Title

 

Authors

R. Franca¹, E. Cuzzoni², A. Zanut², P. Rebora³, S. De Iudicibus², G. Decorti², MG. Valsecchi³ and M. Rabusin^1
1 I.R.C.C.S Burlo Garofolo, UO Pediatric Hemato-Oncology, Trieste, Italy.
² Department of Life Sciences, University of Trieste, Italy.
³ Department of Clinical Medicine and Prevention, Center of Biostatistics for Clinical Epidemiology, University of Milano-Bicocca, Monza, Italy. 

 

Abstract

In the AIEOP-BFM-ALL 2000 trial (Associazione Italiana Ematologia Oncologia Pediatrica/ Berlin-Frankfurt-Münster Acute Lymphoblastic Leukaemia Study Group), 15% of paediatric patients treated according to risk-adapted poly-chemotherapeutic regimens did not achieve remission and relapsed, suggesting that additional risk assessment criteria are needed to better predict an adverse clinical outcome. The aim of the present study was to investigate whether the common polymorphisms (homozygous deletion or "null genotype") of glutathione S-transferase-μ (GST-M1) and glutathione S-transferase-θ (GST-T1) could represent  novel prognostic genetic markers of relapse in childhood primary ALL.  A total of 614 patients was genotyped by multiplex polymerase chain reaction (PCR). Relapse cumulative incidence was estimated by weighted Kaplan-Meier estimates, and Cox model for two-phase design was applied to evaluate the effect of deletions on relapse in the whole cohort of 1999 patients treated with the AIEOP-BFM-ALL 2000 protocols. Overall analysis did not show any significant impact of GST-M1 and GST-T1 genotypes on outcome. However, when patients were stratified by risk group, age class or in vivo prednisone pre-phase response, the prognostic significance of the GST polymorphisms towards an higher rate of relapse emerged for GST-M1 normal and GST-T1 null subjects. Deletion of GST-M1 was associated with a better clinical outcome in adolescent (p=0.052, HR=0.54, 95%CI: 0.29-1.00) and within prednisolone poor responders (PPR, p=0.026, HR=0.45, 95%CI: 0.23-0.91). Deletion of GST-T1 was associated with a worse clinical outcome in 6-9 years old patients (p=0.045, HR=2.48, 95%CI: 1.02-6.01), in those belonging to the standard risk group (p=0.045, HR=4.62, 95%CI: 1.04-20.6) and within prednisolone good responders (PGR, p=0.041, HR=1.62, 95%CI: 1.02-2.58). Our results suggest that GST-M1 and GST-T-1 homozygous  deletions do improve relapse prediction in specific subsets of ALL patients, whose risk has been assessed by already-in-use assessment  criteria.