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\begin{document}

\title{Use of Allopurinol to Manage Skewed 6-Mercaptopurine Metabolism in
Pediatric Maintenance Acute Lymphoblastic Leukemia Treatment}



\author[1]{Mandee Lines}%
\author[2]{Ryan M. Kemper}%
\author[3]{Jordan Wallace}%
\author[1]{Thomas Alexander}%
\author[1]{Carmen Echols}%
\author[1]{Lauren M. Garner}%
\author[1]{Jenna Kaplan}%
\author[1]{Patrick Thompson}%
\author[1]{Daniel J. Crona}%
\author[1]{Kynlon Phillips }%
\affil[1]{University of North Carolina Medical Center}%
\affil[2]{The University of North Carolina at Chapel Hill Eshelman School of Pharmacy}%
\affil[3]{Golisano Children's Hospital of Southwest Florida}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\emph{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/\selectlanguage{greek}µ\selectlanguage{english}L. 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.
\emph{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. \emph{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\%; \emph{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 \textless{} 0.0001).
\emph{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.%
\end{abstract}%



\sloppy


\textbf{1. INTRODUCTION}

Maintenance therapy makes up two-thirds of the total treatment time for
pediatric patients with acute lymphoblastic leukemia
(ALL).\textsuperscript{1} The cornerstone oral chemotherapeutic agents
used during maintenance therapy include daily 6-mercaptopurine (6MP) and
weekly methotrexate (MTX).\textsuperscript{2} Previous studies have
found that patients with adherence rates of \textless{} 95\% to oral
medications during maintenance therapy are two and a half times more
likely to suffer relapse when compared to patients
with\emph{\textgreater{}} 95\% adherence.\textsuperscript{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/\selectlanguage{greek}μ\selectlanguage{english}L.\textsuperscript{4} If the
ANC is lower than 500/\selectlanguage{greek}μ\selectlanguage{english}L, doses of 6MP and oral MTX may be reduced, or
held until adequate recovery. Importantly, germline mutations in either
or both the\emph{TPMT} gene and \emph{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.\textsuperscript{4} Inversely, if the ANC is
greater than 1,500/\selectlanguage{greek}μ\selectlanguage{english}L, 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.\textsuperscript{5} Despite adequate medication adherence
and up front dose adjustments based on \emph{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.\textsuperscript{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.\textsuperscript{4,7-9} For
example, Cohen and colleagues provided clinical interventions for
patients with an average 6MMP:6TGN ratio of \textgreater{}40 in
combination with symptoms of skewed 6MP
metabolism.\textsuperscript{7}There 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/m\textsuperscript{2} in combination with an empiric dose decrease of
the 6MP by 50-75\%.\textsuperscript{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 \emph{TPMT} activity via inhibition of xanthine
dehydrogenase. This leads to increased levels of an intermediate
compound,~thioxanthine, which directly inhibits \emph{TPMT} . Other
proposed mechanisms suggest that allopurinol increases
\emph{HGPRT}activity, accelerating the first step in conversion of 6MP
to 6TGN.\textsuperscript{10}

Supportive literature for the use of allopurinol in skewed 6MP
metabolism currently consists of case reports and small retrospective
cohort studies.\textsuperscript{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.

\textbf{2. METHODS}

\textbf{2.1. Study design}

This was a single center, retrospective cohort study of pediatric
oncology patients at the University of North Carolina Medical Center
(UNCMC) from April 1, 2014, through May 31, 2022. Eligibility criteria
included patients aged 0 to 18 years who received their full maintenance
treatment for B-cell or T-cell ALL at the UNCMC Pediatric Oncology
Department and had 6MMP and 6TGN levels collected during maintenance
therapy to assess for skewed metabolism. Exclusion criteria included a
diagnosis of non-B-cell or T-cell leukemia (i.e., MPAL, NK-cell ALL,
lymphoblastic lymphoma), metabolites drawn outside of maintenance
therapy, metabolites collected only to assess non-adherence with
therapy, or if any part of maintenance therapy was received at an
outside hospital.

