Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije
Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia
Autori
Milošević, GoranKotur, Nikola
Krstovski, Nada
Lazić, Jelena
Zukić, Branka
Stanković, Biljana
Janić, Dragana
Katsila, Theodora
Patrinos, George P.
Pavlović, Sonja
Dokmanović, Lidija
Članak u časopisu (Objavljena verzija)
Metapodaci
Prikaz svih podataka o dokumentuApstrakt
Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi up...otrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije.
Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and averag...e 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.
Ključne reči:
TPMT / ITPA / akutna limfoblastna leukemija (ALL) / ABCC4 / ABCB1 / 6merkaptopurin (6-MP) / TPMT / ITPA / childhood acute lymphoblastic leukemia (ALL) / ABCC4 / ABCB1 / 6-mercaptopurine (6-MP)Izvor:
Journal of Medical Biochemistry, 2018, 37, 3, 320-327Izdavač:
- Društvo medicinskih biohemičara Srbije, Beograd i Versita
Finansiranje / projekti:
- Retke bolesti: molekularna patofiziologija, dijagnostički i terapijski modaliteti i socijalni, etički i pravni aspekti (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41004)
DOI: 10.1515/jomb-2017-0060
ISSN: 1452-8258
WoS: 000439420700006
Scopus: 2-s2.0-85133149194
Institucija/grupa
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Milošević, Goran AU - Kotur, Nikola AU - Krstovski, Nada AU - Lazić, Jelena AU - Zukić, Branka AU - Stanković, Biljana AU - Janić, Dragana AU - Katsila, Theodora AU - Patrinos, George P. AU - Pavlović, Sonja AU - Dokmanović, Lidija PY - 2018 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/1116 AB - Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije. AB - Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL. PB - Društvo medicinskih biohemičara Srbije, Beograd i Versita T2 - Journal of Medical Biochemistry T1 - Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije T1 - Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia EP - 327 IS - 3 SP - 320 VL - 37 DO - 10.1515/jomb-2017-0060 ER -
@article{ author = "Milošević, Goran and Kotur, Nikola and Krstovski, Nada and Lazić, Jelena and Zukić, Branka and Stanković, Biljana and Janić, Dragana and Katsila, Theodora and Patrinos, George P. and Pavlović, Sonja and Dokmanović, Lidija", year = "2018", abstract = "Akutna limfoblastna leukemija je najčešća maligna bolest decjeg doba. Optimalna upotreba antileukemijskih lekova dovela je do smanjenja toksičnosti i neželjenih događaja, kao i do povećanja stope preživljavanja. Tiopurinski lekovi, uključujući 6-merkaptopurin, predstavljaju najčešće korišćene antileukemijske lekove u lečenju dece obolele od akutne limfoblastne leukemije, koji se koriste u toku faze održavanja. Persona lizovana terapija 6-merkaptopurinom, prilagođena TPMT genotipu svakog pacijenta, već je implementirana u terapijske protokole. Cilj ove studije je bio da ispita ulogu varijanti u genima TPMT, ITPA, ABCC4 i ABCB1 kao prediktora ishoda i toksičnosti uzrokovane 6-merkaptopurinom u toku faze održavanja u lečenju pedijatrijske akutne limfoblastne leukemije. Metode: U studiju je bilo uključeno 68 dece obolele od akutne limfoblastne leukemije. Pacijenti su lečeni primenom A LL IC-BFM 2002 ili A LL IC-BFM 2009 protokola. Toksičnost i neželjeni događaji su posmatrani i beleženi upotrebom surogat markera (broj nedelja bez terapije, broj epizoda leukopenije i prosecna doza 6-merkaptopurina) a probabilisticki modeli su korišćeni za predikciju ukupne toksicnosti uzrokovane primenom 6-merkaptopurina. Rezultati: Studija je potvrdila da pacijenti oboleli od akutne limfoblastne leukemije koji imaju neaktivni TPMT alel zahtevaju redukciju doze 6-merkaptopurina. Varijante u genima ITPA i ABCC4 nisu bile povezane sa toksicnošću koja je uzrokovana primenom 6-merkaptopurina u toku faze održavanja. Nosioci varijante u genu ABCB1 su ispoljili veću hepatotoksicnost. Probabilisticki model Neural net kojim su posmatrane sve analizirane genske varijante se pokazao kao najbolji predikcioni model. Primenom ovog modela bilo je moguće razlikovati A LL pacijente sa lošom i dobrom tolerancijom 6-merkaptopurina u 71% slucajeva (AUC=0,71). Zaključak: Ova studija doprinosi dizajniranju panela farmakogenetskih markera koji bi se koristili za predikciju toksicnosti uzrokovane primenom tiopurinskih lekova kod dece obolele od akutne limfoblastne leukemije., Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype-tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Methods: Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to A LL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leukopenia and average 6-mercaptopurine dose) and a probabilistic model was employed to predict overall 6-mercaptopurine related toxicity. Results: We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (A U C = 0 .7 l). Conclusions: This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.", publisher = "Društvo medicinskih biohemičara Srbije, Beograd i Versita", journal = "Journal of Medical Biochemistry", title = "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije, Variants in TPMT, ITPA, ABCC4 and ABCB1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia", pages = "327-320", number = "3", volume = "37", doi = "10.1515/jomb-2017-0060" }
Milošević, G., Kotur, N., Krstovski, N., Lazić, J., Zukić, B., Stanković, B., Janić, D., Katsila, T., Patrinos, G. P., Pavlović, S.,& Dokmanović, L.. (2018). Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry Društvo medicinskih biohemičara Srbije, Beograd i Versita., 37(3), 320-327. https://doi.org/10.1515/jomb-2017-0060
Milošević G, Kotur N, Krstovski N, Lazić J, Zukić B, Stanković B, Janić D, Katsila T, Patrinos GP, Pavlović S, Dokmanović L. Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije. in Journal of Medical Biochemistry. 2018;37(3):320-327. doi:10.1515/jomb-2017-0060 .
Milošević, Goran, Kotur, Nikola, Krstovski, Nada, Lazić, Jelena, Zukić, Branka, Stanković, Biljana, Janić, Dragana, Katsila, Theodora, Patrinos, George P., Pavlović, Sonja, Dokmanović, Lidija, "Polimorfizmi u genima TPMT, ITPA, Abcc4 i ABCB1 kao prediktori toksičnosti uzrokovane primenom 6-merkaptopurina kod dece obolele od akutne limfoblastne leukemije" in Journal of Medical Biochemistry, 37, no. 3 (2018):320-327, https://doi.org/10.1515/jomb-2017-0060 . .