PENGARUH POLIMORFISME GENA ASPARAGINE SYNTHETASE TERHADAP KEGAGALAN TERAPI PENDERITA LEUKEMIA LIMFOBLASTIK AKUT ANAK

RATIH HERNAWATI, DR.dr.Sri Mulatsih,Sp.A(K); dr. Sumadiono, SpA(K)

2015 | Tesis | S2 KEDOKTERAN KLINIK/MS-PPDS

Latar belakang: L-asparaginase merupakan salah satu dari berbagai macam obat anti kanker dalam protokol terapi pediatric ALL. Polimorfisme dari gena asparagine synthetase (ASNS), sebagai tandem repeated sequences, sebelumnya dilaporkan mempunyai kemampuan mengurangi aktivitas biologi dari L-asparaginase sehingga menginduksi kegagalan terapi. Tujuan : mengetahui hubungan antara polimorfisme gena ASNS dengan luaran terapi LLA. Metode : Anak dengan LLA yang dimondokkan ke bagian Anak RS Dr. Sardjito (Yogyakarta), Dr. Hasan Sadikin (Bandung), Dr. Moewardi (Solo), Dr. Kariadi (Semarang), and Dr. Soetomo (Surabaya) di Indonesia selama periode 2010-2011 dan mendapatkan protokol Indonesian ALL 2006 dimasukkan dalam penelitian. Kami meneliti pengaruh polimorfisme gena ASNS diantara anak-anak yang tidak mencapai remisi komplit atau relaps (sebagai kasus), dan anak dengan remisi komplit pada akhir fase induksi dan pasien yang telah selesai terapi dan masih hidup tanpa relaps (sebagai kontrol) terhadap luaran terapi. Adanya polimorfisme gena ASNS ditentukan dengan menggunakan metode PCR sebagaimana dijelaskan sebelumnya. Hasil : 123 anak dimasukkan dalam penelitian. Pada kelompok kasus didapatkan usia median 61 bulan (4-198), sementara kelompok kontrol 50 bulan (19-165). Tiga (2.4%) dari 123 anak mengalami drop out dan akhirnya dieksklusi. PCR dilakukan pada sampel sebanyak 120 anak. Hasil PCR hanya dapat diiterpretasikan pada 112 anak, terdiri dari 56 kasus dan 56 kontrol. Polimorfisme gena ASNS muncul pada 28 (50%) dari 56 kasus dan 22 (39,28%) dari 56 kontrol (P = 0,254). Kami meneliti klasifikasi risiko, angka lekosit dan polimorfisme gena ASNS, namun tidak ada hasil yang bermakna pada ketiga variabel tersebut. Anak dengan LLA yang memiliki polimorfisme gena ASNS tidak berpengaruh pada kegagalan terapi (OR = 1,545; 95% CI, 0,730-3,271; P = 0,254). Kesimpulan : Tidak ditemukan adanya hubungan antara polimorfisme gena ASNS dengan kegagalan terapi pada anak dengan LLA yang menerima protokol Indonesian ALL 2006. Penelitian klinis yang bermakna membutuhkan penelitian lebih lanjut.

Background L-asparaginase is one of the anti-neoplastic agents, which constitute various treatment protocols of pediatric acute lymphoblastic leukemia (ALL). Polymorphisms of the asparagine synthetase (ASNS) gene, as tandem repeated sequences, reportedly has the capability of reducing the biologic activity of L-asparaginase and therefore, induce treatment failure. The present study aimed to determine the relationship between polymorphisms of the ASNS gene and the outcome of pediatric ALL treatment. Methods Children with ALL, who had been admitted to the Department of Child Health, Dr. Sardjito (Yogyakarta), Dr. Hasan Sadikin (Bandung), Dr. Moewardi (Solo), Dr. Kariadi (Semarang), and Dr. Soetomo (Surabaya) General Hospitals in Indonesia during the period of 2010-2011 and received the Indonesian ALL 2006 protocol, were enrolled in this study. We investigated the influence of the ASNS gene polymorphisms between children, who did not achieve complete remission (CR) or relaps (cases), and children with CR in the end of induction phase of treatment and successfully treated patients which lived without relapsed (controls) toward the outcome of pediatric ALL treatment. Presence of the ASNS gene polymorphisms was determined using the previously described, PCR-based methods. Results A total of 123 children were enrolled in the present study. Case children had the median age of 61 months (range, 4-198), while control children were 50 months (range, 19-165). Three (2.4%) of 123 children dropped out and therefore, were excluded. PCR was performed on samples obtained from the remaining 120 children. PCR findings were only interpretable in 112 children, which consisted of 56 case and 56 control children. Presence of the ASNS gene polymorphisms was observed in 28 (50%) of 56 case and 22 (39,28%) of 56 control children (P = 0,254). We investigated disease risk classification, white blood cell count and polymorphisms of the ASNS gene, the result was none of them had statistic significances. Children with polymorphism of ASNS gene did not have influence to treatment failure (OR, 1.545; 95% CI, 0.730-3.271; P = 0.254). Conclusion There was no relationship between the presence of polymorphisms of the ASNS gene and treatment failure in pediatric ALL receiving anti-leukemic treatment with the Indonesian ALL 2006 protocol. Clinical significance in ALL requires further studies.

Kata Kunci : polymorphisms, ASNS, childhood ALL