Meta-analysis of randomised trials comparing thiopurines in childhood acute lymphoblastic leukaemia

G Escherich, S Richards, L C Stork, A J Vora, Childhood Acute Lymphoblastic Leukaemia Collaborative Group (CALLCG), G Escherich, S Richards, L C Stork, A J Vora, Childhood Acute Lymphoblastic Leukaemia Collaborative Group (CALLCG)

Abstract

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.

Figures

Figure 1
Figure 1
Effect of thiopurine on overall event rate within trials, (a) overall, (b) for NCI standard risk patients only. TG, thioguanine; MP, mercaptopurine; O-E, observed minus expected; Var, variance; O.R., odds ratio; CI, confidence interval ; SD, standard deviation; NS, not significant; 2P, 2-tailed p value. *95% CI for total.
Figure 2
Figure 2
Descriptive event free survival curves showing effect of thiopurine (a) overall (b) within subgroup of males aged under 10 years. MP, mercaptopurine; TG, thioguanine; SD, standard deviation; NS, not significant; 2P, 2-tailed p value.
Figure 3
Figure 3
Effect of thiopurine on overall event rate within subgroups. TG, thioguanine; MP, mercaptopurine; O-E, observed minus expected; Var, variance; O.R., odds ratio; CI, confidence interval ; SD, standard deviation; NS, not significant; 2P, 2-tailed p value.

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Source: PubMed

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