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.