TPMP 변이 유전형을 가진 소아 급성림프모구백혈병 환자에서의 맞춤 유지 치료
Adaptation of ALL maintenance treatment in TPMT variant genotype patients
Abstract
Introduction Thiopurine S-methyltransferase (TPMT) is one of the key enzymes involving the metabolism of thiopurine drugs, which is widely used in the treatment of pediatric acute lymphoblastic leukemia (ALL). 6-Mercaptopurine (6-MP) is converted into metabolites such as 6-thioguainine nucleotides (6-TGN) and 6-methylmercaptopurine (6-MeMPN) by TPMT intracellularly. The purpose of this study was to evaluate the 6MP treatment and metabolites during the maintenance period in patients with TPMT variant genotype. Patients and Methods The results of the TPMT tests among the patients diagnosed with cancer in pediatric department were collected. In patients with the TPMT variant genotype, clinical data were collected on diagnosis, 6MP dosage, 6-TGN, 6-MeMPN, survival and treatment-related toxicity. Results TPMT genotype was tested in 655 childhood cancer patients. Among these, 627 (95.7%) were wild type, 27 (4.1%) had single variant allele, and 1 patient had variants on both allele (*3/*3). Of the 28 patients with TPMT variant genotype, 13 patients underwent leukemia maintenance chemotherapy with 6-mercaptopurine. Eight patients were *1/*3 heterozygote, 2 patients were *1/*6 heterozygote, 1 patient was *3/*3 homozygote, and 2 patients were *1/? novel allele heterozygote genotype. (each, c.532T>C and c.340G>A) Median 6-MP dose at the start and end of maintenance treatment was 20.7 and 24.8 mg/msup>2/sup>/day, respectively. In 8 patients, the dose of 6-MP was increased during treatment, but in 4 patients (including the *3/*3 variant patient), 6-MP dose was decreased due to recurrent cytopenia or high 6-TGN levels. The median 6-TGN/6MP dose ratio of TPMT variant heterozygote patients was 50.9 (range, 10.3-97.7), which was higher than previous reported ratio of TPMT non-variant patients. The median 6-MeMPN/6-TGN ratio representing the TPMT activity was 1, lower than previously reported in non-TPMT variant patients. (range, 0-22) Neutropenic fever occurred in 3 of 13 patients. Three herpes zoster, and one chickenpox occurred during maintenance treatment. All infections were treated without complications. Discussion 6-MP dose during maintenance treatment could be increased safely with monitoring of 6-TGN and 6-MeMPN level in TPMT variant ALL patients. In the future, efforts will be made to increase the accuracy of predictions by measuring DNA-TGN.