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.