The Role of TPMT and NUDT-15 Genetic Polymorphisms in 6-Mercaptopurine Dose Tolerability among Pediatric B-Cell ALL Patients in Saudi Arabia

Introduction: 6-MP is an essential antimetabolite used during the maintenance phase of acute lymphoblastic leukemia (ALL) therapy.Children from various regions, including Saudi Arabia, have been reported to exhibit lower dose tolerance for 6-MP.The (COG) protocols standardize the 6-MP starting dose at 75 mg/m2/day.This study investigates the impact of (TPMT) and (NUDT-15) polymorphisms on drug dose tolerability in children with B-cell ALL in Saudi Arabia. Methodology:We prospectively assessed 146 pediatric ALL patients treated on COG-adapted protocols from six centers across Saudi Arabia, focusing on 82 with available DNA samples.Genetic sequencing of four TPMT and two NUDT15 variant alleles was performed using Sanger sequencing.The relationship between these genetic polymorphisms and 6-MP dose tolerability was analyzed.Results: Among patients with intronic TPMT variant allele (Type A, rs2518463), 56 of 81 (69.1%) were heterozygous, requiring a median 6-MP dose reduction of 43.1%, whereas 30.9% with negative polymorphism needed a 29.7% reduction (P=0.894).TPMT variant allele (Type B, rs2842934) was present in 76 of 81 (93.8%) patients; 56.8% were homozygous, necessitating a 46.7% reduction, and 37% were heterozygous, needing a 33.3% reduction (P=0.687).