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Purpose. The aim of this study was to compare leucocyte and erythrocyte thioguanine nucleotide (TGN) cytotoxic metabolite concentrations in children with lymphoblastic leukaemia taking mercaptopurine (MP) or thioguanine (TG) as part of their long-term remission maintenance chemotherapy. Methods. Ten consecutive children treated on the MRC ALL97 protocol were studied. Six were randomized to TG and four to MP. Leucocyte and erythrocyte thiopurine nucleotide metabolites were measured after the children had been titrated to the standard thiopurine protocol dose, or higher. Results. Children taking TG accumulated significantly higher erythrocyte TGN concentrations than those taking MP (median difference 1171 pmol/8×108 erythrocytes, 95% CI 766 to 2169, P<0.02), but there was no significant difference in the concentration range of leucocyte TGNs generated from TG or MP. In those children taking TG, median TGN concentrations were 5142 pmol/8×108 leucocytes and 1472 pmol/8×108 erythrocytes (3.5-fold difference, median difference 3390 pmol/8×108 cells, 95% CI 1559 to 7695, P=0.005), compared to 5422 pmol/8×108 leucocytes and 261 pmol/8×108 erythrocytes (20-fold difference, median difference 5054 pmol/8×108 cells, 95% CI 2281 to 6328, P=0.03) in those taking MP. Conclusions. Despite the accumulation of significantly higher erythrocyte TGN concentrations for TG compared with MP, the accumulation of leucocyte TGNs in children taking TG was similar to the range of leucocyte TGNs in children taking MP. Therefore, when correlating intracellular TGNs to clinical effect, the range of erythrocyte TGN metabolites will be higher for those children taking TG than in those taking MP. [ABSTRACT FROM AUTHOR]

Results of three consecutive completed UK trials (1980-1997) for childhood lymphoblastic leukaemia are presented. National accrual has progressively increased so that over 90% of all the country's ALL cases were treated on the latest trial reported, UKALLXI. From 1980 to 1990, event-free and overall survival progressively improved, following adoption of an American therapy template and use of two post-remission intensification modules. Since 1990 despite demonstration of the benefit of a third intensification module overall event-free survival (EFS) has not improved further. Survival remains high due to a good retrieval rate especially for those relapsing off treatment after receipt of two intensification pulses. Possible reasons for the plateau in event-free survival (including type and dose of induction steroid, dropping of induction anthracycline, type and dose of asparaginase, gaps early in therapy following intensification, and overall lack of compliance in maintenance) are being explored in the latest protocol ALL '97. Cranial irradiation had been successfully replaced by a long course of intrathecal methotrexate injections for the majority of patients. Age (<1 year >10 years) sex (male) and white count >50 x 10(9)/l plus slow initial bone marrow clearance were consistently the most important independent prognostic indicators during this time period. Rome/NCI criteria accurately predict standard and high-risk groups for B cell lineage, but not consistently for T cell disease. This international collaborative venture might help us to define those truly at highest risk, and how we can optimise therapy for specific subgroups including T-ALL and those with unfavourable cytogenetics. [ABSTRACT FROM AUTHOR]

Treatment of children with acute lymphoblastic leukaemia (ALL) aims to cure all patients with as little toxicity as possible and, if possible, to restrict further intensification of chemotherapy to patients with an increased risk of relapse. However in Medical Research Council (MRC) trial UKALL X two short myeloablative blocks of intensification therapy given at weeks 5 and 20 were of benefit to children in all risk groups. The successor trials, MRC UKALL XI and MRC ALL97, tested whether further intensification would continue to benefit all patients by randomising them to receive, or not, an extended third intensification block at week 35. After a median follow-up of 4 years (range 5 months to 8 years), 5 year projected event-free survival was superior at 68% for the 894 patients allocated a third intensification compared with 60% for the 887 patients who did not receive one (odds ratio 0.75, 95% CI 0.63-0.90, 2P = 0.002). This difference was almost entirely due to a reduced incidence of bone marrow relapses in the third intensification arm (140 of 891 in the third intensification arm vs. 171 of 883 in the no third intensification, 2P = 0.02). Subgroup analysis suggests benefit of the third intensification for all risk categories. Overall survival to date is no different in the two arms, indicating that a greater proportion of those not receiving a third intensification arm and subsequently relapsing can be salvaged. These results indicate that there is benefit of additional intensification for all risk subgroups of childhood ALL. [ABSTRACT FROM AUTHOR]

It is 50 years since the first effective drug for childhood lymphoblastic leukaemia (ALL) was described. At that time the outlook for such children was certain death. Now patients have an odds-on chance of normal health and life expectancy. Although the greatest gains have been made in recent years, the classes of drug that have achieved this have all been available for over 20 years. It is their better deployment and the greater understanding of their pharmacology that have allowed both more effective protocols to be devised and long term adverse effects to be recognised and avoided. Supportive treatment has also improved in parallel. Three major problems remain: how to recognise children in whom conventional therapy will fail; how to prevent failure; and how to treat it if it occurs. Therapy will fail in some children for pharmacological reasons - noncompliance or constitutional (genetic) drug resistance. For such children in vitro drug sensitivity testing and greater pharmacological vigilance may help by identifying those at risk and allowing intervention. In others, treatment will fail because of intrinsically resistant disease that either develops despite therapy or regrows from a minimal residue. Despite wider application of sophisticated immunological and genetic studies both at diagnosis or later, recognising poor-prognosis children prospectively is hampered by the lack of a biological classification system that is sufficiently sensitive and specific to categorise all patients reliably. In those where there is no doubt about high-risk status, treatment failure rates are still unacceptably high whatever therapy is given, and salvage therapy in any child who relapses is a continuing challenge. [ABSTRACT FROM AUTHOR]

The effect of cotrimoxazole on the utilization of 6-mercaptopurine (6MP) was studied in a group of children receiving remission maintenance treatment for lymphoblastic leukaemia (ALL). This was done by measuring the level of an active metabolite of 6MP, 6-thioguanine nucleotide (6TGN), and comparing it both with the drug dose and with subsequent neutropenia in the presence or absence of concurrent cotrimoxazole. In children who were not taken cotrimoxazole, the concentration of 6TGN showed a significant positive correlation with the dose and a significant negative correlation with the absolute neutrophil count 2 weeks later. In those who were taking the antibiotic both these relationships were lost. This suggests that cotrimoxazole can interfere with both the absorption and the cytotoxicity of 6MP and may, in turn, alter its antileukaemic effect. [ABSTRACT FROM AUTHOR]