Utilization of Thiopurine Metabolites and Allopurinol in Pediatric Acute Lymphoblastic Leukemia: Consideration for an Algorithmic Approach

Abstract

Persistently elevated absolute neutrophil counts during maintenance for acute lymphoblastic leukemia is a risk factor for relapse and may be related to wild-type thiopurine methyltransferase activity and overly efficient shunting of 6-mercaptopurine to hepatotoxic metabolites (6-methylmercaptopurine nucleotides), leading to low 6-thioguanine nucleotides. 6-mercaptopurine is also metabolized by xanthine oxidase, and therefore allopurinol, an inhibitor of xanthine oxidase, allows for increased 6-thioguanine nucleotides and decreased 6-methylmercaptopurine nucleotide. Here, we report our experience with allopurinol for persistently elevated absolute neutrophil count or hepatotoxicity and suggest an algorithmic approach for checking thiopurine metabolites and initiating allopurinol in acute lymphoblastic leukemia maintenance.

Key factors associated with 6‐thioguanine and 6‐methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease

“…A 6MMP:6TGN ratio of >20, identified shunters, which may benefit from coadministration of allopurinol in children and thiopurine dose reduction to 25-33%. [36][37][38] T A B L E 3 6-methylmercaptopurine nucleotide concentrations* according to patients' characteristics and treatment. Hepatic and haematological biological adverse effects were more frequent in ALL than in IBD.…”

“…Low 6TGN concentrations were more frequently reported in IBD and high 6MMPN in ALL. A 6MMP:6TGN ratio of >20, identified shunters , which may benefit from coadministration of allopurinol in children and thiopurine dose reduction to 25–33% 36–38 …”

Effects of allopurinol on 6-mercaptopurine metabolism in unselected patients with pediatric acute lymphoblastic leukemia: a prospective phase II study

“…18 Allopurinol has been used in selected ALL patients suffering from 6MP induced hepatic toxicity during MT, with the same effects on 6MP metabolite balance and decreased hepatic toxicity, so far published only in case reports or small retrospective studies. 19 We wanted to investigate if allopurinol has the same impact on the 6MP metabolism in patients without previous signs of skewed metabolism. The rationale is that it seems reasonable to increase the e-TGN levels also in these patients, since the antileukemic effects of 6MP are believed to be mediated mainly by TGN, and allopurinol could potentially lead to higher e-TGN without increasing the side effects and myelotoxicity that an increased 6MP dose would lead to.…”