Thiopurine methyltransferase polymorphisms in children with acute lymphoblastic leukemia.

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. 6-mercaptopurine (6-MP) and methotrexate are backbone drugs for maintenance phase of treatment. Purine Analogs 6-MP/6-thioguanine/azathiopurine are metabolized to its inactive form by the enzyme thiopurine methyltransferase (TPMT). Ninety percent of the population harbor wild type on both alleles (TPMT wild/wild), 10% are heterozygous, that is, one allele is mutant (TPMT wild/mutant) and 0.3% are homozygous, that is, both allele are mutant (TPMT mutant/mutant). In heterozygous and homozygous variant, activity of enzyme is low, leading to a higher incidence of toxicity (myelosuppression).

AIM

The primary objective was to access the polymorphism of the enzyme, TPMT, in Children with ALL. Secondary objective was to correlate TPMT genotype with 6-MP toxicities.

MATERIALS AND METHODS

Seventy-two children with newly diagnosed ALL during first maintenance phase were serially enrolled after obtaining consent. Five ml of peripheral blood was drawn and DNA extracted. TPMT 2 polymorphisms were performed using Allele specific polymerase chain reaction (PCR) and TPMT 3B and 3C are performed by PCR-restriction fragment length polymorphism.

RESULTS

Sixty-nine children of 72 (95.8%) were wild for TPMT polymorphism and 3 (4.2%) were heterozygous for TPMT. Among the heterozygous variant one each (33.3%) were heterozygous for 2A, 3A, 3C. Febrile neutropenia was the most common toxicity in both wild and heterozygous group.

CONCLUSION

The frequency of TPMT polymorphisms in children with ALL is 4.2%. Heterozygous variant is this study are one each (33%) of 2A, 3A, 3C.