ALL-051: The Influence of Thiopurine Methyltransferase Gene Polymorphism on Egyptian Children with Acute Lymphoblastic Leukaemia

Abstract

Context Gene polymorphisms involved in thiopurine methyltransferase (TPMT) transport, metabolism, or targeting are responsible for the variable drug response and regulates thiopurine therapeutic efficacy and toxicity. Objective To determine the frequency of TPMT gene polymorphism in Egyptian children with acute lymphoblastic leukaemia (ALL) and its influence on chemotherapy response and toxicity. This may allow identify patients who are at high risk for developing toxicity based on each patient's genetic constitution to individualized drug treatment. Design Paediatric patients with ALL, who were treated with BFM 90 or CCG 1991 standard risk protocol, and who experienced myelosuppression toxicity and required interruption and/or modification of thiopurine chemotherapy were recruited over a one-year period. Seventy healthy age- and sex-matched children served as controls. They subjected to clinical assessment, haematological panel investigations, and TPMT gene polymorphism for G238C, G460A, and A719G alleles assessment using PCR followed by RFLP analysis. Results Sixty-four ALL patients out of 150 who were regularly attending pediatric Hematology/Oncology clinic were recruited. The male: female ratio was 40 (62.5%): 24 (37.5%) and their mean age was 6.16 ± 3.16 years. Their diagnosis was T lineage (27%) and pre-B phenotype (73%). Thirty-two patients were on maintenance and another thirty-two were finished with their chemotherapy. Among the 64 patients and 70 control (288 examined allies), neither the studied leukemic patients nor the controls had the mutant TPMT variant alleles in either homozygous or heterozygous form. Myelosuppression toxicity in form of different degrees of neutropenia was detected in all patients, necessitating 6-MP dose modification for most of patients, either once (53.1%), twice (15.6%), or ≥three times (25.1%) during their maintenance course. Patients required stopping 6-MP for less than a week (62.5%), up to 2 weeks (28.1%), or >2 weeks (6.3%). Patients also developed infection that mostly (71%) necessitated hospitalization. Infections and febrile neutropenia were common causes of 6-MP dose modification and interruption. Conclusions The absence of any allelic variation responsible for the low TPMT activity in the studied leukemic patients, together with the fact that patients experienced signs of myelosuppression toxicity during the course of chemotherapy; would suggest the existence of additional factors in the development of 6-MP cytotoxicity.