Childhood lymphoblastic leukaemia: Sex difference in 6-mercaptopurine utilization

Abstract

Summary Twelve boys and 10 girls on similar long term remission maintenance treatment for lymphoblastic leukaemia had 79 random assays of their red cell 6 thioguanine nucleotide (6TGN) concentrations performed as an index of cytotoxic activity generated by oral 6-mercaptopurine (6MP).Correlation between the dose of 6MP and 6TGN was statistically significant in the girls (r=0.58, P<0.001) but not in the boys (r=0.15). Additionally, as a group the boys tolerated more 6MP (P<0.05), despite similar prescribing criteria, but this did not result in a higher mean 6TGN concentration or increased myelotoxicity.It appears that girls develop 6MP cytotoxicity at lower doses and more predictably than boys. If so, this may be relevant to the as yet unexplained but marked sex difference in prognosis apparent in some studies.The cytotoxic effect of 6-mercaptopurine (6MP) can be related to incorporation of 6MP derived 6-thioguanine nucleotide (6TGN) into DNA (Tidd & Paterson, 1974). We have been measuring the 6TGN found in red cells from children taking 6MP as part of remission maintenance treatment for acute lymphoblastic leukaemia (ALL), and somewhat to our surprise, have found a sex difference in the relationship between 6MP dose, 6TGN concentration and myelosuppression. This may be relevant to the higher late relapse rate frequently seen in boys and explain why such a sex difference in prognosis is found with some treatment schedules but not others. Patients and methodsConsecutive children with ALL treated at the Sheffield Children's Hospital were studied. The children had all been in complete remission for at least 6 months, and were treated with an identical maintenance schedule (the Medical Research Council regimen UKALL VIII). This consisted of daily 6MP (75 mg m 2) and weekly methotrexate (20 mg m -2), both oral, and both prescribed as a target dose based on body surface area. Doses were reduced to 75%, 50% and 0% of the target on the basis of neutropenia or thrombocytopenia at the time of prescription and always in parallel. Both of these drugs were taken as a single early morning dose on an empty stomach. Monthly pulses of a single dose of i.v. vincristine (1.5mgm 2) and 5 days oral prednisone (40 mgm-2) were also given to all patients irrespective of blood counts.Blood for 6TGN assay was obtained at the time of venepuncture for vincristine administration, and so monthly in most children for the study period. The children had been taking 6MP for between 7 months and 2 years, and were in good health at the time of assay. As co-trimoxazole has been found to interfere with 6MP metabolism, (Rees et al., 1984) it was ensured that no patients were taking this drug at the time of study, though all received it for the first 6 months of remission maintenance treatment as per protocol.Red blood cell (RBC) 6TGN was assayed by the method of Lennard & Maddocks (1983). Briefly, this involved extracting the nucleotide from 100pl of packed RBCs (containing -8 x108 cells) by a modification of the 6-thioinosinic acid assay of Fletche...

Veno‐occlusive disease in patients receiving thiopurines during maintenance therapy for childhood acute lymphoblastic leukaemia

“…It suggests a sex‐linked genetic polymorphism present in the degradation pathways of 6‐TG leading to the accumulation of sinusoidal toxic metabolites in the liver. So far, these pathways remain uncharacterized and speculative (Lilleyman et al , 1984). Given the gender bias, predictably TPMT activity does not predispose to the development of VOD; however, neither does the dose of thiopurine administered nor the red cell intracellular concentration of TGNs.…”

Relationship Between Azathioprine Dosage and Thiopurine Metabolites in Pediatric IBD Patients

“…Higher methylated metabolite levels in women versus men were also reported in a large patient population. 32,42 Boys tolerated higher doses of MP than girls on the same prescribing criteria and might develop myelotoxicity less readily and less predictably than girls. Because high 6-MeMPN levels are associated with hepatotoxicity 15 and myelotoxicity, 26 girls may develop AZAinduced hepatotoxicity and myelotoxicity more readily than boys, and so close attention should be paid in monitoring drug concentrations, hematological, and hepatic parameters in thiopurine-treated girls with IBD.…”

“…24 However, that study 22 reported that women formed more 6-TGN levels than men, whereas gender did not predict 6-TGN levels in this study. 32 Sex and age at diagnosis were reported as independent variables associated with the risk of relapse in children with acute lymphoblastic leukemia 42 and patients with CD 33 during thiopurine therapy. Sex differences in thiopurine metabolism were preliminarily described in children with acute lymphoblastic leukemia.…”

“…[19][20][21][22] 6-TGN levels have been shown to increase after dose escalation in several patients, 7,8,16,[23][24][25] whereas metabolite levels have been shown to decrease after a dose reduction to avoid toxicity in some others with high exposure, 9,26 raising the question as to whether a relationship between the drug dose and metabolite levels exists but has not yet been detected. 8,24,32,33 Moreover, univariate regression and even multivariate regression may result in false conclusion in the case of hierarchical data structure, where metabolite measurements are repeatedly performed during the treatment. Infliximab has been supposed to affect the 6-TGN level in 2 studies.…”

Thiopurine methyltransferase activity in a Korean population sample of children*

“…Boys seem to tolerate 6-mercaptopurine better than girls, inasmuch as cytotoxicity develops at lower doses and more predictably in girls than in boys. [34][35][36][37] It has been speculated that pharmacokinetic mechanisms could be the cause for the higher relapse rate of ALL in boys than in girls. Several studies on gender-related differences in RBC TPMT activity have reported higher activities of male subjects in adult population samples.1,3,10,38 In healthy children CLINICAL P HARMACOLOGY &THERAPEUTICS JULY 1996 from 1 to 10 years old, Klemetsdal et at.32 found only minor and nonsignificantly higher RBC TPMT activity in boys than in girls (11.1 units [n = 871 versus 10.6 units [n = 711).…”