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

  • Sanjeev Khera
  • Amita Trehan
  • Prateek Bhatia
  • Minu Singh
  • Deepak Bansal
  • Neelam Varma
Original Article



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.


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.


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.


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


ALL 6 Mercaptopurine Single neucleotide polymorphism Myelosuppression Drug dose 


6 MP



Single nucleotide polymorphism


Acute lymphoblastic leukaemia


Thiopurine methyltransferase


Inosine triphosphate pyrophosphatase


Nucleoside diphosphate linked moiety-type motif 15


Indian Childhood Collaborative Leukaemia Group 2015




PCR amplification and restriction enzyme digestion


Alanine transferase


Febrile neutropenia


Absolute neutrophil count


Hardy Weinberg equilibrium


Analysis of variance




Total leucocyte count


Complete blood count


Polymerized chain reaction


Compliance ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 12 KB)
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Supplementary material 2 (DOCX 12 KB)
280_2018_3732_MOESM3_ESM.docx (15 kb)
Supplementary material 3 (DOCX 14 KB)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Pediatric Hematology and Oncology, Department of Pediatrics, Advanced Pediatrics CentrePostgraduate Institute of Medical Education and ResearchChandigarhIndia
  2. 2.Department of HematologyPostgraduate Institute of Medical Education and ResearchChandigarhIndia

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