Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

6 MP:

6-Mercaptopurine

SNP:

Single nucleotide polymorphism

ALL:

Acute lymphoblastic leukaemia

TPMT:

Thiopurine methyltransferase

ITPA:

Inosine triphosphate pyrophosphatase

NUDT15:

Nucleoside diphosphate linked moiety-type motif 15

ICICLE:

Indian Childhood Collaborative Leukaemia Group 2015

MTX:

Methotrexate

PCR-RFLP:

PCR amplification and restriction enzyme digestion

ALT:

Alanine transferase

FN:

Febrile neutropenia

ANC:

Absolute neutrophil count

HWE:

Hardy Weinberg equilibrium

ANOVA:

Analysis of variance

6TGN:

6-Thioguanine

TLC:

Total leucocyte count

CBC:

Complete blood count

PCR:

Polymerized chain reaction

References

  1. Wall AM, Rubnitz JE (2003) Pharmacogenomic effects on therapy for acute lymphoblastic leukemia in children. Pharmacogenomics J, 3:128

    Article  PubMed  CAS  Google Scholar 

  2. Evans WE et al (2001) Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J Clin Oncol 19(8):2293–2301

    Article  PubMed  CAS  Google Scholar 

  3. Moriyama T, Relling MV, Yang JJ (2015) Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood 125(26):3988–3995

    Article  PubMed  CAS  Google Scholar 

  4. Relling MV et al (1999) Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J Natl Cancer Inst 91(23):2001–2008

    Article  PubMed  CAS  Google Scholar 

  5. Relling MV et al (2013) Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 93(4):324–325

    Article  PubMed  CAS  Google Scholar 

  6. Chang JG et al (2002) Molecular analysis of thiopurine S-methyltransferase alleles in South-east Asian populations. Pharmacogenetics 12(3):191–195

    Article  PubMed  CAS  Google Scholar 

  7. Srimartpirom S et al (2004) Thiopurine S-methyltransferase genetic polymorphism in the Thai population. Br J Clin Pharmacol 58(1):66–70

    Article  PubMed  CAS  Google Scholar 

  8. Tanaka Y et al (2012) The activity of the inosine triphosphate pyrophosphatase affects toxicity of 6-mercaptopurine during maintenance therapy for acute lymphoblastic leukemia in Japanese children. Leuk Res 36(5):560–564

    Article  PubMed  CAS  Google Scholar 

  9. Yang SK et al (2014) A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet 46(9):1017–1020

    Article  PubMed  CAS  Google Scholar 

  10. Chiengthong K et al (2016) NUDT15 c.415C> T increases risk of 6-mercaptopurine induced myelosuppression during maintenance therapy in children with acute lymphoblastic leukemia. Haematologica 101(1):e24–e26

    Article  PubMed  CAS  Google Scholar 

  11. Yates CR et al. (1997) Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med 126:608–614

    Article  PubMed  CAS  Google Scholar 

  12. Cao H, Hegele RA (2002) DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. J Hum Genet 47:620

    Article  PubMed  CAS  Google Scholar 

  13. Schmiegelow K et al (2014) Mercaptopurine/methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol 36(7):503–517

    Article  PubMed  CAS  Google Scholar 

  14. Kapoor G et al. (2010) Thiopurine S-methyltransferase gene polymorphism and 6-mercaptopurine dose intensity in Indian children with acute lymphoblastic leukemia. Leuk Res 34:1023–1026

    Article  PubMed  CAS  Google Scholar 

  15. Davavala SK et al (2014) Prevalence of TPMT polymorphism in Indian patients requiring immunomodulator therapy and its clinical significance. Indian J Gastroenterol 33(1):41–45

    Article  PubMed  Google Scholar 

  16. Desire S et al (2010) Frequency of TPMT alleles in Indian patients with acute lymphatic leukemia and effect on the dose of 6-mercaptopurine. Med Oncol 27(4):1046–1049

    Article  PubMed  CAS  Google Scholar 

  17. Soler AM et al. (2017) TPMT and NUDT15 genes are both related to mercaptopurine intolerance in acute lymphoblastic leukaemia patients from Uruguay. Br J Haematol 181:252–255

    Article  PubMed  Google Scholar 

  18. Wan Rosalina WR et al (2012) Polymorphism of ITPA 94C> A and risk of adverse effects among patients with acute lymphoblastic leukaemia treated with 6-mercaptopurine. J Clin Pharm Ther 37(2):237–241

    Article  PubMed  CAS  Google Scholar 

  19. Kim HT et al (2017) NUDT15 genotype distributions in the Korean population. Pharmacogenet Genom 27(5):197–200

    Article  CAS  Google Scholar 

  20. Schmiegelow K, Bruunshuus I (1990) 6-Thioguanine nucleotide accumulation in red blood cells during maintenance chemotherapy for childhood acute lymphoblastic leukemia, and its relation to leukopenia. Cancer Chemother Pharmacol 26(4):288–292

    Article  PubMed  CAS  Google Scholar 

  21. Yang JJ et al (2015) Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J Clin Oncol 33(11):1235–1242

    Article  PubMed  CAS  Google Scholar 

  22. Farfan MJ et al (2014) Prevalence of TPMT and ITPA gene polymorphisms and effect on mercaptopurine dosage in Chilean children with acute lymphoblastic leukemia. BMC Cancer 14(1):299

    Article  PubMed  Google Scholar 

  23. Ma X et al (2014) Inosine triphosphate pyrophosphohydrolase (ITPA) polymorphic sequence variants in Chinese ALL children and possible association with mercaptopurine related toxicity. Int J Clin Exp Pathol 7(7):4552–4556

    PubMed  CAS  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pediatric Hematology and Oncology, Department of Pediatrics, Advanced Pediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, 160012, India

    Sanjeev Khera, Amita Trehan, Prateek Bhatia, Minu Singh & Deepak Bansal

  2. Department of Hematology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

    Neelam Varma

Authors
  1. Sanjeev Khera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amita Trehan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Prateek Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Minu Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Deepak Bansal
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Neelam Varma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amita Trehan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khera, S., Trehan, A., Bhatia, P. et al. Prevalence of TPMT, ITPA and NUDT 15 genetic polymorphisms and their relation to 6MP toxicity in north Indian children with acute lymphoblastic leukemia. Cancer Chemother Pharmacol 83, 341–348 (2019). https://doi.org/10.1007/s00280-018-3732-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-018-3732-3

Keywords

Search

Navigation