1. INTRODUCTION
Maintenance therapy makes up two-thirds of the total treatment time for pediatric patients with acute lymphoblastic leukemia (ALL).1 The cornerstone oral chemotherapeutic agents used during maintenance therapy include daily 6-mercaptopurine (6MP) and weekly methotrexate (MTX).2 Previous studies have found that patients with adherence rates of < 95% to oral medications during maintenance therapy are two and a half times more likely to suffer relapse when compared to patients with> 95% adherence.3 Response to oral 6MP is often guided by close monitoring of the absolute neutrophil count (ANC). The therapeutic range for a patient’s ANC during maintenance therapy is between 500-1,500/μL.4 If the ANC is lower than 500/μL, doses of 6MP and oral MTX may be reduced, or held until adequate recovery. Importantly, germline mutations in either or both theTPMT gene and NUDT15 gene may affect a patient’s response to 6MP, as they are the main enzymes that metabolize 6MP. Mutations resulting in intermediate or poor metabolism of 6MP may result in prolonged myelosuppression if 6MP doses are not appropriately adjusted prior to starting.4 Inversely, if the ANC is greater than 1,500/μL, doses of 6MP or oral MTX may be increased until the ANC falls within the desired therapeutic range.
In addition to the desired myelosuppression, 6MP is associated with other adverse drug effects including hepatotoxicity, nausea, rash, and hypoglycemia.5 Despite adequate medication adherence and up front dose adjustments based on TPMT/NUDT15 -related metabolism, there may be patients whose ANC does not respond as expected, or those who experience severe adverse effects at recommended starting doses.6 In these patients, quantification of the 6MP metabolites, 6-methylated mercaptopurine (6MMP) and 6-thioguanine nucleotide (6TGN), is conducted by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess for skewed 6MP metabolism. Historically, the inactive 6MMP metabolite, as well as the active form of the metabolite, 6-methylated mercaptopurine nucleotide (6MMPN) have been associated with risk for hepatotoxicity and other adverse effects while the 6TGN metabolite has been associated with anti-leukemic effects and myelosuppression. While normal ranges of 6MMP are typically higher than 6TGN normal ranges, some available literature suggests that highly elevated ratios of 6MMP:6TGN correlate with clinical symptoms of skewed metabolism.4,7-9 For example, Cohen and colleagues provided clinical interventions for patients with an average 6MMP:6TGN ratio of >40 in combination with symptoms of skewed 6MP metabolism.7There is, however, a paucity of data providing a true definition on what 6MMP:6TGN ratio should be considered “skewed.”
Current frontline protocols for pediatric ALL provide guidance on the potential management of skewed 6MP metabolism. These protocols suggest the addition of daily allopurinol at a dose of 50 mg/m2 in combination with an empiric dose decrease of the 6MP by 50-75%.4 Allopurinol, a xanthine oxidase inhibitor, is typically used in the pediatric oncology population for the prevention of uric acid accumulation in tumor lysis syndrome. Though the mechanism is not entirely understood, it has been suggested that allopurinol may alter the metabolism of purine analogs, leading to decreased levels of 6MMP and increased levels of 6TGN. One proposed mechanism for the altered metabolism of 6MP is that allopurinol indirectly inhibits TPMT activity via inhibition of xanthine dehydrogenase. This leads to increased levels of an intermediate compound, thioxanthine, which directly inhibits TPMT . Other proposed mechanisms suggest that allopurinol increases HGPRTactivity, accelerating the first step in conversion of 6MP to 6TGN.10
Supportive literature for the use of allopurinol in skewed 6MP metabolism currently consists of case reports and small retrospective cohort studies.4,7-9 Therefore, the purpose of this study is to contribute to the collection of available literature in supporting the safety and efficacy of allopurinol for skewed 6MP metabolism, as well as aiding in defining skewed metabolism based on the 6MMP and 6TGN metabolite ratio.