Oncotarget

Research Papers:

GSTA1 diplotypes affect busulfan clearance and toxicity in children undergoing allogeneic hematopoietic stem cell transplantation: a multicenter study

Marc Ansari, Patricia Huezo-Diaz Curtis _, Chakradhara Rao S. Uppugunduri, Mohammed Aziz Rezgui, Tiago Nava, Vid Mlakar, Laurence Lesne, Yves Théoret, Yves Chalandon, Lee L. Dupuis, Tao Schechter, Imke H. Bartelink, Jaap J. Boelens, Robbert Bredius, Jean-Hugues Dalle, Saba Azarnoush, Petr Sedlacek, Victor Lewis, Martin Champagne, Christina Peters, Henrique Bittencourt and Maja Krajinovic

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Oncotarget. 2017; 8:90852-90867. https://doi.org/10.18632/oncotarget.20310

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Abstract

Marc Ansari1,2, Patricia Huezo-Diaz Curtis1,2,*, Chakradhara Rao S. Uppugunduri 1,2,*, Mohammed Aziz Rezgui3, Tiago Nava1,3,5,6, Vid Mlakar1,2, Laurence Lesne 1,2, Yves Théoret3,4,5, Yves Chalandon7, Lee L. Dupuis8, Tao Schechter8, Imke H. Bartelink9,17, Jaap J. Boelens9, Robbert Bredius10, Jean-Hugues Dalle11, Saba Azarnoush11, Petr Sedlacek12, Victor Lewis13, Martin Champagne14, Christina Peters15, Henrique Bittencourt3,4,5,16 and Maja Krajinovic3-5,16,18

1 Department of Pediatrics, CANSEARCH Research Laboratory, Faculty of Medicine, Geneva, Switzerland

2 Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospital, Geneva, Switzerland

3 Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montreal, Quebec, Canada

4 Department of Pharmacology, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

5 Clinical Pharmacology Unit, CHU Sainte-Justine, Montreal, Quebec, Canada

6 Faculty of Medicine, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

7 Department of Medical Specialties, Division of Hematology, Geneva University Hospital, Geneva, Switzerland

8 Department of Haematology/Oncology, Blood and Marrow Transplant Unit, The Hospital for Sick Children, Toronto, Ontario, Canada

9 Pediatric Blood and Marrow Transplantation Program, University Medical Center, Utrecht, The Netherlands

10 Department of Pediatrics, Center of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands

11 Pediatric Hematology Department, Robert Debré Hospital, Assistance Publique, Hôpitaux de Paris, Paris, France

12 Department of Pediatric Hematology and Oncology Teaching Hospital, 2nd Medical School, Charles University, Prague, Czech Republic

13 Department of Pediatrics, Alberta Children’s Hospital, Calgary, Alberta, Canada

14 Department of Hematology, Hospital Verdun, Montreal, Quebec, Canada

15 Department of Pediatrics, Stem Cell Transplantation Unit, St Anna Children’s Hospital, Vienna, Austria

16 Department of Pediatrics, Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada

17 Department of Medicine, The University of California San Francisco, San Francisco, CA, USA

18 On Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation, Leiden, The Netherlands

* These authors have contributed equally to this work

Correspondence to:

Patricia Huezo-Diaz Curtis, email:

Keywords: busulfan, pharmacokinetics, pharmacogenetics, toxicity, hematopoietic stem cell transplantion

Received: July 18, 2017 Accepted: July 23, 2017 Published: August 27, 2017

Abstract

Busulfan (BU) dose adjustment following therapeutic drug monitoring contributes to better outcome of hematopoietic stem cell transplantation (HSCT). Further improvement could be achieved through genotype-guided BU dose adjustments. To investigate this aspect, polymorphism within glutathione S transferase genes were assessed. Particularly, promoter haplotypes of the glutathione S transferase A1 (GSTA1) were evaluated in vitro, with reporter gene assays and clinically, in a pediatric multi-center study (N =138) through association with BU pharmacokinetics (PK) and clinical outcomes. Promoter activity significantly differed between the GSTA1 haplotypes (p<0.001) supporting their importance in capturing PK variability. Four GSTA1 diplotype groups that significantly correlated with clearance (p=0.009) were distinguished. Diplotypes underlying fast and slow metabolizing capacity showed higher and lower BU clearance (ml/min/kg), respectively. GSTA1 diplotypes with slow metabolizing capacitywere associated with higher incidence of sinusoidal obstruction syndrome, acute graft versus host disease and combined treatment-related toxicity (p<0.0005). Among other GST genes investigated, GSTP1 313GG correlated with acute graft versus host disease grade 1-4 (p=0.01) and GSTM1 non-null genotype was associated with hemorrhagic cystitis (p=0.003). This study further strengthens the hypothesis that GST diplotypes/genotypes could be incorporated into already existing population pharmacokinetic models for improving first BU dose prediction and HSCT outcomes. (No Clinicaltrials.gov identifier: NCT01257854. Registered 8 December 2010, retrospectively registered).


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