Patients were initially identified by UNCMC Pharmacy Analytics based on
the pre-specified inclusion and exclusion criteria. Data were manually
extracted from the institutional electronic medical record (EMR) for
each patient from the beginning of maintenance therapy until the end of
chemotherapy or May 31, 2022, whichever came first. UNCMC did not have a
written institutional protocol for the initiation of allopurinol for
skewed metabolism at the time of this study. Patients were started on
allopurinol at the discretion of the primary oncologist. Common practice
for the starting dose of allopurinol at UNCMC was 50
mg/m\textsuperscript{2}, which was either rounded to the nearest tablet
size or administered as an exact dose using a compounded oral
suspension.\textsuperscript{12} This dosing was based on the
recommendations from Brackett, et al.\textsuperscript{4} Generally,
initiation of allopurinol was considered when patients displayed skewed
metabolites along with inadequate myelosuppression, hepatotoxicity
and/or other undesirable side effects associated with 6MP such as rash,
hypoglycemia, and GI upset.

\textbf{2.2. Study Outcomes}

The primary outcome of this study evaluated the percentage of time
within therapeutic ANC range (defined as 500 -- 1,500/\selectlanguage{greek}μ\selectlanguage{english}L) in the
allopurinol cohort, with a comparison of values pre-initiation of
allopurinol and post-initiation of allopurinol. ANC values were
collected for all patients from the start of maintenance until the end
of maintenance or May 31, 2022, whichever came first. Secondary
endpoints included a comparison of the percentage of time within
therapeutic ANC range between the allopurinol cohort and the standard
treatment cohort, as well as the change in 6MMP:6TGN metabolite ratios
within the allopurinol cohort compared to the standard treatment cohort.
The resolution of hepatotoxicity, GI symptoms, rash, and hypoglycemia in
the allopurinol cohort were also evaluated. All metabolite values
obtained during maintenance therapy were collected for each patient.
Patients in the allopurinol cohort with hepatotoxicity as a rationale
for either metabolite collection or allopurinol initiation had AST, ALT,
total bilirubin, and direct bilirubin values collected from the
initiation of allopurinol, and for the 12 weeks following. Resolution of
hepatotoxicity was defined as AST and ALT values less than 5x ULN and/or
total bilirubin and direct bilirubin within normal limits at 12 weeks
post allopurinol initiation. GI symptoms, rash, and hypoglycemia data
were all obtained through provider progress notes. Resolution of GI
symptoms, rash, and hypoglycemia were defined as subjective improvement
based on provider notes at 12 weeks post allopurinol initiation.
Descriptive dosing characteristics of allopurinol and 6MP post
allopurinol initiation were collected.

\textbf{2.3. Data analysis}

For all descriptive statistics (e.g., baseline clinical and demographic
characteristics, 6MMP:6TGN ratios, etc.), categorical variables were
summarized as counts and percentages. Continuous variables were
summarized as medians with first to third quartiles, or as means with
standard deviation, as appropriate.

All inferential statistical testing was two-sided with an alpha level
set to \emph{0.05 (P\textless{}0.05).} A paired t-test was used if the
data was normally distributed, and parametric testing was appropriate.
If non-parametric testing was appropriate, a Wilcoxon matched-pairs
signed rank test was used. For secondary endpoints with categorical or
binary variables (e.g., differences in incidence of symptom reduction),
a Chi-square test or Fisher's exact test was used, as appropriate. For
paired continuous variables (e.g., before and after allopurinol in the
same patient), a paired t-test was used when assumptions for parametric
testing were met (i.e., normal distribution of data), while a Wilcoxon
matched-pairs signed rank test was used when non-parametric testing was
more appropriate. Finally, for non-paired continuous data, a t-test was
used when parametric testing was appropriate, and a Mann-Whitney test
was used as the non-parametric alternative. All statistical testing was
performed in SAS JMP v16 (SAS, Cary, NC), while figures were created
using GraphPad Prism v9.5 (GraphPad, San Diego, CA) and using R v4.1.0
(R Foundation for Statistical Computing), RStudio (RStudio), and the
ggplot2 package v3.4.2.\textsuperscript{11}

\textbf{3. RESULTS}

\textbf{3.1. Patient Characteristics}

One-hundred and seventeen pediatric subjects with a diagnosis of B-cell
or T-cell ALL who had 6MMP and 6TGN metabolites drawn during maintenance
therapy were identified by the UNCMC Pharmacy Analytics team. Twenty-two
patients were deemed ineligible for final analyses, including subjects
with metabolites drawn only to assess medication non-adherence (n=12),
subjects who received a portion of their ALL maintenance therapy at an
institution outside UNCMC (n=5), subjects who had metabolites drawn
outside of maintenance therapy (n=3), a subject with allopurinol
initiated outside of the study time frame (n=1), and a subject who was
\textgreater{}18 years-old at the time of allopurinol initiation (n=1).
Ultimately, a total of 95 patients met study inclusion criteria with 32
patients receiving allopurinol for management of skewed 6MP metabolism
during their maintenance therapy (34\%) (Figure 1).

