Table 3.

Recommended Dosing of Thiopurines by NUDT15 phenotype

		Mercaptopurine		Azathioprine		Thioguanine
Phenotype	Implications for thiopurine phenotypic measures	Dosing recommendations for mercaptopurine	Classification of strong	Dosing recommendations for azathioprine	Classification of recommendations	Dosing recommendations for thioguanine	Classification of recommendations
NUDT15 Normal metabolizer	Normal risk of thiopurine-related leukopenia, neutropenia, myelosuppression	Start with normal starting dosea (e.g., 75mg/m2/day or 1.5mg/kg/day) and adjust doses of mercaptopurine (and of any other myelosuppressive therapy) without any special emphasis on mercaptopurine compared to other agents. Allow at least 2 weeks to reach steady-state after each dose adjustment (4, 27, 30).	Strong	Start with normal starting dosea (e.g., 2–3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady-state after each dose adjustment (4, 30, 37).	Strong	Start with normal starting dosea (40–60 mg/day). Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment (4, 16).	Strong
NUDT15 Intermediate metabolizer OR Possible NUDT15 Intermediate metabolizer	Increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression	Start with reduced starting doses (30%−80% of normal dose) if normal starting dosea is ≥75 mg/m2/day or ≥ 1.5 mg/kg/day (e.g. start at 25–60 mg/m2/day or 0.45–1.2 mg/kg/day) and adjust doses of mercaptopurine based on degree of myelosuppression and disease-specific guidelines. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents (4, 11, 15, 24, 25, 27, 30, 38, 39). If normal starting dose is already <75mg/m2/day or < 1.5mg/kg/day, dose reduction may not be recommended.	Strong	Start with reduced starting doses (30%−80% of normal dose) if normal starting dosea is 2–3 mg/kg/day, (e.g. 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2–4 weeks to reach steady-state after each dose adjustment (4, 30, 37, 38).	Strong	Start with reduced doses (50% to 80% of normal dose) if normal starting dosea is ≥40–60 mg/m2/day (e.g. 20–48 mg/m2/day) and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 2–4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents (4, 16).	Moderate
NUDT15 Poor metabolizer	Greatly increased risk of thiopurine-related leukopenia, neutropenia, myelosuppression	For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (4, 26, 30, 38).	Strong	For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily dosesa (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady-state after each dose adjustment (28, 30, 37, 38, 40).	Strong	Reduce doses to 25% of normal dosea and adjust doses of thioguanine based on degree of myelosuppression and disease-specific guidelines. Allow 4–6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative non-thiopurine immunosuppressant therapy (4).	Strong

^aNormal starting doses vary by race/ethnicity and treatment regimens. If standard dose is below normal recommended dose, dose reduction might not be recommended for intermediate metabolizers.