Clinical

Thioguanine too toxic for maintenance treatment of childhood leukemia

Last Updated: 2006-10-13 18:30:19 -0400 (Reuters Health)

NEW YORK (Reuters Health) - Because of its hepatotoxicity and its increased risk of fatal infection, 6-thioguanine should not replace 6-mercaptopurine as the optimal continuing therapy in children with lymphoblastic leukemia in remission, UK researchers report in the October 14th issue of The Lancet.

For maintenance treatment of childhood lymphoblastic leukemia, 6-mercaptopurine has been the standard agent, while 6-thioguanine was reserved for intensification courses, Dr. Ajay Vora, from Sheffield Children's Hospital, and colleagues note. However, laboratory research suggests that the two drugs are metabolized differently, and that lymphoblasts are more sensitive to 6-thioguanine than to 6-mercaptopurine.

Dr. Vora and colleagues compared the two agents for use as maintenance treatment in children with lymphoblastic leukemia. After induction therapy with 6-thioguanine was completed, 748 patients were randomized to ongoing treatment with 6-thioguanine (40 mg/m�), and 744 to 6-mercaptopurine (75 mg/m�) during interim maintenance and continuing therapy.

At year 5, event-free survival did not differ significantly (80% for 6-mercaptopurine and 81% for 6-thioguanine). Dr. Vora's team also saw no differences in overall survival or in risk of CNS or non-CNS relapse, even after analysis of outcomes among specific subgroups.

However, 6-thioguanine was associated with a higher mortality during leukemia remission, primarily caused by bacterial or viral infection (1.7% versus 3.9%, p = 0.01), although these rates did not differ between groups during phases requiring more intensive treatment.

Cases of hepatitis were diagnosed among 11% of patients when they were taking 6-thioguanine, as well as veno-occlusive disease, portal hypertension, and splenomegaly that persisted throughout the remainder of the trial. In contrast, hepatic toxicity occurred in < 2% of children when they were taking 6-mercaptopurine.

In a related editorial, Dr. Martin Stanulla from Hannover Medical School in Germany and the Italian National Cancer Institute Regina Elena in Rome concur with the conclusion drawn by Dr. Vora's team, that "the toxicity profile related to 6 thioguanine is a serious concern and that long-term outcome of these patients should be assessed."

Lancet 2006;368:1339-1348,1304-1306.