There were no significant differences in baseline demographics between
the allopurinol cohort and the standard treatment cohort (Table 1). The
average age at the start of maintenance in the allopurinol cohort was 7
years and 5 years in the standard treatment cohort. Fifty-six percent
were female in the allopurinol cohort and 44\% were female in the
standard treatment cohort, while most patients in both cohorts
self-identified as White.

Among the 32 patients in the allopurinol cohort, the median time point
for allopurinol initiation was on day 218, corresponding to maintenance
cycle 3, day 48. The average dose of 6MP prior to allopurinol initiation
was 83 (\emph{+} 16) mg/m\textsuperscript{2}/day, which was decreased to
an average dose of 37 (\emph{+} 10) mg/m\textsuperscript{2}/day after
allopurinol initiation. The average dose of allopurinol was 63 (\emph{+}
19) mg/m\textsuperscript{2}/day. The rationale for initiating
allopurinol was inadequate myelosuppression (50\%), followed by
hepatotoxicity (43\%), GI upset (22\%), rash (13\%), or other clinical
reasons (16\%). Rational for allopurinol initiation was not mutually
exclusive, and patients often had more than one reason for therapeutic
intervention.

\textbf{3.2. Absolute Neutrophil Count Analysis}

When assessing the percentage time spent in therapeutic ANC range for
the allopurinol cohort before and after initiation of allopurinol, there
was a significant increase in the median percentage of time spent within
the therapeutic ANC range after allopurinol was initiated (median (IQR);
27\% (15-58) vs. 43\% (26-55); \emph{P=} 0.03). Patients in the
allopurinol cohort prior to allopurinol initiation had a similar
percentage of time spent in therapeutic ANC range when compared to
patients in the standard treatment cohort (median (IQR); 27\% (15-58)
vs. 29\% (20-53); \emph{P=} 0.68). Median time spent in therapeutic ANC
range was greater within the allopurinol cohort after allopurinol
initiation when compared to patient in the standard treatment cohort.
(median (IQR); 43\% (26-55) vs. 29\% (23-53); \emph{P=} 0.08) (Table 4
and Figure 2).

\textbf{3.3. Metabolite Ratio Analysis}

The most common rationale for obtaining 6MP metabolites in both cohorts
was inadequate myelosuppression (47\% vs. 70\%; OR=0.54 (95\% CI,
0.31-0.94); \emph{P} =0.04). In many cases, patients had multiple
reasons for metabolite collection in addition to inadequate
myelosuppression including hepatotoxicity, rash, and GI upset.

There were significant decreases in the median metabolite ratios
(6MMP:6TGN) when assessing the pre-initiation of allopurinol ratios to
the post-initiation of allopurinol ratios in the allopurinol cohort
(median (IQR); 86.7 (54.8-127.7) vs. 3.6 (1.7-11.4);\emph{P\textless{}}
0.0001). (Table 2 and Figure 3).

\textbf{3.4. 6MP-Related Toxicity Analysis}

Patients in the allopurinol cohort who were initiated on allopurinol for
hepatotoxicity, with or without inadequate myelosuppression, had
significantly decreased AST, ALT, total bilirubin, and direct bilirubin
values 12 weeks after initiating allopurinol (\emph{P=} 0.002,\emph{P=}
0.0006, \emph{P=} 0.005, and \emph{P=} 0.006, respectively) (Table 5
(Figure 3) For patients started on allopurinol, 100\% (n=4) of patients
with rash, 85\% (n=6) of patients with GI upset, and 80\% (n=4) of
patients with other clinical reasons obtained had complete resolution of
their specific symptoms by 12 weeks post-allopurinol initiation.

\textbf{3.5. Observed Relapse}

One case of relapse was observed in the allopurinol cohort and 3 cases
of relapse were observed in the non-allopurinol cohort.

