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.