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Therapy

Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine

Leukemia volume 15, pages 1706–1712 (2001)Cite this article

Abstract

6-Mercaptopurine (6-MP) is metabolized by thiopurine S-methyltransferase (TPMT), an enzyme subject to genetic polymorphism. We investigated the relationships between the TPMT locus (TPMT activity and genotype) and the pharmacological response to 6-MP during maintenance therapy of 78 children with acute lymphoblastic leukemia (ALL). For each patient, 6-MP dosage, leukocyte counts and occurrence of infectious episodes were monitored on an 8 week basis. Higher 6-MP dosage was associated with higher TPMT activity (P = 0.03) and higher average leukocyte counts (P < 0.01). Eight patients (10%) carrying a TPMT mutant genotype (one homozygous and seven heterozygous) received lower 6-MP doses (average: 48 vs 65 mg/m2/day; P = 0.02) and had on average lower leukocyte counts (2834 vs 3398 cells/mm3; P = 0.003) than patients carrying the wild-type TPMT genotype. Higher occurrence of infectious episodes graded 2 or 3 was correlated with higher 6-MP dosage (P < 0.01) but no difference was observed between TPMT mutants and TPMT wild-type patients. Patients who received 6-MP dosage above the group median (62 mg/m2/day) or having a TPMT activity above the group median (21.5 nmol/h/ml) had a higher percentage of 8 week periods with infectious episodes requiring treatment (34% vs 17% and 33% vs 19%, respectively) than those with 6-MP dose or TPMT activity below the group median (P < 0.01). In the last 25 patients enrolled in the study, steady-state erythrocyte thioguanine nucleotide (TGN) concentrations were associated with lower leukocyte counts (P = 0.01) but not with a higher occurrence of infectious episodes. In contrast, higher steady-state erythrocyte methylmercaptopurine nucleotide (MeMPN) concentrations were associated with higher 6-MP dosage (P < 0.01) and higher occurrence of infectious episodes (P < 0.001). In conclusion, during maintenance therapy of ALL, children with higher TPMT activity receive a higher 6-MP dosage and may have infectious episodes caused by metabolism of 6-MP into methylmercaptopurine nucleotides.

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Acknowledgements

We thank the patients and their parents for participating in this study, and the nurses for taking care of the patients. We also thank Caroline Delnevo for secretarial assistance. This work was supported by grants from AFSSAPS (Agence Française de Sécurité Sanitaire des Produits de Santé) and INSERM (Institut National de la Santé et de la Recherche Médicale).

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Authors and Affiliations

  1. Service de Pharmacologie Pédiatrique et Pharmacogénétique, Hôpital Robert Debré, Paris, France

    T Dervieux, Y Médard, V Guigonis & E Jacqz-Aigrain

  2. Departement de Biostatistique et Epidémiologie, Groupe Hospitalier Bichat, Paris, France

    P Verpillat

  3. Service d'Hémato-Immunologie, Hôpital Robert Debré, Paris, France

    M Duval, B Lescoeur & E Vilmer

  4. European Organization for Research and Treatment of Cancer (EORTC), Brussels, Belgium

    S Suciu

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Dervieux, T., Médard, Y., Verpillat, P. et al. Possible implication of thiopurine S-methyltransferase in occurrence of infectious episodes during maintenance therapy for childhood lymphoblastic leukemia with mercaptopurine. Leukemia 15, 1706–1712 (2001). https://doi.org/10.1038/sj.leu.2402259

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