Search

Mercaptopurine has been used in continuing treatment of childhood acute lymphoblastic leukaemia since the mid 1950s. Recent advances in the understanding of thiopurine pharmacology indicated that thioguanine (TG) might be more effective than mercaptopurine (MP). The US and UK cooperative groups began randomised thiopurine trials and agreed prospectively to a meta-analysis. All randomised trials of TG versus MP were sought, and data on individual patients were analysed by standard methods. Combining three trials (from US, UK and Germany), the overall event-free survival (EFS) was not significantly improved with TG (odds ratio (OR)=0.89; 95% confidence interval 0.78-1.03). Apparent differences in results between trials may be partly explained by the different types of patients studied. The larger treatment effect reported in males in the US trial was confirmed in the other trials. There was heterogeneity between sex/age subgroups (P=0.001), with significant EFS benefit of TG only observed for males aged <10 years old (OR=0.70; 0.58-0.84), although this did not result in a significant difference in overall survival (OR=0.83; 0.62-1.10). Additional toxicity occurs with TG. Mercaptopurine remains the standard thiopurine of choice, but further study of TG may be warranted to determine whether it could benefit particular subgroups. [ABSTRACT FROM AUTHOR]

Purpose: In preclinical studies, thioguanine (TG) has been shown to be more potent than the standard acute lymphoblastic leukemia (ALL) maintenance agent, mercaptopurine (MP), suggesting that TG may be more efficacious than MP in the treatment of childhood ALL. As part of a pilot trial in which TG was used in place of MP, we studied the plasma pharmacokinetics of oral TG and measured steady-state plasma and CSF TG concentrations during a continuous intravenous infusion (CIVI) in children with newly diagnosed standard-risk ALL.Methods: Nine plasma samples were collected after each patient's first 60 mg/m2 oral TG dose during maintenance. CIVI TG (20 mg/m2/h over 24 h) was administered during the consolidation phase of therapy, and simultaneous plasma and CSF samples were collected near the end of the infusion. TG was measured by reverse-phase HPLC with ultraviolet detection. Erythrocyte TG nucleotide (TGN) concentrations were measured 7 days after a course of CIVI TG and prior to the start of each maintenance cycle.Results: After oral TG (n = 35), the mean (+/- SD) peak plasma concentration was 0.46 +/- 0.68 microM and the AUC ranged from 0.18 to 9.5 microM.h (mean 1.5 microM.h). Mean steady-state plasma and CSF TG concentrations during CIVI (n = 33) were 2.7 and 0.5 microM, respectively. The mean (+/- SD) TG clearance was 935 +/- 463 ml/min per m2. Plasma TG concentrations did not correlate with erythrocyte TGN concentrations after oral or CIVI TG. The 8-OH-TG metabolite was detected in plasma and CSF.Conclusions: TG concentrations that are cytotoxic to human leukemia cell lines can be achieved in plasma after a 60 mg/m2 oral dose of TG and in plasma and CSF during CIVI of TG. [ABSTRACT FROM AUTHOR]

The Children's Cancer Group (CCG) found that children with moderate risk acute lymphoblastic leukemia (ALL) had an improved 5-year event-free survival (EFS) rate when treated with therapy that included a doubled delayed intensification (DDI) vs a single DI (SDI) phase. Because of increased toxicity with DDI, it is important to determine whether subgroups of children with ALL can be identified who have excellent outcomes with SDI therapy. TEL-AML1 fusion and hyperdiploid DNA content are present in the leukemic blasts of significant proportions of children with ALL and have been associated with an excellent prognosis. In this study, we retrospectively examined the impact of TEL-AML1 status and ploidy on treatment outcome in a cohort of 75 children with standard risk ALL treated at our institution between 1983 and 1993 with SDI therapy. TEL-AML1 fusion was present in 19/43 (44%) evaluable cases. Fifteen of 56 (27%) evaluable cases were classified as hyperdiploid based on a modal chromosome number of >/=51 and/or a DNA index of >/=1.16. The 7-year EFS was 81% for the 19 TEL-AML1-positive patients vs 54% for the 24 TEL-AML1-negative patients (P = 0.0264). In multivariate analyses, TEL-AML1-positive status was associated with a superior EFS (P = 0.02) even when the intial white blood count was included in the model. Overall survival (OS) at 7 years for TEL-AML1-positive patients was 100% vs 83% for TEL-AML1-negative patients (P = 0.0677). There were no differences in 7-year EFS or OS based on ploidy comparisons. These results underscore the need to examine closely the effects of treatment intensification on specific biologically defined subgroups of children with ALL. [ABSTRACT FROM AUTHOR]