Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine

W. E. Evans, Yi Hon Yuen Yi Hon, L. Bomgaars, S. Coutre, M. Holdsworth, R. Janco, D. Kalwinsky, F. Keller, Z. Khatib, J. Margolin, J. Murray, J. Quinn, Y. Ravindranath, K. Ritchey, W. Roberts, Z. R. Rogers, D. Schiff, C. Steuber, F. Tucci, N. KornegayE. Y. Krynetski, M. V. Relling

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Abstract

Purpose: 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. Patients and 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, x2). 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)2293-2301
Number of pages9
JournalJournal of Clinical Oncology
Volume19
Issue number8
StatePublished - Apr 15 2001

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thiopurine methyltransferase
6-Mercaptopurine
Azathioprine
Genotype
Phenotype
Poisons
Thiopurine S methyltranferase deficiency
Restriction Fragment Length Polymorphisms
Alleles
High Pressure Liquid Chromatography

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Evans, W. E., Yuen Yi Hon, Y. H., Bomgaars, L., Coutre, S., Holdsworth, M., Janco, R., ... Relling, M. V. (2001). Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. Journal of Clinical Oncology, 19(8), 2293-2301.

Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. / Evans, W. E.; Yuen Yi Hon, Yi Hon; Bomgaars, L.; Coutre, S.; Holdsworth, M.; Janco, R.; Kalwinsky, D.; Keller, F.; Khatib, Z.; Margolin, J.; Murray, J.; Quinn, J.; Ravindranath, Y.; Ritchey, K.; Roberts, W.; Rogers, Z. R.; Schiff, D.; Steuber, C.; Tucci, F.; Kornegay, N.; Krynetski, E. Y.; Relling, M. V.

In: Journal of Clinical Oncology, Vol. 19, No. 8, 15.04.2001, p. 2293-2301.

Research output: Contribution to journalArticle

Evans, WE, Yuen Yi Hon, YH, Bomgaars, L, Coutre, S, Holdsworth, M, Janco, R, Kalwinsky, D, Keller, F, Khatib, Z, Margolin, J, Murray, J, Quinn, J, Ravindranath, Y, Ritchey, K, Roberts, W, Rogers, ZR, Schiff, D, Steuber, C, Tucci, F, Kornegay, N, Krynetski, EY & Relling, MV 2001, 'Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine', Journal of Clinical Oncology, vol. 19, no. 8, pp. 2293-2301.
Evans, W. E. ; Yuen Yi Hon, Yi Hon ; Bomgaars, L. ; Coutre, S. ; Holdsworth, M. ; Janco, R. ; Kalwinsky, D. ; Keller, F. ; Khatib, Z. ; Margolin, J. ; Murray, J. ; Quinn, J. ; Ravindranath, Y. ; Ritchey, K. ; Roberts, W. ; Rogers, Z. R. ; Schiff, D. ; Steuber, C. ; Tucci, F. ; Kornegay, N. ; Krynetski, E. Y. ; Relling, M. V. / Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. In: Journal of Clinical Oncology. 2001 ; Vol. 19, No. 8. pp. 2293-2301.
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title = "Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine",
abstract = "Purpose: 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. Patients and 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, x2). 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. Conclusion: 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.",
author = "Evans, {W. E.} and {Yuen Yi Hon}, {Yi Hon} and L. Bomgaars and S. Coutre and M. Holdsworth and R. Janco and D. Kalwinsky and F. Keller and Z. Khatib and J. Margolin and J. Murray and J. Quinn and Y. Ravindranath and K. Ritchey and W. Roberts and Rogers, {Z. R.} and D. Schiff and C. Steuber and F. Tucci and N. Kornegay and Krynetski, {E. Y.} and Relling, {M. V.}",
year = "2001",
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TY - JOUR

T1 - Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine

AU - Evans, W. E.

AU - Yuen Yi Hon, Yi Hon

AU - Bomgaars, L.

AU - Coutre, S.

AU - Holdsworth, M.

AU - Janco, R.

AU - Kalwinsky, D.

AU - Keller, F.

AU - Khatib, Z.

AU - Margolin, J.

AU - Murray, J.

AU - Quinn, J.

AU - Ravindranath, Y.

AU - Ritchey, K.

AU - Roberts, W.

AU - Rogers, Z. R.

AU - Schiff, D.

AU - Steuber, C.

AU - Tucci, F.

AU - Kornegay, N.

AU - Krynetski, E. Y.

AU - Relling, M. V.

PY - 2001/4/15

Y1 - 2001/4/15

N2 - Purpose: 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. Patients and 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, x2). 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. Conclusion: 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.

AB - Purpose: 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. Patients and 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, x2). 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. Conclusion: 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.

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