Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine.
OBJECTIVE
To assess thiopurine S-methyltransferase (TPMT) phenotype and genotype in patients who were intolerant to treatment with mercaptopurine (MP) or azathioprine (AZA), and to evaluate their clinical management.


METHODS
TPMT phenotype and thiopurine metabolism were assessed in all patients referred between 1994 and 1999 for evaluation of excessive toxicity while receiving MP or AZA. TPMT activity was measured by radiochemical analysis, TPMT genotype was determined by mutation-specific polymerase chain reaction restriction fragment length polymorphism analyses for the TPMT*2, *3A, *3B, and *3C alleles, and thiopurine metabolites were measured by high-performance liquid chromatography.


RESULTS
Of 23 patients evaluated, six had TPMT deficiency (activity < 5 U/mL of packed RBCs [pRBCs]; homozygous mutant), nine had intermediate TPMT activity (5 to 13 U/mL of pRBCs; heterozygotes), and eight had high TPMT activity (> 13.5 U/mL of pRBCs; homozygous wildtype). The 65.2% frequency of TPMT-deficient and heterozygous individuals among these toxic patients is significantly greater than the expected 10% frequency in the general population (P <.001, chi(2)). TPMT phenotype and genotype were concordant in all TPMT-deficient and all homozygous-wildtype patients, whereas five patients with heterozygous phenotypes did not have a TPMT mutation detected. Before thiopurine dosage adjustments, TPMT-deficient patients experienced more frequent hospitalization, more platelet transfusions, and more missed doses of chemotherapy. Hematologic toxicity occurred in more than 90% of patients, whereas hepatotoxicity occurred in six patients (26%). Both patients who presented with only hepatic toxicity had a homozygous-wildtype TPMT phenotype. After adjustment of thiopurine dosages, the TPMT-deficient and heterozygous patients tolerated therapy without acute toxicity.


CONCLUSIONS
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.
Evans
W E
WE
St Jude Children's Research Hospital and University of Tennessee, Memphis 38101-0318, USA. william.evans@stjude.org
Hon
Y Y
YY
Bomgaars
L
L
Coutre
S
S
Holdsworth
M
M
Janco
R
R
Kalwinsky
D
D
Keller
F
F
Khatib
Z
Z
Margolin
J
J
Murray
J
J
Quinn
J
J
Ravindranath
Y
Y
Ritchey
K
K
Roberts
W
W
Rogers
Z R
ZR
Schiff
D
D
Steuber
C
C
Tucci
F
F
Kornegay
N
N
Krynetski
E Y
EY
Relling
M V
MV
D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001379:Azathioprine / Q000009:adverse effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005838:Genotype; D006760:Hospitalization; D006801:Humans; D007223:Infant; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects*; D008780:Methyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy; D010641:Phenotype; D017713:Platelet Transfusion; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000235:genetics
D000964:Antimetabolites, Antineoplastic; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine