Thiopurine S-Methyltransferase Gene Polymorphism Is Predictive of Azathioprine-Induced Myelosuppression in Heart Transplant Recipients

Abstract

Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-methyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with four prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G460A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transplant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation-specific polymerase chain reaction-based methods) was observed in four patients (A719G: n = 2; A719G plus G460: n = 2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutation A719G and there was a 40% drop in neutrophils in the two other patients. Discontinuation of AZA in the four mutant patients corrected for the drop. Presence of TPMT mutations is associated with a greater likelihood of agranulocytosis. Determination of these mutations could reduce the risk for hematological side-effects.

Thiopurine S-Methyltransferase Genotype Predicts Azathioprine-Induced Myelotoxicity in Kidney Transplant Recipients

“…Stringent study inclusion criteria were employed and only those individuals who were able to tolerate AZA for 30 days duration were evaluated for associations between TPMT genotype and biochemical and clinical data. Consequently, this study population did not demonstrate a high frequency of adverse drug reactions including neutropenia and thrombocytopenia, in contrast to patients in other pharmacogenetic studies who were unable to tolerate AZA or 6MP and required reduced dosages or discontinuation of therapy (4,(10)(11)(12)30). As a retrospective study neither intended to examine nor powered to determine differences in PTA, this study has identified that individuals with a detected TPMT mutation had a higher likelihood to have changes in erythroid indices that was not associated with AZA dose or cyclosporinemia.…”

“…Azathioprine can cause bone marrow suppression and has been associated with leukopenia, thrombocytopenia, macrocytosis without megaloblastic anemia and rarely pure red cell aplasia (29). Individuals with genetic mutations of the TPMT enzyme inadvertently initiated on azathioprine or 6MP therapy have manifested clinical intolerance resulting in reduction or discontinuation of azathioprine dosages (4,(10)(11)(12)30).…”

Drug Therapy in the Heart Transplant Recipient

“…54 It is expected that the therapeutic benefits and side-effect profiles for RAD will be similar to those for SIR. [55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73] …”

From Pharmacokinetics to Pharmacogenomics: A New Approach to Tailor Immunosuppressive Therapy

“…TPMT * 1 is the most common allele (wild type), whereas three mutant alleles, namely TPMT * 2 (G238C substitution) and TPMT * 3 (A719G and/or G460A), are responsible for the trimodal frequency distribution of TPMT activity in the white population (40). The presence of both these mutations (TPMT * 2 and 3) was associated with a greater likelihood of myelosuppression in a group of 30 heart transplant recipients (41). Interestingly, agranulocytosis did not occur in patients with the wild genotype, but in those carrying the TPMT3/A719G mutation.…”

“…Interestingly, agranulocytosis did not occur in patients with the wild genotype, but in those carrying the TPMT3/A719G mutation. Thus, patients with reduced TPMT activity are at risk of excessive toxicity, including fatal myelosuppression, after receiving standard doses of AZA (41,42). On the other hand, those patients with increased TPMT activity could no longer benefit from AZA treatment.…”