Introduction
Advances in multi-agent chemotherapy for treatment of acute lymphoblastic leukemia (ALL) have improved overall survival to nearly 90% 1. Purine antimetabolites play a crucial role in these excellent survival rates. 6-Mercaptopurine (6-MP) currently forms the backbone of all lymphoblastic leukemia maintenance treatment protocols and 6-MP dose intensity has proven to be one of the most important determinants of overall event free survival2,3. Although typically well tolerated, some individuals experience undesirable side effects including hypoglycemia, hepatotoxicity, and pancreatitis. A report from Children’s Hospital Los Angeles of a single institution cohort indicated 27% of patients experienced hepatotoxicity and 11% developed pancreatitis. Of these, 38% of patients with hepatotoxicity and 67.9% of those with pancreatitis had treatment modifications to include dose reduction or chemotherapy delays 4.
6-MP is metabolized in 3 distinct pathways leading to the production of thiouric acid, 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopurine nucleotides (6-MMPN). Around 70% of the drug is metabolized via xanthine oxidase (XO) through the intermediate thioxanthine (TX) to the inactive metabolite thiouric acid (6-TU) and excreted in urine 5. The second pathway is via enzymes of the purine salvage pathway such as hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and inosine-5’-monophosphate dehydrogenase (IMPDH) to form the thioguanine nucleotide (6-TGN) that is believed to mediate the main therapeutic effects of 6-MP (Figure 1). 6-TGN is a purine agonist that incorporates into DNA of leukocytes inhibiting DNA synthesis and downstream T-cell proliferation leading to the ultimate immunosuppressive effect of the chemotherapy5,6. 6-TGN is toxic to all cells and in excess poses an increased risk for severe myelosuppression 6,7. The final arm is methylation of 6-MP by thiopurine-S-methyltransferase (TPMT) to form 6-methylmercaptopurine (6-MMP), an inactive molecule that has no known biologic effect but can be further metabolized by HGPRT to form 6-methylmercaptopurine nucleotide (6-MMPN), which also inhibitsde novo purine synthesis 5,6. 6-MMPN is felt to be the source of the adverse effects of 6-MP therapy, as hypoglycemic episodes during fasting have been associated with high levels of 6-MMPN8 and hepatotoxicity has been associated with 6-MMPN levels >5 000 ρmol/8x108 erythrocytes.9,10.
Allopurinol is a xanthine oxidase inhibitor which results in increased metabolism of 6-MP toward 6-TGN but also away from 6-MMPN11-13. How allopurinol results in decreased 6-MMPN is not well understood as it is not known to inhibit the TPMT enzyme. Nevertheless, numerous prior case studies have demonstrated clinical effectiveness for ameliorating 6-MP-induced hypoglycemia, hepatotoxicity, and recurrent pancreatitis by dose reduction of 6-MP combined with allopurinol when 6-TGN levels are increased with decreased levels of 6-MMPN 14-17.
The goal of this study is to characterize the incidence of symptomatic hypoglycemia, hepatotoxicity, and pancreatitis as well as the incidence of 6-MP metabolite shunting (overproduction of 6-MMPN with underproduction of 6-TGN) within a single institution practice. We will then describe cases where allopurinol was used and its effects on symptoms and metabolite levels. We further propose an algorithm to combine allopurinol with 6-MP to allow therapeutic efficacy while minimizing toxicity.