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; P= 0.0004)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
> 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.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/m2 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.4 Conversely, Cohen and colleagues had
a defined criteria for starting doses through institutional guidelines.
They required a 6MMP:6TGN ratio of >40 to begin allopurinol
and used standardized doses based on weight.7Similarly, Vasta and colleagues outlined that if the 6-MMPN metabolite
>10,000 pmol/8 x 108 RBC, the patient
should be initiated on allopurinol at a standard daily dose based on
age.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 >20, whereas the Cohen study defined
skewed metabolism as a 6MMP:6TGN ratio of >40. The Vasta
study defined it based on the 6-MMPN level alone, rather than using a
6MMP:6TGN ratio.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 >40 used in the
Cohen study.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 >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
>86, but it is possible that starting patients on
allopurinol at a metabolite ratio of >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 TPMT and through acceleration atHGPRT . 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.