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Franca et al. Cancer Drug Resist 2019;2:256-70 Cancer
DOI: 10.20517/cdr.2019.004 Drug Resistance

Review Open Access

Pharmacogenetics of thiopurines

Raffaella Franca , Giulia Zudeh , Sofia Pagarin , Marco Rabusin , Marianna Lucafò , Gabriele
4
4
2,3
4,5
1
Stocco , Giuliana Decorti 1,4
3
1 Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste 34127, Italy.
2 PhD Course in Reproductive and Developmental Sciences, University of Trieste, Trieste 34127, Italy.
3 Department of Life Sciences, University of Trieste, Trieste 34127, Italy.
4 Institute for Maternal and Child Health I.R.C.C.S. Burlo Garofolo, Trieste 34127, Italy.
5 Experimental and Clinical Pharmacology Unit, Centro di riferimento oncologico, I.R.C.C.S., Aviano 33081, Italy.
Correspondence to: Dr. Gabriele Stocco, Department of Life Sciences, University of Trieste, via A. Fleming 22, Trieste 34127, Italy.
E-mail: stoccog@units.it
How to cite this article: Franca R, Zudeh G, Pagarin S, Rabusin M, Lucafò M, Stocco G, Decorti G. Pharmacogenetics of
thiopurines. Cancer Drug Resist 2019;2:256-70. http://dx.doi.org/10.20517/cdr.2019.004

Received: 14 Jan 2019 First Decision: 26 Feb 2019 Revised: 16 Mar 2019 Accepted: 21 Mar 2019 Published: 19 Jun 2019

Science Editor: Enrico Mini Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Polychemotherapeutic protocols for the treatment of pediatric acute lymphoblastic leukemia (ALL) always include
thiopurines. Specific approaches vary in terms of drugs, dosages and combinations. Such therapeutic schemes, including
risk-adapted intensity, have been extremely successful for children with ALL who have reached an outstanding 5-year
survival of greater than 90% in developed countries. Innovative drugs such as the proteasome inhibitor bortezomib and
the bi-specific T cell engager blinatumomab are available to further improve therapeutic outcomes. Nevertheless, daily
oral thiopurines remain the backbone maintenance or continuation therapy. Pharmacogenetics allows the personalization
of thiopurine therapy in pediatric ALL and clinical guidelines to tailor therapy on the basis of genetic variants in TPMT
and NUDT15 genes are already available. Other genes of interest, such as ITPA and PACSIN2, have been implicated in
interindividual variability in thiopurines efficacy and adverse effects and need additional research to be implemented
in clinical protocols. In this review we will discuss current literature and clinical guidelines available to implement
pharmacogenetics for tailoring therapy with thiopurines in pediatric ALL.

Keywords: Thiopurines, acute lymphoblastic leukemia, therapy personalization, thiopurine methyltransferase, NUDT15,
PACSIN2, inosine triphosphate pyrophosphatase, pharmacogenetics clinical implementation

INTRODUCTION
Thiopurines such as mercaptopurine and thioguanine (MP and TG, Figure 1A and B respectively) are
lympholytic drugs used in all phases of therapy for acute lymphoblastic leukemia (ALL), with MP being part

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
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