\textbf{4. DISCUSSION}

To date, this study represents the largest population of pediatric
oncology patients with B-cell or T-cell ALL initiated on allopurinol for
skewed metabolism of 6MP. Results from this study showed allopurinol
treatment was associated with a significantly increased percentage of
time spent in therapeutic ANC range. These results are comparable to a
small study of 13 pediatric patients with ALL who were started on
allopurinol for presumed skewed 6MP metabolism. Cohen et at. found
allopurinol treatment was associated with an increase in the percentage
of time spent in therapeutic ANC range (10\% pre-allopurinol vs. 36.4\%
post-allopurinol; \emph{P=} 0.0004)\textsuperscript{7}, which was
similar to the 43\% time in therapeutic ANC range our subjects achieved
after allopurinol treatment.

Additionally, the resolution of hepatotoxicity in this study
demonstrates similar results to the Vasta et al. study. The median AST
and ALT values in this study tended to quickly decrease after the
initiation of allopurinol and rise slightly after continued concomitant
treatment with allopurinol and 6MP. Total bilirubin and direct bilirubin
quickly decreased after the initiation of allopurinol with a trend of
staying within normal limits throughout continued use of allopurinol and
6MP. Vasta and colleagues determined that 37 of the 42 (88\%) patients
included for analysis had at least one episode of elevated ALT values
\textgreater{} 3x the ULN. Of these 37 patients, 12 of them were
initiated on allopurinol. Eleven of the 12 patients experienced
resolution of their transaminitis following the initiation of
allopurinol.\textsuperscript{9}

One major difference between the Cohen et al. study, Vasta et al. study,
and this study is the use of an institutional protocol for allopurinol
initiation. UNCMC does not currently have an institutional protocol for
the initiation of allopurinol in patients with skewed 6MP metabolism.
Currently, the recommendations from Brackett, et al. suggest starting
allopurinol 50 mg/m\textsuperscript{2} in combination with decreasing
the 6MP dose by 50-75\% for patients with evidence of skewed metabolism,
and provider judgment based on clinical symptoms, are utilized in
determining which patients are eligible for allopurinol use for skewed
6MP metabolism.\textsuperscript{4} Conversely, Cohen and colleagues had
a defined criteria for starting doses through institutional guidelines.
They required a 6MMP:6TGN ratio of \textgreater{}40 to begin allopurinol
and used standardized doses based on
weight.\textsuperscript{7}Similarly, Vasta and colleagues outlined that
if the 6-MMPN metabolite \textgreater{}10,000 pmol/8 x
10\textsuperscript{8} RBC, the patient should be initiated on
allopurinol at a standard daily dose based on age.\textsuperscript{9}

Another area of uncertainty is the lack of a standard definition for
skewed metabolism based on 6MP metabolite ratios. One study, performed
at Texas Children's Hospital, defined skewed 6MP metabolism as a
metabolite ratio of \textgreater{}20, whereas the Cohen study defined
skewed metabolism as a 6MMP:6TGN ratio of \textgreater{}40. The Vasta
study defined it based on the 6-MMPN level alone, rather than using a
6MMP:6TGN ratio.\textsuperscript{7-9}

Our data revealed that subjects who were initiated on allopurinol had a
median ratio of 6MMP:6TGN of 86.7. Interestingly, the median metabolite
ratio for the standard treatment cohort was 41.1, which was very similar
to the definition of a 6MMP:6TGN ratio \textgreater{}40 used in the
Cohen study.\textsuperscript{7} One consideration, and limitation to
this study, is understanding that the standard treatment cohort is not a
true ``baseline'' group with which to compare metabolite ratios.
Subjects with metabolites drawn during maintenance therapy who did not
receive allopurinol still had symptoms of possible skewed metabolism
documented in the EMR (i.e., inadequate myelosuppression,
hepatotoxicity, rash, and GI upset), which was often the reason why the
metabolite levels were obtained. Therefore, the standard treatment
cohort cannot be considered a true baseline group for comparison.
However, because the median ratio in the standard treatment cohort was
significantly elevated when compared to the ratio of the
post-allopurinol initiation allopurinol cohort (41.4 vs. 3.6), our data
suggests alignment with the Cohen study where skewed metabolism may be
defined as 6MMP:6TGN ratio of \textgreater{}40. Based on the data
presented in this study it is appropriate to assume that allopurinol can
be used for skewed 6MP metabolism in patients with ratios
\textgreater{}86, but it is possible that starting patients on
allopurinol at a metabolite ratio of \textgreater{}40 may help prevent
escalation of 6MP-induced toxicities and could potentially increase the
percent time that the patient is in goal ANC range.

