Dosage of 6-Mercaptopurine in Relation to Genetic TPMT and ITPA Variants: Toward Individualized Pediatric Acute Lymphoblastic Leukemia Maintenance Treatment. Issue 2 (March 2020)

• Record Type: Journal Article
• Authors: Kouwenberg, Theodorus W.; van den Bosch, Bianca J.C.; Bierau, Jörgen; te Loo, Dunja Maroeska W.M.; Coenen, Marieke J.H.; Hagleitner, Melanie M.
• Is Part Of: Journal of pediatric hematology/oncology. Volume 42:Issue 2(2020)
• Publication Date: 2020-03
• Subjects: acute lymphoblastic leukemia -- 6-mercaptopurine -- TPMT -- ITPA -- pharmacogenetics; Pediatric hematology -- Periodicals; Tumors in children -- Periodicals; 618.9215
• DOI: 10.1097/MPH.0000000000001707
• Languages: English
• ISSNs: 1077-4114

Abstract

Abstract : 6-mercaptopurine (6-MP) is the mainstay in pediatric acute lymphoblastic leukemia (ALL) maintenance treatment. Variants in genes coding for thiopurine S-methyl transferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) are known to influence 6-MP metabolism. We determined TPMT and ITPA genotype and enzyme activity and the mean 6-MP doses during maintenance treatment in 40 children treated for ALL according to the Dutch Childhood Oncology Group (DCOG)-ALL11 protocol in the Radboudumc Amalia Children's Hospital, Nijmegen, The Netherlands. Patients with genetic variants in TPMT (N=3) had significantly lower TPMT enzyme activity (mean 0.46 vs. 0.72 µmol/mmol hemoglobin/h, P =0.005). Although the difference was not statistically significant, they were treated with lower mean 6-MP doses (28.1 mg/m 2 [SD 25.5 mg/m 2 ] vs. 41.3 mg/m 2 [SD 17.2 mg/m 2 ], P =0.375). In patients with genetic ITPA variants (N=21), ITPA enzyme activity was significantly lowered (mean 3.67 vs. 6.84 mmol/mmol hemoglobin/h, P <0.0005). The mean 6-MP doses did not differ between patients with and without variants in ITPA (40.0 mg/m 2 [SD 20.3 mg/m 2 ] vs. 40.6 mg/m 2 [SD 14.9 mg/m 2 ], P =0.663). The TPMT genotype, but not the ITPA genotype, should be considered as part of standard evaluation before starting ALL maintenance treatment.