Uticaj ekspresije gena za humani koncentrativni nukleozidni transporter 3 i prisustva alela CYP2B6*6 na odgovor na terapiju fludarabinom i ciklofosfamidom kod bolesnika sa hroničnom limfocitnom leukemijom
Association of human concentrative nucleoside transporter 3 gene expression and CYP2B6*6 аllele with the response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia patients
Author
Vuković, VojinMentor
Mihaljević, Biljana
Committee members
Bila, JelenaAntić, Darko
Đurđević, Predrag

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Hemioterapija na bazi fludarabina i ciklofosfamida predstavlja osnov lečenja
pacijenata sa hroničnom limfocitnom leukemijom (HLL) mlađe životne dobi i bez značajnih
komorbiditeta. Kod nekih pacijenata efekat terapije može biti uslovljen aberantnom
ekspresijom i/ili mutacijama gena koji utiču na farmakodinamiku i farmakokinetiku
antileukemijskih lekova. Sa druge strane, ustanovljeni su brojni kliničko-laboratorijski i
molekularno-genetički markeri prognoze koji su značajni u predikciji kliničkog toka,
prvenstveno vremena do prve terapije (time to first treatment, TTFT) i ukupnog
preživljavanja (overall survival, OS). Oni se poslednjih godina u cilju jačanja prognostičke
vrednosti kombinuju unutar različitih prognostičkih modela, među kojima su za predikciju
TTFT naročito relevantni Skor rizika od progresije (Progression.Risk Score, PRS) i Skor MD
Anderson centra za kancer iz 2011 (MD Anderson Cancer Center 2011 score, MDACC
2011), dok je za predviđanje OS najznačajniji Internacionalni p...rognostički indeks za HLL
(The International Prognostic Index for CLL, CLL-IPI). Cilj rada je da se ispita uticaj
farmakogenetike, tačnije ekspresije gena SLC28A3 koji kodira hCNT3 protein, jedan od
transportera za fludarabin, i varijantnog alela CYP2B6*6 gena za citohrom P450 2B6, koji
učestvuje u metabolizmu ciklofosfamida, na ishod lečenja FC protokolom kod pacijenata sa
HLL-om. Takođe, cilj je da se u grupi ovih pacijenata utvrdi vrednost skorova CLL-IPI, PRS
i MDACC 2011 u predikciji TTFT, OS, vremena bez progresije (progression free survival,
PFS) i odgovora na terapiju. Konačno, ispitaće se veza farmakogenetičkih karakteristika i
skorova.
Metodologija: U studiju je uključeno 57 pacijenata sa HLL-om koji su lečeni FC
protokolom, većinom u prvoj liniji. Pacijenti su stratifikovani prema skorovima CLL-IPI,
PRS i MDACC 2011, nakon čega je ispitana njihova prognostička vrednost u pogledu TTFT,
odgovora na terapiju, PFS i OS...
Fludarabine plus cyclophosphamide (FC) chemotherapy is the basis of
treatment protocols used in management of chronic lymphocytic leukemia (CLL). In some
patients, response to therapy may be affected by aberrant function of genes involved in
pharmacokinetics and pharmacodynamics of the drugs. On the other hand, numerous
clinical, biological and genetic prognostic markers which predict the clinical course of CLL,
primarily time to first treatment (TTFT) and overall survival (OS) have been established. In
recent times, they have been combined to make different prognostic models in order to
enhance their prognostic value. The most relevant prognostic models used for prediction of
TTFT are the Progression-Risk Score (PRS), and the MD Anderson Cancer Center Score
2011 (MDACC 2011), while CLL-International Prognostic Index (CLL-IPI), although the
most powerful for prediction of OS, is also being used to estimate TTFT. The aim of this
research was to assess the impact of pharmacogenetic varia...bility, namely expression of
SLC28A3 gene and the presence of CYP2B6*6 variant allele, on the FC treatment efficacy.
Also, one of the objectives was to investigate CLL-IPI, PRS, and MDACC 2011 prognostic
values regarding TTFT, first line treatment response, progression-free survival (PFS) and OS.
Finally, the association of pharmacogenetics and prognostic models was investigated.
Methods: Fifty-seven CLL patients treated with FC, most of them in the first treatment line,
were enrolled in this study. Patients were stratified according to the prognostic models CLLIPI,
PRS and MDACC 2011 and their prognostic significance regarding TTFT, treatment
response, PFS and OS was examined. Considering the fact that the loss of TP53 gene
function is one of the main causes of chemoresistance, patients with mutated and/or deleted
TP53 were excluded from pharmacogenetic analyses, thus eliminating the possibility of its
influence on the treatment outcome...