Allopurinol use during pediatric acute lymphoblastic leukemia maintenance therapy safely corrects skewed 6‐mercaptopurine metabolism, improving inadequate myelosuppression and reducing gastrointestinal toxicity

Abstract

Background: Inadequate myelosuppression during maintenance therapy for acute lymphoblastic leukemia (ALL) is associated with an increased risk of relapse. One mechanism is skewed metabolism of 6-mercaptopurine (6MP), a major component of maintenance therapy, which results in preferential formation of the hepatotoxic metabolite (6-methyl mercaptopurine [6MMP]) with low levels of the antileukemic metabolite, 6-thioguanine nucleotides (6TGN). Allopurinol can modify 6MP metabolism to favor 6TGN production and reduce 6MMP. Methods: Patients in maintenance were considered for allopurinol treatment who had the following features: (a) Grade ≥3 hepatotoxicity; (b) Grade ≥2 nonhepatic gastrointestinal (GI) toxicity; or (c) persistently elevated absolute neutrophil count (ANC) despite >150% protocol dosing of oral chemotherapy. Results: From 2013 to 2017, 13 ALL patients received allopurinol: nine for hepatotoxicity, five for inadequate myelosuppression, and three for nonhepatic GI toxicity (four met multiple criteria). Allopurinol was well tolerated, without significant adverse events. Allopurinol resulted in a significant decrease in the average 6MMP/6TGN ratio (mean reduction 89.1, P = .0001), with a significant increase in 6TGN (mean 550.4, P = .0008) and a significant decrease in 6MMP (mean 13 755, P = .0013). Patients with hepatotoxicity had a significant decrease in transaminase elevation after starting allopurinol (alanine transaminase [ALT] mean decrease 22.1%, P = .02), and all with nonhepatic GI toxicity had improved symptoms. Those with inadequate myelosuppression had a significant increase in the time with ANC in goal (mean increase 26.4%, P = .0004). Conclusions: Allopurinol during ALL maintenance chemotherapy is a safe, feasible, and effective intervention for those who have altered metabolism of 6MP causing toxicity or inadequate myelosuppression.

Utilization of Thiopurine Metabolites and Allopurinol in Pediatric Acute Lymphoblastic Leukemia: Consideration for an Algorithmic Approach

“…The patients with high ANC required continued 6MP dose titration, and some eventually had an improvement in their ANC similar to the response reported by Brackett et al14 and Cohen et al16 with concomitant improvement in their 6TGNs. Hepatoxicity may not be related to the risk of long-term hepatic fibrosis but is more likely in patients with wild-type TPMT and correlates inversely with 6TGN levels 19–22.…”

“…Further study is required to validate our proposed algorithm, especially in consideration of the potential side effects of allopurinol, threshold TGN levels as well as altering 6MP metabolism away from 6MMPN. Cohen et al 16 utilized a 6MMPN to 6TGN ratio of > 40 before initiation of allopurinol when on at least 150% dosing of oral chemotherapy, while Conneely et al 26 suggest initiation when the 6MMPN to 6TGN ratio is > 20. In addition, we did not routinely check TPMT genotyping and did not check inosine triphosphate in any patient though this could have provided additional useful information.…”

“…8,12,13 Subsequently, based on adult data utilizing allopurinol to improve the therapeutic effect of 6MP in inflammatory bowel disease patients, 3 groups have reported treatment of a combined 32 pediatric ALL patients utilizing allopurinol to shift metabolism from the 6MMPN to the 6TGN pathway. [13][14][15][16] Additional reports have noted benefits in 6MMPN-related hypoglycemia and 6MP-related pancreatitis with the initiation of allopurinol. [16][17][18] Here, we report our institutional experience and suggest an algorithmic approach for patients in ALL maintenance therapy.…”

“…Early studies noted that oral 6MP dosing with allopurinol pretreatment could increase peak plasma concentration of 6MP by 500% secondary to inhibition of xanthine oxidase, as inactivation of 6MP is catalyzed by xanthine oxidase or TPMT (Supplementary Fig., Supplemental Digital Content 1, http://links.lww.com/JPHO/A484). 8,12,13 Subsequently, based on adult data utilizing allopurinol to improve the therapeutic effect of 6MP in inflammatory bowel disease patients, 3 groups have reported treatment of a combined 32 pediatric ALL patients utilizing allopurinol to shift metabolism from the 6MMPN to the 6TGN pathway 13–16. Additional reports have noted benefits in 6MMPN-related hypoglycemia and 6MP-related pancreatitis with the initiation of allopurinol 16–18.…”

Increments in DNA-thioguanine level during thiopurine-enhanced maintenance therapy of acute lymphoblastic leukemia

“…As an alternative allopurinol has been used to ameliorate this propensity to hepatotoxicity as it shifts patients to a TPMT low-activity phenotype. 33 However, TPMT heterozygocity is not associated with higher DNA-TG. 34 …”