 Folate supplementation has been widely used to counteract MTX-induced toxicity without compromising efficacy in rheumatoid arthritis208 or posttransplantation.209 However, folate supplementation should probably be avoided during maintenance therapy, as it has been shown to influence both 6MP metabolism210 and myelotoxicity.211 Finally, trimethoprim-sulfamethoxazole given as Pneumocystis jiroveci pneumonia prophylaxis212 interferes with MTX213 and 6MP pharmacokinetics,214 and also enhances myelotoxicity leading to lower prescribed 6MP and MTX doses,215 but in spite hereof does not seem to increase relapse rates,215 and thus seems safe to prescribe to avoid this life-threatening infection.
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.
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