Drug-related toxicities represent an important clinical concern in chemotherapy, genetic variants could help tailoring treatment to patient. A pharmacogenetic multicentric study was performed on 508 pediatric acute lymphoblastic leukemia patients treated with AIEOP-BFM 2000 protocol: 28 variants were genotyped by VeraCode and Taqman technologies, deletions of GST-M1 and GST-T1 by multiplex PCR. Toxicities were derived from a central database: 251 patients (49.4%) experienced at least one gastrointestinal (GI) or hepatic (HEP) or neurological (NEU) grade III/IV episode during the remission induction phase: GI occurred in 63 patients (12.4%); HEP in 204 (40.2%) and NEU in 44 (8.7%). Logistic regression model adjusted for sex, risk and treatment phase revealed that ITPA rs1127354 homozygous mutated patients showed an increased risk of severe GI and NEU. ABCC1 rs246240 and ADORA2A rs2236624 homozygous mutated genotypes were associated to NEU and HEP, respectively. These three variants could be putative predictive markers for chemotherapy-related toxicities in AIEOP-BFM protocols.
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PR was partially supported by the grant MIUR-SIR 2014 (RBSI14LOVD). We thank AGMEN (Associazione Genitori Malati Emopatici Neoplastici)-Friuli Venezia Giulia (Italy) and IRCCS Burlo Garofolo in Trieste (Italy) for supporting the pharmacogenetic project.
RF was the principal investigator and contributed to study design, genetic analysis, data interpretation and paper writing; PR is responsible for the study design and statistical analysis; NB recruited patients and collected the clinical data; FF and VC discussed results and revised the manuscript; AB, AC, CM, MZ, RP, FP, GB, MCP and FL recruited patients and collected the clinical data; PD contributed for genetic analysis; MGV and GD discussed results and revised the manuscript; MR contributed to study design, co-ordinated the clinical part, discussed results and revised the manuscript.
The authors declare no conflict of interest.
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Franca, R., Rebora, P., Bertorello, N. et al. Pharmacogenetics and induction/consolidation therapy toxicities in acute lymphoblastic leukemia patients treated with AIEOP-BFM ALL 2000 protocol. Pharmacogenomics J 17, 4–10 (2017). https://doi.org/10.1038/tpj.2015.83
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