Preponderance of Thiopurine S-Methyltransferase Deficiency and Heterozygosity Among Patients Intolerant to Mercaptopurine or Azathioprine

Abstract

There is a significant (> six-fold) overrepresentation of TPMT deficiency or heterozygosity among patients developing dose-limiting hematopoietic toxicity from therapy containing thiopurines. However, with appropriate dosage adjustments, TPMT-deficient and heterozygous patients can be treated with thiopurines, without acute dose-limiting toxicity.

Pharmacogenomics: Challenges and Opportunities

“…Rare individuals who are homozygous for loss of function variants are at high risk for bone marrow aplasia during therapy with standard doses, and this is stated in the package label. Ten percent of persons carry a single abnormal allele and are also at increased risk for bone marrow toxicity (18,19). Conversely, "standard" doses of mercaptopurine that are used in the 90% of patients with functional alleles mutations (see Glossary) may in fact be inadequate for achieving an optimal antileukemic effect (20).…”

Clinical significance of polymorphism of thiopurine methyltransferase gene in children with acute lymphoblastic leukemia during programmed therapy

“…Генетический полиморфизм ТРМТ представляет собой наиболее частый вариант, влияющий на метаболизм так называемых тиопури-нов, включая 6-MP. Полиморфизм может приводить к значительному снижению активности фермента и повышению риска лейкопении, ассоциированной с лечением [23][24][25][26]. В настоящее время известно бо-лее 20 генетических вариантов с низкой функцио-нальной активностью ТРМТ, 2 из которых -ТРМТ*2…”

A novel TPMT missense mutation associated with TPMT deficiency in a 5-year-old boy with ALL

“…These patients are at a high risk of developing severe and potentially fatal haematopoietic toxicity after treatment with standard doses of thiopurines caused by an accumulation of 6-TGN metabolites. [3][4][5] Furthermore, children with ALL heterozygous for TPMT, constituting about 10% of Caucasian and AfricanAmerican populations, are also at greater risk of thiopurine haematotoxicity. 4 Prospective measurement of erythrocyte TPMT activity is therefore emerging as a routine safety measure prior to therapy to avoid toxicity.…”