Влијанието на Ц677Т полиморфизмот на генот за МТХФРврз инциденцијата на токÑичните ефекти од виÑоките дози МТХ кај деца Ñо акутна лимфоблаÑтна леукемија

In current protocols for treatment of acute lymphoblastic leukemia in childhood methotrexate (MTX) is one of the crucial cytostatics. The occurrence of MTX toxicity is still  Ð° great problem because of the interpatient differences in drug metabolism. These differences may  be due  to polymorphisms of genes involved in the folate metabolism. The present study was carried out to determine the prevalence of MTHFR  C677T polymorphism in children with acute lymphoblastic leukemia (ALL). Also the effect of the genotype on the toxic  effects during therapy with high doses of МТХ in 45 patients with ALL treated in accordance with the protocol ALL BFM 95 and ALL BFM 2000 was evaluated. All 45 patients with ALL were genotyped for MTHFR C677T polymorphism. Correlation with the presence of a certain polymorphism and toxic effects of the chemotherapy with high doses of МТХ was  made in the Department  for hematology and oncology at the University Clinic for children's diseases – Skopje. The control group included 32 healthy patients. In the study group 24 (53.3%) children had a wild type of polymorphism (CC), 15 (33.33%) children were heterozygous (CT) for MTHFR C677T polymorphism, and 6 (13.33%) children were homozygous for the variant type  of the polymorphism (ТТ). The  correlation of the genotype with МТХ toxicity indicated a statistical significance only for oral mucositis, while for the other toxic effects there was no statistically significant correlation. In our study the results indicated that oral mucositis was statistically significantly more frequently identified in the case of the variant carriers for this polymorphism. For the other toxic effects caused by the therapy with high doses of МТХ no statistically  significant correlation with MTHFR C677T polymorphism was  identified. This  occurrence maybe due  to the small number of patients analyzed in this study and the possible protective influence of other genetic polymorphisms included in the folate metabolism, which were not subject to consideration of this study.Во актуелните протоколи за третман на акутна лимфоблаÑтна леукемија во  Ð´ÐµÑ‚Ñката возраÑÑ‚ метотрекÑатот (МТХ) е еден од круцијалните цитоÑтатици. Предвидувањето на појавата на токÑични ефекти во тек на терапијата Ñо МТХ претÑтавува Ñè уште голем проблем заради индивидуалните разлики во метаболизмот на лекови кај пациентите. Овие разлики можеби Ñе должат на приÑуÑтво на полиморфизми на гените вклучени  Ð²Ð¾  Ñ„олатниот метаболизам. Целта на  Ñтудијата беше  Ð´Ð°  Ñе одреди инциденцијата на МТХФР Ц677Т полиморфизмот кај децата Ñо акутна лимфоблаÑтна леукемија (ÐЛЛ) и да Ñе анализира влијанието на генотипот врз  Ð¼Ð°Ð½Ð¸Ñ„еÑтацијата на токÑичните ефекти во тек на терапија Ñо виÑоки дози МТХ кај пациенти Ñо ÐЛЛ третирани по  Ð¿Ñ€Ð¾Ñ‚околот ÐЛЛ БФМ  95. Беше вклучена и контролна група  Ð¾Ð´ 32 здрави иÑпитаници. Беше  Ð½Ð°Ð¿Ñ€Ð°Ð²ÐµÐ½Ð° генотипизација за полиморфизмот Ц677Т кај 45 пациенти Ñо ÐЛЛ и негова корелација Ñо токÑичните ефекти од хемотерапијата Ñо виÑоки дози  ÐœÐ¢Ð¥ анализирани од болничките иÑтории на пациенти Ñо ÐЛЛ лекувани на Одделот за хематологија и онкологија при  ÐˆÐ—У УниверзитетÑка клиника за детÑки болеÑти - Скопје.  Ð’о ÑтудиÑката група 15 (33,33%) пациенти беа хетерозиготи (ЦТ) за полиморфизмот Ц677Т на генот MTHFR, а 6 (13,33%) пациенти хомозиготи (ТТ). Во контролната група  10 иÑпитаници  (31,25%) беа  хетерозиготи за полиморфизмот (ЦТ), а 6 иÑпитаници (18,75%) хомозиготи (ТТ). Корелацијата на генотипот Ñо токÑичните ефекти од виÑоките дози  Ð½Ð° МТХ покажа ÑтатиÑтичка ÑигнификантноÑÑ‚ Ñамо за орален мукозит, додека беше ÑтатиÑтички неÑигнификантна за оÑтанатите токÑични ефекти. Оваа појава можеби Ñе должи на малата група пациенти којашто беше анализирана во оваа Ñтудија и можното протективно влијание на  Ð´Ñ€ÑƒÐ³Ð¸  Ð³ÐµÐ½Ñки полиморфизми вклучени во фолатниот метаболизам, а кои не беа предмет на оваа Ñтудија

