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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 5, pp 875–880 | Cite as

Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia

  • Shaik Mohammad NaushadEmail author
  • Patchava Dorababu
  • Yedluri Rupasree
  • Addepalli Pavani
  • Digumarti Raghunadharao
  • Tajamul Hussain
  • Salman A. Alrokayan
  • Vijay Kumar Kutala
Original Article
  • 77 Downloads

Abstract

Purpose

The rationale of the current study was to develop 6-mercaptopurine (6-MP)-mediated hematological toxicity prediction model for acute lymphoblastic leukemia (ALL) therapeutic management.

Methods

A total of 96 children with ALL undergoing therapy with MCP-841 protocol were screened for all the ten exons of TPMT, exon 2, exon 3 and intron 2 of ITPA using bidirectional sequencing. This dataset was used to construct prediction models of leucopenia grade by constructing classification and regression trees (CART) followed by smart pruning.

Results

The developed CART model indicated TPMT*12 and TPMT*3C as the key determinants of toxicity. TPMT int3, int4 and int7 polymorphisms exert toxicity when co-segregated with one mutated allele of TPMT*12 or TPMT*3C or ITPA exon 3. The developed CART model exhibited 93.6% accuracy in predicting the toxicity. The area under the receiver operating characteristic curve was 0.9649.

Conclusions

TPMT *3C and TPMT*12 are the key determinants of 6-MP-mediated hematological toxicity while other variants of TPMT (int3, int4 and int7) and ITPA ex2 interact synergistically with TPMT*3C or TPMT*12 variant alleles to enhance the toxicity. TPMT and ITPA variants cumulatively are excellent predictors of 6-MP-mediated toxicity.

Keywords

Acute lymphoblastic leukemia 6-Mercaptopurine Thiopurine methyl transferase Glutamate carboxypeptidase II Machine learning Leucopenia grade 

Notes

Acknowledgements

We acknowledge the team of Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Hyderabad for their cooperation for this study.

Author contributions

The study was conceived and designed by DR and VKK. The research and analytical work was carried out by SMN, PD, SAA and TH. The statistical models were developed and manuscript was drafted by SMN and VKK.

Funding

No funding was received for this work.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Shaik Mohammad Naushad
    • 1
    Email author
  • Patchava Dorababu
    • 2
  • Yedluri Rupasree
    • 1
  • Addepalli Pavani
    • 1
  • Digumarti Raghunadharao
    • 3
  • Tajamul Hussain
    • 4
    • 5
  • Salman A. Alrokayan
    • 5
    • 6
  • Vijay Kumar Kutala
    • 7
  1. 1.Head-Biochemical Genetics and PharmacogenomicsSandor Speciality Diagnostics Pvt LtdHyderabadIndia
  2. 2.Department of PharmacologyApollo Institute of Medical Sciences and ResearchHyderabadIndia
  3. 3.Homibhabha Cancer Hospital and Research CentreVisakhapatnamIndia
  4. 4.Center of Excellence in Biotechnology Research, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
  5. 5.Research Chair for Biomedical Applications of Nanomaterials, Department of Biochemistry, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
  6. 6.Biochemistry Department, College of ScienceKing Saud UniversityRiyadhSaudi Arabia
  7. 7.Department of Clinical Pharmacology and TherapeuticsNizam’s Institute of Medical SciencesHyderabadIndia

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