Thioguanine-Related Veno-Occlusive Disease (VOD) of the Liver in Children with Acute Lymphoblastic Leukemia (ALL): Report from United Kingdom Medical Research Council (UK MRC) Trial ALL97

Reviewer: Walter Sall, MD
OncoLink
Last Modified: December 8, 2002

Presenter: Ajay J. Vora
Presenter's Affiliation: Children's Hospital, Sheffield
Type of Session: Scientific

Background

MRC ALL97 randomized non-B ALL patients aged 1-18 to thioguanine (TG) and dexamethasone or mercaptopurine (MP) and prednisolone.
Similar to CCG 1952, a small but significant number of patients receiving TG developed VOD of the liver (8% in CCG 1952).
TG related VOD is characterized by tender hepatomegaly, thrombocytopenia out of proportion to neutropenia and portal hypertension.
TG related VOD was first reported in the 1970s in combination with Ara-C and later, with busulfan.

Materials and Methods

The ALL97 study employed a treatment regimen similar to CCG 1952. It consisted of induction followed by 1st intensification, CNS treatment, 2nd intensification, 3rd intensification and then continuing maintenance.
55% of patients were standard risk as defined by NCI criteria. 35% were intermediate risk and 15% were high risk.
1631 patients accrued from January 1997 to June 2002.
All patients were changed to MP and the study was closed early because of the incidence of liver VOD.

Results

81 of 749 (11%) patients developed liver VOD. Ages ranged from 1-14 years.
86% of cases occurred during TG maintenance.
In VOD patients: median ALT was 154, median bilirubin was 30, median platelet trough was 21.
After median F/U of 36 months, LFTs normalized in 46 patients, in a median time of 3.7 weeks.

Author's Conclusions

Risk of VOD in TG treated patients on ALL97 was 11%, with a 7% rate of significant morbidity
Splenomegaly or thrombocytopenia persisted in approximately 15% of VOD patients.
Long term prognosis is uncertain given the short follow-up thus far.
No evidence has yet been found of an efficacy difference between MP and TG in these patients.

Clinical/Scientific Implications

TG related liver VOD is a problem for a significant minority of ALL patients in this study. If long term follow up should continue to show no advantage to the use of TG over MP in ALL maintenance, elimination of TG from ALL treatment regimens could be justified. If the final results of this and other studies should show an efficacy advantage of TG over MP, then further studies of TG related VOD may be justified in order to learn how to minimize the risk of this serious morbidity. The risks and benefits of TG in ALL certain deserves further investigation.

Oncolink's ASH Coverage made possible by an unrestricted Educational Grant from Ortho Biotech.