ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

Abstract

Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA , both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT , NUDT15 , and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Association of NUDT15 c.415C>T and FPGS 2572C>T Variants with the Risk of Early Hematologic Toxicity During 6-MP and Low-Dose Methotrexate-Based Maintenance Therapy in Indian Patients with Acute Lymphoblastic Leukemia

“…The frequency of the NUDT15 c.415T allele in the present study is 9.8%, and we did not observe any homozygous variant genotype carriers. This observed frequency is similar to another report from North India (9.5%) [ 21 ], and higher than that of the Middle Eastern population (0.7%) [ 26 ], but lower than those of the Chinese and Japanese populations (15–20%) [ 35 ]. These observations highlight the importance of NUDT15 variants in predicting early TRT during maintenance therapy in ALL patients of South Indian origin, similar to the other Asian populations [ 21 , 33 , 34 ].…”

“…This is in contrast to the Caucasians, where common thiopurine methyltransferase ( TPMT ) variants were shown to be associated with 6-MP-induced myelosuppression [ 24 ]. Therefore, we selected NUDT15 (rs116855232) and TPMT (rs1142345) genetic variants, which are reported affect 6-MP outcome [ 25 , 26 ] ( Table 1 ). Several variants in genes encoding metabolism, transporter proteins and in the folate pathway ( Table 1 ) may play a role in determining toxicity and efficacy of the MTX.…”

Genetic Polymorphisms of Drug-Metabolizing Enzymes Involved in 6-Mercaptopurine-Induced Myelosuppression in Thai Pediatric Acute Lymphoblastic Leukemia Patients

“…Recently, genetic polymorphisms of TPMT and NUDT15 have been proposed to be involved with an increased risk of myelosuppression in patients treated with thiopurine drugs, including 6-MP and its prodrug, azathioprine. 4,8,9,14,15,18,19 To the authors' knowledge, this is the first study evaluating the common TPMT variant and all known loss-of-function NUDT15 variants in Thai pediatric ALL patients.…”

NUDT15 polymorphism in healthy children with Bai nationality in Yunnan of China

“…Genotyping of NUDT15 , rather than TPMT , is strongly recommended to be detected in patients with Crohn's disease before initiating thiopurine drugs 12 . The association of NUDT15 polymorphism with thiopurine intolerance and myelotoxicity has largely been reported in pediatric patients with ALL 13–40 (Table 1). Interestingly, the NUDT15 variation is rarely found in European and African populations as compared with Asian populations, suggesting variability of the NUDT15 gene across different ethnic populations 22 .…”