Another limitation of this study includes the lack of a full
understanding of the mechanism of how allopurinol helps correct skewed
6MP metabolism. Literature has described two proposed mechanisms,
through inhibition of \emph{TPMT} and through acceleration
at\emph{HGPRT} . Even though these mechanisms have been previously
described in the literature, it is still unknown if allopurinol is
having additional affects on metabolites of 6MP that are not well known.
Without a full understanding of the mechanism, as well as survival data
for patients who are started on allopurinol for skewed metabolism,
larger studies with longer follow-up are needed to assess relapse and
mortality risks associated with allopurinol use for skewed 6MP
metabolism. Despite the limitation of small numbers and short follow-up,
we did not observe an increased risk of relapse, which contributes
another small step to the safety of this approach. Evaluation of these
potential risks should be compared to the possible benefits of
allopurinol for skewed 6MP metabolism on an individual patient basis.

An additional limitation is the retrospective nature of this study.
Information on rash, hypoglycemia, and GI upset was subjective and
collected through chart review of the provider documentation in the
institutional EMR. As previously mentioned, another study limitation was
the lack of an institutional protocol for initiating allopurinol.
Subjects were initiated on allopurinol therapy based on provider
discretion, without defined criteria needing to be met prior to starting
therapy, therefore introducing potential selection bias. However, this
is reflective of a real world setting and the subjective nature of
clinical symptoms and provider / patient decision making about many of
the cases of skewed 6MP metabolism.

In conclusion, this study determined that the use of allopurinol for
skewed 6MP metabolism significantly increased the percentage of time
spent within therapeutic ANC range. It also found that allopurinol had a
significant effect on the decreasing metabolite ratios and
hepatotoxicity associated with 6MP. Larger prospective studies are
needed to fully assess the long-term effects of allopurinol on relapse
rates and overall survival. Overall, allopurinol appears to be an
effective method for the management of skewed 6MP metabolism. Correction
of skewed 6MP metabolism increases the percentage time spent within
therapeutic range and decreases adverse drug side effects associated
with 6MP, allowing patients to continue their oral chemotherapy.

\textbf{5. CONFLICT OF INTEREST}

The authors do not have any conflicts of interest to disclose.

\textbf{6. ACKNOWLEDGEMENTS}

The authors have no further acknowledgements to address.

\textbf{7. FUNDING}

The authors have no funding sources to disclose. No funding was provided
for this study.

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\item
  Allen LV Jr, Erickson MA 3rd. Stability of acetazolamide, allopurinol,
  azathioprine, clonazepam, and flucytosine in extemporaneously
  compounded oral liquids.~\emph{Am J Health Syst Pharm} .
  1996;53(16):1944-1949. doi:10.1093/ajhp/53.16.1944
\end{enumerate}

