Discussion
In our small cohort, we found a much higher incidence of individuals
with documented 6-MMPN levels above 10 000 pmol/8 x
108 RBC than expected based on previous reports18,19; over 50% of our patients had shunting of 6-MP
with associated toxicities. By contrast, previously documented rates of
symptomatic 6-MMPN derangements in individuals were 20-30% in
gastroenterology literature 19,20. It should be noted
that the 6-MP dosing used in inflammatory bowel disease treatment is
lower than that used in oncology. This higher dosing may explain the
increased incidence of shunting in our oncology population. Our
experience suggests that 6-MP metabolite levels should be monitored
during maintenance therapy, particularly in the setting of known 6-MP
toxicities, to prevent chemotherapy holds and dose reductions. In
addition, because it is standard protocol to escalate 6-MP dosing when a
patient’s absolute neutrophil count (ANC) is not adequately suppressed,
we have noted that increases in 6-MP doses further exacerbate shunting
and its adverse effects.
Allopurinol has a well-documented safety profile in its use for gout21. A similar safety profile was documented in our
cohort. There were no direct adverse events after initiation of
allopurinol in our patients despite the risk for increased
myelosuppression if dosing is not carefully determined. Previously,
because 6-MP was only available in 50 mg tablets, it was difficult to
make fine dose adjustments in order to better establish the therapeutic
dose. Combined therapy with allopurinol amplifies the clinical effect of
6-MP dose changes and it can cause undesired myelosuppression if dosing
is not carefully titrated. We, therefore, provide an algorithm for
combination therapy with a simple protocol for determining correct
dosing for patients that has worked well for our center (Figure 3). In
addition, the FDA approval of a liquid formulation of mercaptopurine
makes it easier to manage combination therapy. In those patients in our
series who were treated with allopurinol there was no apparent decrement
in event free or survival outcomes.
Our series demonstrates efficacy for the use of allopurinol in the
management of mercaptopurine side effects. Adverse effects related to
mercaptopurine therapy including hepatotoxicity, hypoglycemia, and acute
pancreatitis were reversed in all patients. While the chronic
pancreatitis with insulin-dependent diabetes experienced by one patient
was unchanged by the addition of allopurinol to the treatment regimen,
this likely reflects the damage from the initial insult to the pancreas
and not a lack of improvement with allopurinol. Patients started on
combination therapy with allopurinol experienced reversal of undesired
toxicities, suggesting that combination therapy may be beneficial for
many more patients in the future.
Interestingly, a much higher percentage of males than females
experienced shunting in our cohort. One possible explanation for this
difference is the higher levels of TPMT activity often found in
males22 that could theoretically result in higher
levels of 6-MMPN levels if this higher activity were not balanced by the
other enzymatic pathways. TPMT activity has also been shown to have
racial differences, with Caucasians having higher TPMT levels, which
would suggest a higher rate of shunting among Caucasian
patients23. Perhaps due to our small cohort size we
did not find significant differences between ethnicities, although it is
interesting to note that 4 of the 5 African American patients in our
cohort were ‘shunters. Of course, larger studies may be able to examine
this finding in more detail and are warranted.
It has become our institution’s practice to monitor for signs of
aberrant mercaptopurine metabolism, including hepatotoxicity,
neutropenia (or neutrophilia), hypoglycemia, and pancreatitis. In these
settings we begin monitoring 6-MMPN and 6-TGN levels. For those with
markedly elevated 6-MMPN >10 000 pmol/8 x
108 RBC, we consider the addition of allopurinol.
Considerations for the addition of allopurinol in each case include
severity of toxicity and symptoms as well as compliance with current
chemotherapy regimens. For those patients who agree to treatment with
the combination of allopurinol-mercaptopurine we start with an age-based
oral allopurinol dose (50 mg daily for age <5 years, 100 mg
daily for age 5-10 years, 200 mg daily for age 10-15 years, and 300 mg
daily for those over 15 years). Because of the enzyme blockade by
allopurinol, we concomitantly reduce 6-MP to
25mg/m2/dose. For our younger children, utilizing
liquid mercaptopurine can be beneficial in order to have tighter
titration of the dose and effect. We then adjust 6-MP and allopurinol
doses to achieve a goal of normalization of toxicities, absolute
neutrophil count in the therapeutic window of 500-1 500 cells/µL and a
6-MMPN level of <5 000 pmol/8 x 108 RBC. If
the 6-MMPN level is not substantially decreased with the addition of
allopurinol, a higher dose of allopurinol dose should be attempted as
there are individual variations in allopurinol effectiveness that
require some patients to be on a higher allopurinol dose. Steroid and
vincristine dosing during maintenance were not adjusted. Methotrexate
dosing was also not adjusted during early phases of
allopurinol-mercaptopurine titration, however if after several months
ANC levels persisted >1500 cells/µL, then increasing
methotrexate to 125% dosing was considered. Figure 3 offers an
algorithmic approach to management.
It should be noted that the mechanism by which the addition of
allopurinol to mercaptopurine therapy results in increased 6-TGN and
decreased 6-MMPN is not fully understood. Preliminary laboratory
experiments performed at our institution showed that allopurinol may
cause decreased 6-MMPN levels due to tissue specific effects of 6-MP
metabolism24. When 6-TGN and 6-MMPN levels are
measured clinically, the levels are determined from red blood cells
which are not undergoing cell division. In previous treatment protocols
incorporating 6-Thioguanine (6-TG), which is directly converted to 6-TGN
without any other metabolism, the 6-TG was found to be more hepatotoxic
than 6-MP. Patients who are clinically treated with combination therapy
have much higher 6-TGN levels than patients who are only on 6-MP and
thus previous guidelines for 6-TGN therapeutic levels cannot be used to
determine dosage efficacy. In addition, the extremely high 6-TGN levels,
we achieved, with combination therapy while known to cause
myelosuppression, did not result in hepatotoxicity. Based on our
preliminary data, we suggest these changes in metabolite levels are due
to the tissue specific effects of allopurinol on 6-MP metabolism; but
further studies are required to confirm this finding.
One major limitation in this analysis is missing data for some
individuals. Metabolite data was not checked in all of those who were
eligible. Additionally, the frequency of checking metabolite data in
patients also differs among those who were started on allopurinol. Of
those who were started on allopurinol, Patients 2 and 12 were started
based on clinical toxicities and did not have metabolite levels checked
prior to allopurinol start. It is important to note that this lack of
metabolite data could potentially indicate that our findings are an
underestimation of the incidence of mercaptopurine metabolite shunting.
Additionally, 6-MMPN and 6-TGN levels for our patients who did not
exhibit clinical toxicities were not obtained for most of the cohort;
these levels could have been useful to better establish a normal profile
of 6-MMPN and 6-TGN levels, as well as a therapeutic window for the
ratio of 6-MMPN:6-TGN which could be useful for guiding the initiation
and benefits of allopurinol to mercaptopurine therapy. With use of this
proposed algorithm, we think combination therapy has the potential to
become routine practice in oncology.