Aims: We aimed to investigate the impact of various genetic polymorphisms affecting thiopurine metabolism pathways and toxicity in paediatric acute lymphoblastic leukaemia patients for the first time in Korea. Methods: From May 2006 to September 2016, 139 paediatric acute lymphoblastic leukaemia patients treated with combination chemotherapy including 6-mercaptopurine were included in the study. One hundred and twenty-three variants in 43 genes, including TMPT and NUDT15, were screened using targeted genotyping, such as a MassARRAY system, direct sequencing and polymerase chain reaction-restriction fragment length polymorphism methods. Among the polymorphisms screened, 103 polymorphisms of 43 genes were included for further analyses. Results: The genetic polymorphisms in the ABCC4, AHCY, ATIC, FAM8A6P, GART, GNG2, GSTA1, MTHFD1, MTHFR, NUDT15, PACSIN2, TYMS and XDH genes, and an intronic polymorphism between HIVEP2 and AIG1, and TPMT genotype were associated with thiopurine metabolism (P < 0.05). Genetic polymorphisms in the ABCC4, ADK, ATIC, GART, GMPS, GSTP1, IMPDH1, ITPA, KCNMA1, MOCOS, MTRR, NUDT15, SLC19A1, SLC28A3, SLC29A1, SLCO1B1, TYMP and XDH genes were associated with thiopurine-related toxicities; neutropenia, hepatotoxicity and treatment interruption (P < 0.05).Conclusions: Findings of this study may provide basic knowledge for personalized medicine for thiopurinxe treatment in paediatric acute lymphoblastic leukaemia patients.
BackgroundIn our previous SMC NB-2004 study of patients with high-risk neuroblastomas, which incorporated total-body irradiation (TBI) with second high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT), the survival rate was encouraging; however, short- and long-term toxicities were significant. In the present SMC NB-2009 study, only TBI was replaced with 131I-meta-iodobenzylguanidine (MIBG) treatment in order to reduce toxicities.MethodsFrom January 2009 to December 2013, 54 consecutive patients were assigned to receive tandem HDCT/auto-SCT after nine cycles of induction chemotherapy. The CEC (carboplatin + etoposide + cyclophosphamide) regimen and the TM (thiotepa + melphalan) regimen with (for metastatic MIBG avid tumors) or without (for localized or MIBG non-avid tumors) 131I-MIBG treatment (18 or 12 mCi/kg) were used for tandem HDCT/auto-SCT. Local radiotherapy, differentiation therapy with 13-cis-retinoic acid, and immunotherapy with interleukin-2 were administered after tandem HDCT/auto-SCT.ResultsFifty-two patients underwent the first HDCT/auto-SCT and 47 patients completed tandem HDCT/auto-SCT. There was no significant immediate toxicity during the 131I-MIBG infusion. Acute toxicities during the tandem HDCT/auto-SCT were less severe in the NB-2009 study than in the NB-2004 study. Late effects such as growth hormone deficiency, cataracts, and glomerulopathy evaluated at 3 years after the second HDCT/auto-SCT were also less significant in the NB-2009 study than in NB-2004 study. There was no difference in the 5-year event-free survival (EFS) between the two studies (67.5 ± 6.7% versus 58.3 ± 6.9%, P = 0.340).ConclusionsIncorporation of high-dose 131I-MIBG treatment into tandem HDCT/auto-SCT could reduce short- and long-term toxicities associated with TBI, without jeopardizing the survival rate.Trial registrationClinicalTrials.gov NCT03061656
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