Influence of variants in genes important for farmacokinetics of 6- mercaptopurine on acute lymphoblastic leukemia treatment in children

Akutna limfoblastna leukemija (ALL) predstavlja najčešću malignu bolest dečjeg doba. Akutna limfoblastna leukemija je klonalna maligna bolest hematopoetskog tkiva, koja se odlikuje klonalnom proliferacijom limfoblasta. a na osnovu njihovih imunofenotipskih karakteristika može se podeliti na B-ćelijske i T-ćelijske. Najčešći oblik akutne limfoblastne leukemije kod dece je B ćelijska prekursorska leukemija. Najčešće se javlja u uzrastu od druge do pete godine života i nešto je češća kod dečaka. Optimalna primena antileukemijskih lekova u sklopu jasno definisanih terapijskih protokola i precizna stratifikacija bolesnika u grupe rizika, uz maksimalnu suportivnu terapiju doveli su do značajnog porasta ukupnog preživljavanja koje sada iznosi i do 90%. Lečenje leukemije kod dece se sastoji iz četiri faze, od kojih je poslednja i najduža, faza održavanja u čijem sklopu se primenjuje lek iz grupe tiopurina – 6-merkaptopurin (6-MP). Toksični efekti ovog leka, pre svega mijelosupresija, kod izvesnog broja dece mogu dovesti do životno ugrožavajućih infekcija kao i do značajnog odlaganja terapije i povećanja rizika za nastanak recidiva bolesti. Enzim tiopurin S-metiltransferaza (TPMT) je najznačajni enzim za inaktivaciju 6-MP i poznato je da deca koja imaju sniženu aktivnost enzima, imaju izraženije toksične efekte i zahtevaju primenu manjih dozu 6-MP. Individualizovana terapija na osnovu TPMT genotipa je postala standard u lečenju akutne limfoblastne leukemije u dece. Osim enzima TPMT, postoji još nekoliko metaboličkih puteva u inaktivaciji i transportu 6-MP koji mogu uticati na povećanu toksičnost tokom primene leka. Inozin trifosfat pirofosfataza je drugi enzim, kodiran od strane ITPA gena, koji inaktiviše 6-MP, i nedovoljna aktivnost ovog enzima takođe doprinosi pojavi izražene mijelotoksičnosti tokom primene 6-MP. P-glikoprotein, kodiran od strane ABCC4 gena, i Multidrug Resistance Protein 4, kodiran od strane ABCB1 gena su transmembranski proteini koji funkcionišu kao efluks pumpe i izbacuju ksenobiotike iz ćelija. Povećana odnosno smanjena aktivnost ovih proteina može dovesti do smanjenog terapijskog efekta lekova odnosno do povećane toksičnosti tokom primene 6-MP. Cilj ovog istraživanja je bio da utvrdi učestalost varijacija u genima TPMT, ITPA, ABCC4 i ABCB1 kod dece obolele od akutne limfoblastne leukemije i njihov uticaj na intenzitet toksičnih efekata 6-MP kao i na ukupno preživljavanje...Acute lymphoblastic leukemia is the most common childhood malignancy. Acute lymphoblastic leukemia is malignant clonal disease of hematopoetic tissue and it is characterized by clonal proliferation of lymphoblasts, which can be of B-cell or T-cell origin. The most prevalent type of acute lymphoblastic leukemia in children is B-cell precursor leukemia. It is most commonly seen in children between age of two and five and there is slight male predominance. Optimal use of antileukemic drugs in the settings of clearly defined therapeutic protocols and precise risk stratification with maximal supportive therapy have led to significant improvement in overall survival, which is now near 90%. Leukemia treatment consists of four phases and last and longest phase is maintenance phase. In this phase, the most important drug is 6-mercaptopurine (6-MP) which belongs to the group of thiopurine drugs. 6-MP induced toxicity, myelosupression as the most prominent one, can in one number of children lead to life-threatening infections as well as significant therapy delay which contributes to increased risk for relapse. Enzyme thiopurine S-methyltransferase (TPMT) is most important inactivation enzyme for 6-MP and it is well established that children with TPMT deficiency have more pronounced toxicity and require lower dose of 6-MP. Personalized therapy based on TPMT genotype has become standard in treatment of acute lymphoblastic leukemia in children. Besides inactivation pathway that utilizes TPMT there are several other metabolic pathways for inactivation and transport mechanisms that can influence toxicity profile of 6-MP. Inosine triphosphate pirophosphatase (ITPA), which is coded by ITPA gene, is one of those 6-MP inactivation enzymes which, when deficient, can contribute to profound myelotoxicity. P-glycoprotein, coded by ABCC4 gene, and Multidrug Resistance Protein 4, coded by ABCB1 gene, are transmembrane transporters that works as efflux-pumps and removes xenobiotics from cells. Increased or reduced activity of these efflux-pumps can lead to reduced therapeutic effect or increased toxicity of 6-MP. Goal of this study was to determine frequency of variations in genes TPMT, ITPA, ABCC4 and ABCB1 in children with acute lymphoblastic leukemia and their influence on 6-MP induced toxicity as well as on overall survival..