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

Stoneham, Sara; Lennard, Lynne; Coen, Pietro G.; Lilleyman, J S; Saha, Vaskar

doi:10.1046/j.1365-2141.2003.04578.x

Cited by 62 publications

(66 citation statements)

References 7 publications

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“…Thiopurines are associated with hepatotoxicity; hepatic transaminase elevations have been related to MeTIMP concentrations after mercaptopurine (48) whereas hepatic veno-occlusive disease is more common after thioguanine than mercaptopurine and seems to be dose related (49). Our data are consistent with the hypothesis that TPMT may contribute to hepatocellular toxicity via methylation of mercaptopurine metabolites (43,45,50) but does not relate to thioguanine hepatotoxicity: we did not observe transaminasemia after thioguanine regardless of Tpmt genotype.…”

Section: Discussionsupporting

confidence: 81%

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

et al. 2007

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The recessive deficiency in thiopurine methyltransferase (TPMT), caused by germ-line polymorphisms in TPMT, can cause severe toxicity after mercaptopurine. However, the significance of heterozygosity and the effect of the polymorphism on thioguanine or in the absence of thiopurines is not known. To address these issues, we created a murine knockout of Tpmt. Pharmacokinetic and pharmacodynamic studies of mercaptopurine and thioguanine were done in Tpmt Tpmt+/À , and Tpmt +/+ mice and variables were compared among genotypes. Methylated thiopurine and thioguanine nucleotide metabolites differed among genotypes after treatment with mercaptopurine (P < 0.0001 and P = 0.044, respectively) and thioguanine (P = 0.011 and P = 0.002, respectively). Differences in toxicity among genotypes were more pronounced following treatment with 10 daily doses of mercaptopurine at 100 mg/kg/d (0%, 68%, and 100% 50-day survival; P = 0.0003) than with thioguanine at 5 mg/ kg/d (0%, 33%, and 50% 15-day survival; P = 0.07) in the Tpmt À/À , Tpmt +/À , and Tpmt +/+ genotypes, respectively. Myelosuppression and weight loss exhibited a haploinsufficient phenotype after mercaptopurine, whereas haploinsufficiency was less prominent with thioguanine. In the absence of drug challenge, there was no apparent phenotype. The murine model recapitulates many clinical features of the human polymorphism; indicates that mercaptopurine is more affected by the TPMT polymorphism than thioguanine; and provides a preclinical system for establishing safer regimens of genetically influenced antileukemic drug therapy. [Cancer Res 2007;67(10):4965-72]

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Section: Discussionsupporting

confidence: 81%

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

et al. 2007

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“…5 As a consequence, 6-MP has remained the preferred drug for maintenance therapy. Veno-occlusive disease, as reported in other studies, 21,22 did not occur in COALL patients. This was also true for trial ALL-REZ 90 for relapsed patients, in which 6-TG was used together with weekly intravenous MTX in maintenance therapy (G Henze, personal communication).…”

Section: Discussionsupporting

confidence: 63%

Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

et al. 2009

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In this study, the long-term outcome of 1818 patients treated in five consecutive clinical trials (the cooperative study group for childhood acute lymphoblastic leukaemia (COALL) 82, 85, 89, 92 and 97) from 24 cooperating centres in Germany is reported. The probability of event-free survival (pEFS) improved significantly from the first two trials conducted in the 1980s (COALL 82 and COALL 85) to the three trials conducted in the 1990s (COALL 89, 92 and 97) (P ¼ 0.001). Through all COALL studies, age X10 years and initial white blood cell count (WBC) X50 Â 10 9 /l and pro-B immunophenotype were of significant prognostic relevance. A refinement of risk assessment has been achieved by in vitro drug sensitivity testing in COALL 92 and 97. In patients with very sensitive leukaemic cells, therapy could be reduced without loss of efficacy. In COALL 97, a further improvement in risk stratification was gained by the molecular assessment of minimal residual disease (MRD) under treatment, which proved to have a superior prognostic effect when compared with in vitro drug sensitivity testing. Importantly, the gradual reduction in central nervous system (CNS) irradiation led to a decreased incidence of brain tumours as a second malignancy. In general, the prevention of treatmentrelated late effects will be one of the major issues in future studies. It remains to be shown whether prolonged infusions of anthracyclines, which have been implemented into the COALL studies after equal efficacy compared with short-time infusions was confirmed, will be associated with fewer cardiac late effects. Another way to prevent late effects may be a more refined risk assessment allowing for a reduction in cumulative treatment burden. A great challenge in the future will be to improve the overall treatment results, which very likely can only be achieved by the identification of molecularly defined subgroups to which novel, rational therapeutic strategies can be applied.

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“…41 In our study and in that of the UK MRC, VOD or DT correlated with longer duration of exposure and higher cumulative dose of TG. 27,42 Data from the latter study, and from the CCG-1942 intravenous TG pilot study, showed no temporal correlation between high plasma levels of TGNs or TG and episodes of VOD. 27,31,32,43 Considering the extensive first-pass intestinal and hepatic metabolism that follows oral dosing of TG, VOD likely reflects damage of sinusoidal endothelium caused directly by parent compound or a hepatic metabolite(s) not formed from MP.…”

Section: Discussionmentioning

confidence: 99%

“…Both VOD and DT occurred in patients receiving TG on the UK MRC protocols, despite the lower starting dose of 40 mg/m 2 . 26,27 No VOD was reported on the German Cooperative Study Group COALL study, with TG doses of 40 to 50 mg/m 2 . However, patients on TG had a 7.5-fold higher incidence of thrombocytopenia without neutropenia than those on MP, 25 similar to the DT described in our study.…”

Section: Discussionmentioning

confidence: 99%

Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

Stork

Matloub

Broxson

et al. 2010

Blood

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

Cited by 62 publications

References 7 publications

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

Differential Effects of Targeted Disruption of Thiopurine Methyltransferase on Mercaptopurine and Thioguanine Pharmacodynamics

Cooperative study group for childhood acute lymphoblastic leukaemia (COALL): long-term results of trials 82,85,89,92 and 97

Oral 6-mercaptopurine versus oral 6-thioguanine and veno-occlusive disease in children with standard-risk acute lymphoblastic leukemia: report of the Children's Oncology Group CCG-1952 clinical trial

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