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

Abstract

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 prognostički 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 variability, 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...