A Retrospective Review of Mercaptopurine Metabolism Reveals High Rate of Patients with Suboptimal Metabolites Successfully Corrected with Allopurinol
Authors: Vasta Lauren Marie , Zanetti Richard C , Parekh Dina S. , Warwick Anne B. , Lieuw Kenneth 
Published: November 2019

Introduction: 6-Mercaptopurine (6-MP) is the most frequently used chemotherapy agent in the management of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL). Skewed drug metabolism can decrease the effectiveness of 6-MP while also resulting in unnecessary toxicities. Each individual's ability to metabolize 6-MP into the desired therapeutic product, 6-thioguanine nucleotide (6-TGN), is directly opposed by the development of the hepatotoxic byproduct, 6-methyl-mercaptopurine (6-MMPN). Certain individuals, referred to as 'shunters,' preferentially generate high levels of 6-MMPN resulting in decreased production of 6-TGN. Current guidelines suggest holding or lowering 6-MP doses in the setting of toxicity. However this approach results in decreased intensity of 6-MP treatment, potentially risking an increase in disease relapse. Allopurinol, a drug used to manage hyperuricemia, can alter 6-MP metabolism to maximize 6-TGN production while reducing the hepatotoxic metabolite, 6-MMPN.
Methods: We performed a single institution, IRB approved, retrospective cohort study to quantify and characterize the rate of shunters treated in our center. Chart review was conducted of ALL and LL patients treated for at least one year of maintenance therapy at our center over a 10 year period from January 1, 2009 to June 1, 2019. Incidents of hypoglycemia (glucose <74), hepatic inflammation (ALT >123), and hypogammaglobulinemia (IgG <400) were recorded. If available, metabolite levels were collected, noting levels of 6-MMPN from 6,000 -10,000 and greater than 10,000 pmol/8 x 108 RBC. If the patient was started on allopurinol, we noted the effects of the intervention on the aforementioned lab values and their clinical course. Stata was utilized for all statistical analysis.
Results: We performed a chart review on 42 eligible patients and included demographic information (Table 1). Using lab data, we documented potential markers of toxicity (Table 2). Seventy four percent of patients had a least one episode of documented hypoglycemia, and 88% had at least one episode of elevated ALT > 3 times the upper limit of normal. Metabolites were checked in 66% (28/42) of our patients. 6-MMPN levels were > 10,000 in 82.1% (23/28). Shunting was observed in 54% of the patients; meaning one half of the patients were eligible for allopurinol combination therapy. Allopurinol was initiated by the primary team for metabolite and laboratory derangements in 12 of 23 patients. All patients who received allopurinol had normalization of laboratory values with combined treatment.
Discussion: In our population of pediatric and young adults treated for leukemia and lymphoblastic lymphoma, over half of the patients were shunters with metabolite derangements and associated signs of toxicity. Current guidelines in the Children's Oncology Group (COG) leukemia protocols recommend checking metabolites in the context of increased sensitivity to 6-MP, as in the case of TPMT and NUDT15 deficient patients, but do not specifically address the more common problem of skewed metabolism. Previous gastroenterology publications suggest there may be as many as 15% of shunters in their population of patients being prescribed 6MP. We found a much higher incidence of shunters among our leukemia population, many of whom had concurrent toxicities. The patients who received allopurinol during their treatment period showed adequate count suppression with reversal of undesired toxicities, suggesting that combination therapy may be beneficial for many more patients in the future. All of these patients remain in remission through 1 Jun 2019, the longest being 6 years post-treatment. Based on our institutional experience, we propose an algorithm for the use of allopurinol in conjunction with chemotherapy for patients with ALL or LL who have inappropriate 6-MP metabolism (Figure 1) to optimize their treatment while decreasing 6-MP associated toxicities.

Disclosures
No relevant conflicts of interest to declare.

OffLabel Disclosure:
Allopurinol inhibits the enzyme, xanthine oxidase, and is commonly used for prevention of tumor lysis syndrome and gout. However, it is understood that allopurinol also affects the metabolism of 6-Mercaptopurine. Allopurinol directs 6MP metabolism towards 6-TGN, the desired product, and away from 6-MMPN. 6-MMPN is associated with increased toxicity in patients. We describe in our abstract the incorporation of allopurinol therapy in many of our patients with abnormal 6-MP metabolism