\textbf{9. TABLES AND FIGURES}

\textbf{TABLE 1} \textbf{Baseline Characteristics.} Baseline clinical
and demographic data are included from the time metabolite testing was
requested. Differences between the two study arms (\emph{P}
\textless{}0.05) were not observed.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Characteristic}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Allopurinol} \textbf{(n=32)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{No Allopurinol} \textbf{(n=63)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P-Value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at start of maintenance (years), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (1--17)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (2--17)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.3\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Weight (kg), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
26.9 (10.2--128)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
20.9 (11--88.7)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
BSA (m\textsuperscript{2}), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.99 (0.48--2.55)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.81 (0.51--1.98)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sex, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.29\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (56)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
28 (44)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14 (44)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
35 (56)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Race, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Race, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Race, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
White\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (56)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
38 (60)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.52\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Black\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (22)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 (13)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (22)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
15 (24)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Asian\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ethnicity, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ethnicity, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Ethnicity, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.62\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Non-Hispanic/Latino\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
25 (78)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
45 (71)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Hispanic/Latino\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (22)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
18 (29)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Trisomy 21 (DS), number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (6)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.58\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.13\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
*\emph{1/*1}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20 (63)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
43 (68)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{*1/*3A} or \emph{*1/*3C}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Not genotyped\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (31)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
10 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} genotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{*1/*1}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
28 (44)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\emph{*1/*4}\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Not genotyped\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
34 (54)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{TPMT} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.12\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Low\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Intermediate\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (3)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
12 (19)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
High (normal)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
28 (88)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
49 (77)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Not collected\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\emph{NUDT15} phenotype, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.7\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Normal\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
29 (46)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Intermediate\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Not collected\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
33 (52)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diagnosis, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diagnosis, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Diagnosis, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.73\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
T-Cell ALL\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
28 (88)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
57 (90)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
B-Cell ALL\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (12)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (10)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Risk status, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Risk status, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Risk status, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.65\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Standard\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
16 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
31 (49)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Intermediate\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (9)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
High\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
13 (41)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
29 (46)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6MP dosage form, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6MP dosage form, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6MP dosage form, number (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.82\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Tablet\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
21 (66)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
43 (68)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Oral Solution\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (34)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
20 (32)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Starting daily dose of 6MP (mg/m\textsuperscript{2}/day), median
(range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
75 (71--77)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
75 (38--78)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.58\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: 6MP, 6-mercaptopurine; ALL, acute lymphoblastic leukemia;
BSA, body surface area; DS, Down syndrome; \emph{NUDT15}, nudix
hydrolase 15 gene; \emph{TPMT}, thiopurine methyltransferase gene.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: 6MP, 6-mercaptopurine; ALL, acute lymphoblastic leukemia;
BSA, body surface area; DS, Down syndrome; \emph{NUDT15}, nudix
hydrolase 15 gene; \emph{TPMT}, thiopurine methyltransferase gene.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: 6MP, 6-mercaptopurine; ALL, acute lymphoblastic leukemia;
BSA, body surface area; DS, Down syndrome; \emph{NUDT15}, nudix
hydrolase 15 gene; \emph{TPMT}, thiopurine methyltransferase gene.\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: 6MP, 6-mercaptopurine; ALL, acute lymphoblastic leukemia;
BSA, body surface area; DS, Down syndrome; \emph{NUDT15}, nudix
hydrolase 15 gene; \emph{TPMT}, thiopurine methyltransferase gene.\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 2 Percent time in therapeutic ANC range and skewed
metabolite resolution.} Median percent time in ANC goal range are
