Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia
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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.
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.
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.
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.
KeywordsAcute lymphoblastic leukemia 6-Mercaptopurine Thiopurine methyl transferase Glutamate carboxypeptidase II Machine learning Leucopenia grade
We acknowledge the team of Department of Medical Oncology, Nizam’s Institute of Medical Sciences, Hyderabad for their cooperation for this study.
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.
No funding was received for this work.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
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 was obtained from all individual participants included in the study.
- 3.Chrzanowska M, Kuehn M, Januszkiewicz-Lewandowska D, Kurzawski M, Droździk M (2012) Thiopurine S-methyltransferase phenotype-genotype correlation in children with acute lymphoblastic leukemia. Acta Pol Pharm 69(3):405–410Google Scholar
- 5.Dorababu P, Nagesh N, Linga VG, Gundeti S, Kutala VK, Reddanna P, Digumarti R (2012) Epistatic interactions between thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) variations determine 6-mercaptopurine toxicity in Indian children with acute lymphoblastic leukemia. Eur J Clin Pharmacol 68(4):379–387CrossRefGoogle Scholar
- 9.Ma XL, Zhu P, Wu MY, Li ZG, Hu YM (2003) Relationship between single nucleotide polymorphisms in thiopurine methyltransferase gene and tolerance to thiopurines in acute leukemia. Zhonghua Er Ke Za Zhi 41(12):929–933Google Scholar
- 10.Hamdan-Khalil R, Allorge D, Lo-Guidice JM, Cauffiez C, Chevalier D, Spire C, Houdret N, Libersa C, Lhermitte M, Colombel JF, Gala JL, Broly F (2003) In vitro characterization of four novel non-functional variants of the thiopurine S-methyltransferase. Biochem Biophys Res Commun 309(4):1005–1010CrossRefGoogle Scholar
- 13.Tanaka Y (2017) Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia. Rinsho Ketsueki 58(8):950–956Google Scholar