Effect of methotrexate polyglutamates on thioguanine nucleotide concentrations during continuation therapy of acute lymphoblastic leukemia with mercaptopurine
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Mercaptopurine
Acute lymphocytic leukemia
Hematology
The antimetabolite mercaptopurine is commonly used as part of treatment regimens for acute lymphoblastic leukemia and as treatment for inflammatory bowel diseases. Adverse effects associated with mercaptopurine include myelosuppression, hepatotoxicity, and hyperpigmentation. We describe a 36-year-old man with Philadelphia chromosome-negative pre-B-cell acute lymphoblastic leukemia who experienced a serious mercaptopurine-induced hypersensitivity reaction requiring prolonged hospitalization and extensive laboratory testing and imaging. He was treated with a multiagent chemotherapy regimen. Mercaptopurine 60 mg/m(2)/day orally was started as part of his third course of chemotherapy. On day 9 of mercaptopurine therapy, the patient developed persistent fevers, skaking chills, and rigors that persisted in the absence of documented infection, consistent with drug fever. All symptoms and signs resolved after discontinuation of mercaptopurine. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship between the patient's development of fever and mercaptopurine therapy. Mercaptopurine-induced fever has been reported in patients with inflammatory bowel diseases, but this case report is the first, to our knowledge, in a patient with acute lymphoblastic leukemia. Health care professionals should be aware of the possible development of fever as a hypersensitivity reaction in patients with acute lymphoblastic leukemia treated with mercaptopurine.
Mercaptopurine
Chills
Discontinuation
Acute lymphocytic leukemia
Adverse drug reaction
Regimen
Hypersensitivity reaction
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Mercaptopurine
Acute lymphocytic leukemia
Hematology
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Mercaptopurine
Acute lymphocytic leukemia
Pharmacodynamics
Regimen
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Mercaptopurine
Thiopurine methyltransferase
Acute lymphocytic leukemia
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Mercaptopurine is used to treat children with acute lymphoblastic leukemia. Mercaptopurine can cause bone marrow suppression and liver toxicity, threatening the lives of children, resulting in interruption or discontinuation of the chemotherapy, increasing the risk of disease recurrence. The mercaptopurine dosage regimens should be adjusted according to drug metabolizing enzyme genotypes, detection of intra-erythrocytic metabolic products, and creating a physical model. Individualized administration should be adopted in order to improve the efficacy and safety of mercaptopurine.
Key words:
6-mercaptopurine; Leukemia, lymphoid; Individualized medicine
Mercaptopurine
Discontinuation
Acute lymphocytic leukemia
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Mercaptopurine
Acute lymphocytic leukemia
Pharmacodynamics
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Mercaptopurine
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Background: Methotrexate is postulated to enhance mercaptopurine activation to thioguanine (INN, tioguanine) nucleotides, but the interaction has never been studied in vivo in cancer cells. Methods: We investigated the effect of methotrexate on mercaptopurine disposition in plasma and leukemic blasts during up-front treatment of 233 children with newly diagnosed acute lymphoblastic leukemia. Children were randomized to receive intravenous mercaptopurine (1 g/m2 over a 6-hour period) or to receive methotrexate (low dose, 6 oral doses of 30 mg/m2, or high dose, 1 g/m2 intravenously), followed by intravenous mercaptopurine. All combinations have been previously used in frontline trials for acute lymphoblastic leukemia. Results: Compared with mercaptopurine alone, methotrexate resulted in higher plasma mercaptopurine concentrations (30.3 ± 14.7 μmol/L versus 23.5 ± 18.0 μmol/L, P < .001) but, conversely, a 13-fold lower thioguanine nucleotide concentration (0.57 ± 0.66 pmol/5 × 106 cells versus 7.4 ± 15.2 pmol/5 × 106 cells, P < .001) in bone marrow leukemic lymphoblasts. Methotrexate was also associated with higher plasma hypoxanthine concentrations compared with those of patients given mercaptopurine alone (8.7 ± 13.5 μmol/L versus 3.8 ± 2.5 μmol/L, P = .029). The percentage change in leukocyte counts measured over a 3-day period showed that mercaptopurine alone had little effect (mean decrease, 20% ± 33%). In contrast, despite causing lower intracellular thiopurine active metabolite concentrations, methotrexate produced a greater decrease in leukocyte counts (mean, 53% ± 35%) compared with those in patients receiving mercaptopurine alone (P < .0001). Conclusion: These pharmacologic findings in the target tissue are consistent with the recently demonstrated lack of clinical benefit of intravenous mercaptopurine in combination with methotrexate. We conclude that, in the setting of newly diagnosed acute lymphoblastic leukemia, methotrexate antagonizes thiopurine metabolite disposition in leukemic blasts after intravenous mercaptopurine. Clinical Pharmacology & Therapeutics (2003) 73, 506–516; doi: 10.1016/S0009-9236(03)00063-8
Mercaptopurine
Lymphoblast
Acute lymphocytic leukemia
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Systemic Exposure to Mercaptopurine as a Prognostic Factor in Acute Lymphocytic Leukemia in Children
Despite a success rate of more than 90 percent in inducing remission in children with acute lymphocytic leukemia, 30 to 40 percent of such children relapse. Maintenance therapy during remission usually includes oral mercaptopurine and methotrexate. Recently, wide variability in the bioavailability of oral mercaptopurine has been demonstrated, and there is concern that this may affect the risk of relapse.
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Acute lymphocytic leukemia
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