Disertasi

Hubungan Kekambuhan Pasien Anak Leukemia Limfoblastik Akut terkait Terapi Vinkristin dengan Polimorfisme Gen Multidrug Resistance 1. = The Association of Relapse in Childhood Acute-Lymphoblastic Leukemia-Related Vincristine Therapy with Polymorphisms of Multidrug Resistance 1.

Latar Belakang: Di Indonesia diperkirakan terdapat 4100 kasus baru kanker anak setiap tahunnya. Kejadian paling banyak adalah leukemia limfoblastik akut (LLA) sebesar 80%. Permasalahannya adalah angka kejadian kekambuhan pasien anak cukup tinggi sekitar 20-40%. Data pasien anak di Bagian Hematologi/Onkologi Departemen Ilmu Kesehatan Anak RSCM/FKUI periode tahun 2005-2011 kejadian kambuh mencapai 40%. Tujuan penelitian ini adalah mengetahui apakah ada hubungan kekambuhan pasien anak LLA terkait terapi vinkristin dengan polimorfisme gen MDR1. Metode: Studi dilakukan di Departemen Ilmu Kesehatan Anak RSCM/FKUI selama periode Februari 2014 sampai Januari 2015 dengan disain penelitian cohort. Kriteria pasien dengan LLA berusia lebih dari satu tahun hingga usia kurang dari 18 tahun. Sampel adalah pasien baru didiagnosis LLA dan pasien sedang menjalani kemoterapi fase induksi. Pemeriksaan sensitifitas obat in vitro dari sampel darah metode flow cytometry dengan menghitung Leukemia Cell Survival Index (LCSI). Penelitian pendahuluan gen MDR1 dengan RFLP dan polimorfisme dengan Multiplex PCR. Data klinis pasien dilihat secara retrospektif dari catatan medis. Inform consent diperoleh dari pasien atau orang tua pasien. Hasil: Sampel memenuhi kriteria inklusi sebanyak 101 pasien terdiri dari 63 (62.4%) laki-laki dan 38 (37.6%) perempuan. Kekambuhan pasien anak LLA dipengaruhi oleh faktor usia,kelompok risiko dan jumlah lekosit (p < 0.05). Kekambuhan tidak dipengaruhi oleh jenis kelamin, imunofenotip, tipe LLA, dan sel blast. Hasil sensitivitas vinkristin sebesar 46.2% sensitif dengan nilai rata-rata LCSI sebesar 32.1%. Polimorfisme gen MDR1 dengan multiplex PCR menunjukkan alel T lebih dominan dibandingkan alel C ( 50.46% vs 31,25%). Pasien anak LLA risiko tinggi yang mempunyai gen MDR1 G2677T genotip GT, C1236T genotip TT dan C3435T genotip TT bermakna menyebabkan kekambuhan (p < 0.05). Simpulan: Risiko kekambuhan pada pasien anak LLA adalah multifaktorial. Tidak ada faktor yang kuat menjadi penyebab kekambuhan. Pola polimorfisme gen MDR1 pada pasien anak LLA di RSCM dapat digunakan untuk meningkatkan hasil terapi.
Kata kunci: leukemia limfoblastik akut, kambuh, gen MDR1, polimorfisme, sensitivitas, leukemia cell survival index.



Background: There are an estimated 4100 new cases of childhood cancer each year in Indonesia. The most common cancer in children is acute lymphoblastic leukemia (ALL) which is approximately 80%. The problem faced is the incidence of relapse in children is quite high, about 20-40%. Data from Hematology-Oncology Division of Child Health Department RSCM/FKUI period 2005-2011, showed that the incidence of relapse reached 40%. The purpose of this study is to investigate whether there is an association of polymorphism related to vincristine therapy. Methods: The study was conducted in the Child Health Department RSCM/FKUI with cohort design from February 2014 to January 2015. The number of patients with ALL included in the study was 101. The patients participated in the study were 1-18 years old, newly diagnosed of ALL, and undergoing chemotherapy induction phase. In vitro examination of drug sensitivity from blood samples was conducted using flow cytometry to determine leukemia cell survival index (LCSI). The preliminary study was done by RFLP and polymorphism by Multiplex PCR. Clinical data of patients were obtained retrospectively from medical records.The informed consent was obtained from the patient or the patient's parents. Results: From 101 patients, there were 63 male (62.4%) and 38 female (37.6%). The occurence of relapse of ALL patients was affected by age, risk group and leukocyte count (p < 0.05). The relapse was not influenced by sex, immunophenotype, ALL- type, and blast cell. Upon sensitivity examination to vincristine, there were as much as 46.2% sensitive cases with the average of LCSI of 32.1%. Among several risk factors which were associated with relapse, there was none to be a major one. MDR1 gene polymorphism with multiplex PCR showed that the T allele was more dominant than the C allele (50.46% vs 31.25%).The high-risk pediatric ALL patients with MDR1 gene G2677T GT genotype, C1236T and C3435T TT genotypes were found to correlated significantly to relapse (p < 0.05). Conclusions: The risk of relapse in pediatric patients with ALL is multifactorial. The data on patterns of MDR1 gene polymorphism in pediatric patients in RSCM obtained in the present study might be used to optimize the success rate of ALL treatment.
Keywords: acute lymphoblastic leukemia, relapse, MDR1 gene, polymorphism, sensitivity, leukemia cell survival index.