ТокÑични ефекти предизвикани од хемотерапија Ñо виÑоки дози метотрекÑат кај деца Ñо акутна лимфоблаÑтна леукемија

Intensification of systemic chemotherapy with incinclusionof high doses methotrexate (MTX) has contributed to the improvement of event-free survival in children with acute lymphoblastic leukemia (ALL). Despite this benefit, this agent might cause serious toxicity, even life-treating events during treatment. Therefore, prediction, early detection and management of toxic effects during therapy with high doses of MTX is still a great challenge for every pediatric oncologist.The aim of our study was to evaluate the incidence of toxic effects of chemotherapy with high doses of MTX (5 g/m^2) and to compare them with toxicity during application of lower doses of MTX (2 g/m^2).Retrospective record review of 77 children with medium risk ALL was done. Patients were treated in the Department of hematology and oncology at the University children's hospital in Skopje. Forty-five of them were treated with 5 g/m^2 and 32 of them were treated with 2 g/m^2 (historic group). Toxicity was registered according to the protocol for acute toxicity, part of the ALL BFM 95 protocol.Toxic effects were predominant in the group treated with higher doses of MTX. The  most significant toxic  effects were hepatotoxicity, oral mucositis and myelosuppression.  More  severe grade of hepatotoxicity and oral mucositis were present in the study group. In our study toxic  effects were more common in the study group due to application of higher doses of MTX.Variations in toxicity between the patients of the study group are probably due  to the genetic differences in the drug absorption, their excretion and cellular transport. Current studies are dedicated on discovering genetic markers which will  be able  to predict the risk  of appearance of MTX toxicity.Intensification of systemic chemotherapy with in- clusion of high doses methotrexate (MTX) has contributed to the improvement of event-free survival in children with acute lymphoblastic leukemia (ALL). Despite this benefit, this agent might cause serious toxicity, even life-treating events during treatment. Therefore, prediction, early detection and management of toxic effects during therapy with high doses of MTX is still a great challenge for every pediatric oncologist.The aim of our study was to evaluate the incidence of toxic effects of chemotherapy with high doses of MTX (5 g/m2) and to compare them with toxicity during application of lower doses of MTX (2 g/m2).Retrospective record review of 77 children with medium risk ALL was done. Patients were treated in the Department of hematology and oncology at the University children's hospital in Skopje. Forty-five of them were treated with 5 g/m2 and 32 of them were treated with 2 g/m2 (historic group). Toxicity was registered according to the protocol for acute toxicity, part of the ALL BFM 95 protocol. Toxic effects were predominant in the group treated with higher doses of MTX. The  most significant toxic  effects were hepatotoxicity, oral mucositis and myelosuppression.  More  severe grade of hepatotoxicity and oral mucositis were present in the study group. In our study toxic  effects were more common in the study group due to application of higher doses of MTX. Variations in toxicity between the patients of the study group are probably due  to the genetic differences in the drug absorption, their excretion and cellular transport. Current studies are dedicated on discovering genetic markers which will  be able  to predict the risk  of appearance of MTX toxicity