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Use of Allopurinol to Manage Skewed 6-Mercaptopurine Metabolism in Pediatric Maintenance Acute Lymphoblastic Leukemia Treatment
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  • Mandee Lines,
  • Ryan M. Kemper,
  • Jordan Wallace,
  • Thomas Alexander,
  • Carmen Echols,
  • Lauren M. Garner,
  • Jenna Kaplan,
  • Patrick Thompson,
  • Daniel J. Crona,
  • Kynlon Phillips
Mandee Lines
University of North Carolina Medical Center
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Ryan M. Kemper
The University of North Carolina at Chapel Hill Eshelman School of Pharmacy
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Jordan Wallace
Golisano Children's Hospital of Southwest Florida
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Thomas Alexander
University of North Carolina Medical Center
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Carmen Echols
University of North Carolina Medical Center
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Lauren M. Garner
University of North Carolina Medical Center
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Jenna Kaplan
University of North Carolina Medical Center
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Patrick Thompson
University of North Carolina Medical Center
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Daniel J. Crona
University of North Carolina Medical Center
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Kynlon Phillips
University of North Carolina Medical Center

Corresponding Author:[email protected]

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Abstract

Background: 6-Mercaptopurine is a cornerstone of maintenance therapy for pediatric ALL. Response to 6MP is typically determined by the ANC. Therapeutic ANC range while receiving 6MP is between 500-1,500/µL. In addition to desired myelosuppression, 6MP is associated with multiple adverse drug effects. Increased doses of 6MP can lead to therapeutic ANC values; however, patients may experience adverse effects before obtaining therapeutic myelosuppression, often deemed “skewed metabolism.” Allopurinol may potentially correct skewed 6MP metabolism. Procedure: Pediatric patients with ALL with 6MMP and 6TGN metabolites drawn during maintenance therapy were analyzed for allopurinol use. The primary outcome evaluated the percentage of time spent in therapeutic ANC range before and after allopurinol initiation. Additionally, the difference in 6MMP:6TGN ratios before and after allopurinol initiation, incidence of hepatotoxicity, and rates of relapse, were analyzed. Results: Ninety-five patients were included for analysis. Thirty-two (34%) patients received allopurinol. There were no significant differences in baseline demographics between the patients who received allopurinol and those who did not. When comparing ANC values pre- and post- allopurinol initiation, a statistically significant increase in the percentage of time spent in therapeutic range was observed (27% vs. 43%; P=0.03). Additionally, when comparing metabolite ratios pre- and post-allopurinol initiation, a statistically significant decrease in 6MMP:6TGN metabolite ratio values was observed (86.7 vs 3.6; P < 0.0001). Conclusions: Allopurinol significantly increased the percent time in therapeutic ANC range and can be safely utilized to significantly lower the ratio of 6MMP:6TGN metabolites, alleviating the undesirable side effects of 6MMP, and optimizing the anti-leukemic effects associated with 6TGN.