Use of allopurinol in children with acute lymphoblastic leukemia to reduce skewed thiopurine metabolism

Abstract

Mercaptopurine (6-MP), a critical component of acute lymphoblastic leukemia (ALL) therapy, is metabolized to 6-thioguanine (6-TGN) which is responsible for its anti-leukemic effect, and to 6-methylmercaptopurine nucleotides (6-MMPN/6-MMP) which can be hepatotoxic. Some patients preferentially metabolize 6-MP to 6-MMPN which may increase the risk of liver injury, reduce serum levels of 6-TGN and potentially increase the risk of relapse. The addition of allopurinol to oral 6-MP has been shown to optimize metabolism towards 6-TGN in patients with inflammatory bowel disease (IBD); however, this use has not been reported in patients undergoing treatment for ALL.

Treatment of Pediatric Acute Lymphoblastic Leukemia

“…For example, genotypic polymorphisms in the enzyme thiopurine methyltransferase are associated with increased myelosuppression and other toxicities, whereas other polymorphisms confer a “hypermetabolizer” state, with decreased levels of the active metabolite. 19 Understanding these differences in metabolism is particularly important because studies have shown that the degree of myelosuppression correlates with relapse risk. 20,21 Accordingly, many protocols include guidelines for dose adjustments to assist in achieving the goal of balancing the risks of inadequate myelosuppression with the risks of severe pancytopenia (infection, bleeding, and so forth).…”

Mercaptopurine/Methotrexate Maintenance Therapy of Childhood Acute Lymphoblastic Leukemia

“…As dose increments of 6MP increase the methylated metabolites and their associated toxicities far more than Ery-6TGN, several alternative treatment strategies have been efficacious in improving the 6TGN/MeMP ratio, including coadministration of allopurinol70,71,90 and splitting the daily 6MP dose in a morning and an evening dose,91,92 but it remains to be determined whether such approaches increase DNA-TG levels, ease 6MP dose adjustments to obtain target WBC/absolute neutrophil counts (ANC) levels, or reduce relapse rates of childhood ALL.…”

Effect of Bcl-2-siRNA on proliferation and apoptosis of pediatric acute B lymphoblastic leukemia (A-BLL) cells

“…The VDLD therapeutic regime that has been used clinically is the first-line approach for treatment of A-BLL. However, recent research has indicated an increase in the rate of resistance to chemotherapeutic drugs; in addition, these drugs impart severe toxic and side effects, thereby restricting the clinical use of this therapeutic regime (Brackett et al, 2014;Melachuri et al, 2014).…”