OP02. OPTIMIZATION OF THERAPY FOR THIOPURINE S-METHYL-TRANSFERASE DEFICIENT CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA PATIENTS
S. AVEIC 1, B. Petrucev 1, L. Dokmanovic 2, M. Radmilovic 1, N. Tosic 1, M. Stojiljkovic 1, T. Karan-Djurasevic 1, T. Kostic 1, D. Janic 2, S. Pavlovic 1 1 Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia and Montenegro 2 University Children's Hospital, Belgrade, Serbia and Montenegro email: zmzg@sezampro.yu
*Corresponding Author:
page: 35

Abstract

Thiopurine S-methyltransferase (TPMT) enzyme inactivates thiopurine drugs (6-mercaptopurine, 6-MP), used in childhood acute lymphoblastic leukemia (ALL) treatment. Patients with low TPMT activity experience severe hematological toxicity when standard 6-MP doses are used. Lower TPMT activity can be due to TPMT gene mutations. Three alleles account for more than 95% of the clinically relevant TPMT variants: TPMT*2, TPMT*3A and TPMT*3C. Wild type is designed as TPMT*1. The purpose of this study was to determine the relevance of TPMT genotype in the management of childhood ALL. Blood samples from 100 ALL children were analyzed for TPMT mutations using PCR-based assays: 89% were homozygous for TPMT*1 (W/W), 10% were heterozygous (W/M): 9% for TPMT*1/*3A, 1% for TPMT*1/*2. One patient was double heterozygous for TPMT*3A/*3B (M/M). For 50 patients TPMT variant alleles were determined retrospectively, after completing the maintenance therapy. For the other 50 patients TPMT variant alleles where determined prospectively. Therapy protocol was modified for W/M patients prospectively analyzed in a way that from the initiatial phase of the maintenance therapy the dose of 6-MP was reduced. In contrast to W/M patients retrospectively analyzed, they neither missed the therapy nor developed neutropenia. Even W/M TPMT patients are at risk of developing thiopurine drug-related leucopenia. Lowering doses of 6-MP in these patients while allowing administration of full dose of metotrexate, might be an optimal way of treatment. These results justify performing TPMT genotyping before initiating thiopurine therapy in all ALL children. They also strongly support the concept of medicine based on pharmacogenetics.




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