Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia

Abstract

Purpose: Toxicity of 6-Mercaptopurine (6MP) is related to single nucleotide polymorphism (SNP) in genes coding for metabolizing enzymes, with TPMT analysis being recommended prior to maintenance therapy. However, ITPA and NUDT15 polymorphisms appear more important in the Asian population.

Method: In this study 63 consecutive patients with ALL, entering maintenance phase of therapy, were evaluated for TPMT, ITPA and NUDT15 polymorphisms by PCR RFLP and confirmed by sequencing. Hematological and hepatic toxicities were monitored for 36 weeks. The groups with and without any of the three studied polymorphisms (Risk SNP + and Risk SNP-) were compared.

Results: Eighteen (28.6%) patients had major polymorphisms, 17 being heterozygous. ITPA(198CA): 11(17.5%); NUDT (415CT): 6(9.5%) and TPMT*3C: in 2(3.1%). Mean cumulative dose of 6MP was lower: 10927 mg/m² in group with one of the polymorphisms compared to 12533 mg/m² in the group without a polymorphism (p = 0.009). The group with Risk SNP + tolerated lesser weeks of full-dose 6MP chemotherapy (20.81 vs 30.40 weeks; p = 0.001). Risk of neutropenia > 3 weeks was pronounced in Risk SNP + group. The individual TPMT, ITPA and NUDT15 polymorphism subgroups had similar cumulative 6MP dose and chemotherapy interruptions. There was no difference in the average cumulative dose of methotrexate in the two groups. No significant hepatotoxicity was noted.

Conclusion: Polymorphisms in ITPA and NUDT15 have a greater prevalence in the north Indian population. Patients with these SNPs tolerate lower doses of 6MP.

Keywords: 6 Mercaptopurine; ALL; Drug dose; Myelosuppression; Single neucleotide polymorphism.