compared between pre- and post-allopurinol initiation, pre-allopurinol
and no allopurinol initiation, and post-allopurinol and no allopurinol
initiation. Additionally, median 6MMP:6TGN ratios are compared between
pre- and post-allopurinol initiation, pre-allopurinol and no allopurinol
initiation, and post-allopurinol and no allopurinol initiation.\emph{P}
\textless{}0.05 were considered significant and bolded below.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Pre-Allopurinol~(n=32)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{Post- Allopurinol~(n=32)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{No Allopurinol~} \textbf{(n=63)}\strut
\end{minipage} & \begin{minipage}[b]{0.19\columnwidth}\raggedright\strut
\textbf{P-Value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\% Time in Range,~median (IQR)~~~\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (15--58)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
43 (26--55)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.03}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\% Time in Range,~median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
27 (15--58)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (20--53)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.68\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\% Time in Range,~median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
43 (26--55)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
29 (20--53)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0.08\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6MMP:6TGN Ratio,~median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
86.7 (54.8--127.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3.6 (1.7--11.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
~--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.0001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6MMP:6TGN Ratio,~median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
86.7 (54.8--127.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
~--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41.4 (10.9--83.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{0.0002}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6MMP:6TGN Ratio,~median (IQR)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
~--\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3.6 (1.7--11.4)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
41.4 (10.9--83.5)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{\textless{}0.0001}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abbreviations: 6MMP, 6-methylmercaptopurine; 6TGN, 6-thioguanine
nucleotide; ANC, absolute neutrophil count; IQR, interquartile range.
Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abbreviations: 6MMP, 6-methylmercaptopurine; 6TGN, 6-thioguanine
nucleotide; ANC, absolute neutrophil count; IQR, interquartile range.
Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abbreviations: 6MMP, 6-methylmercaptopurine; 6TGN, 6-thioguanine
nucleotide; ANC, absolute neutrophil count; IQR, interquartile range.
Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abbreviations: 6MMP, 6-methylmercaptopurine; 6TGN, 6-thioguanine
nucleotide; ANC, absolute neutrophil count; IQR, interquartile range.
Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Abbreviations: 6MMP, 6-methylmercaptopurine; 6TGN, 6-thioguanine
nucleotide; ANC, absolute neutrophil count; IQR, interquartile range.
Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 3 Resolution of 6MP associated toxicities.} AST, ALT,
Total bilirubin, and Direct bilirubin were collected on the 14 patients
initiated on allopurinol for hepatotoxicity. Values were collected
beginning at the start of allopurinol initiation and analyzed for change
over a 12-week period. \emph{P} \textless{}0.05 were considered
significant and bolded below.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Markers of Hepatotoxicity}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Pre-allopurinol} \textbf{(n=14)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{Post-allopurinol} \textbf{(n=14)}\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
\textbf{P-Value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
AST (U/L), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
197.8 (62.0--1032.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
122 (22.8--261.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.002}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
ALT (U/L), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
136.7 (30.7--573.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
51.7 (24.0--119.0)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textbf{0.0006}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Total bilirubin (mg/dL), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.70 (0.18--9.08)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.94 (0.13--1.77)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.005}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Direct bilirubin (mg/dL), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.60 (0.10--7.88)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.20 (0.10--0.52)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
\textbf{0.006}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ALT, alanine aminotransferase, AST; aspartate
aminotransferase Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ALT, alanine aminotransferase, AST; aspartate
aminotransferase Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ALT, alanine aminotransferase, AST; aspartate
aminotransferase Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Abbreviations: ALT, alanine aminotransferase, AST; aspartate
aminotransferase Bold text = statistical significance with a P-value
\textless{}0.05\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{FIGURE 1 Study schematic.} Initial patient data was extracted by
the UNC Pharmacy Analytics team. A detailed breakdown of subjects who
met the inclusion and exclusion criteria for the study is detailed.
Abbreviations: 6MMP, 6-methylmercaptopurine, 6MP, 6-mercaptopurine,
6TGN, 6-thioguanine nucleotide, OSH, Outside hospital.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{FIGURE 2 Resolution of inadequate myelosuppression and skewed
metabolism after allopurinol initiation.} Panel \textbf{A} shows the
average ANC over the course of maintenance therapy. Panel \textbf{B}
shows the median percent time in range for patients before and after
allopurinol treatment, as well as the median percent time in range for
patients who did not receive allopurinol. Panel \textbf{C} shows the
average 6MMP/6TGN metabolite ratio over the course of maintenance
therapy. Panel\textbf{D} shows the median 6MMP/6TGN metabolite ratio for
patients before and after allopurinol treatment, as well as the median
metabolite ratio for patients who did not receive allopurinol. The green
vertical line in panels \textbf{A} and \textbf{C} indicates the average
start date of allopurinol during maintenance therapy for all patients
who received it (mean = 229 days). The red and blue lines in indicate
mean values for patients who were not treated with allopurinol and those
who were treated with allopurinol, respectively, and are 95\% confidence
intervals. The data in panels \textbf{B} and \textbf{D} represent the
medians of selected data with interquartile ranges. Abbreviations: 6MMP,
6-methylmercaptopurine, 6TGN, 6-thioguanine nucleotide, ANC, absolute
neutrophil count. Figure created with BioRender.com.

\textbf{FIGURE 3 Resolution of hepatotoxicity markers after allopurinol
initiation.} ALT (\textbf{A} ), AST (\textbf{B} ), Total Bilirubin
(\textbf{C} ) and Direct Bilirubin (\textbf{D} ), kinetics are described
graphically to demonstrate the effectiveness of allopurinol treatment
for 6MP-induced hepatotoxicity. The green vertical line in each panel
indicates the average start date of allopurinol after hepatotoxicity was
documented. The harder dashed line indicates five times the upper limit
of normal for each lab value, while the softer dashed lines indicate the
normal range for each lab value. The blue lines show the average lab
value for patients treated with allopurinol during the first twelve
weeks after documented hepatotoxicity, and the shaded areas as 95\%
confidence intervals. Figure created with BioRender.com.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

