Table 1.
Recommended dosing of thiopurines by thiopurine methyltransferase phenotype.
| TPMT status | Mercaptopurine |
Thioguanine |
||
|---|---|---|---|---|
| Effects on mercaptopurine metabolism | Dosing recommendations for mercaptopurine | Effects on thioguanine metabolism | Dosing recommendations for thioguanine | |
| Homozygous wild-type or normal, high activity | Lower concentrations of TGNs metabolites, higher methylTIMP, this is the “normal” pattern | Start with normal starting dose (e.g., 75 mg/m2/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents | Lower concentrations of TGNs metabolites, but note that TGNs after thioguanine are 5–10× higher than TGNs after mercaptopurine | Start with normal starting dose. Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. |
| Heterozygote or intermediate activity | Moderate to high concentrations of TGNs metabolites; low concentrations of methylTIMP | Start with reduced doses (start at 30–70% of full dose: e.g., at 50 mg/m2/day or 0.75 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. In those who require a dosage reduction based on myelosuppression, the median dose may be ∼40% lower (44 mg/m2/day) than that tolerated in wild-type patients (75 mg/m2/day). In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents | Moderate to high concentrations of TGNs metabolites; but note that TGNs after thioguanine are 5–10× higher than TGNs after mercaptopurine | Start with reduced doses (reduce by 30–50%) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing thioguanine over other agents |
| Homozygous variant, mutant, low, or deficient activity | Extremely high concentrations of TGNs metabolites; fatal toxicity possible without dose decrease; no methylTIMP metabolites | Start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/day given just 3 days/week) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. In setting of myelosuppression, emphasis should be on reducing mercaptopurine over other agents | Extremely high concentrations of TGNs metabolites; fatal toxicity possible without dose decrease | Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents |
TGNs, thioguanine nucleotide; TIMP, thioinosine monophosphate (secondary metabolite of mercaptopurine); TPMT, thiopurine-S-methyl transferase (Relling et al., 2011).