Thioguanine response

Thioguanine, known chemically as 2-amino-1,7-dihydro-6H-purine-6-thione, is an analogue of the nucleic acid constituent guanine, and is closely related structurally and functionally to mercaptopurine.

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Metabolism and Genetic Polymorphism

Several published studies indicate that patients with reduced TPMT or NUDT15 activity receiving usual doses of mercaptopurine, accumulate excessive cellular concentrations of active 6-TGNs, and are at higher risk for severe myelosuppression. In a study of 1028 children with ALL, the approximate tolerated mercaptopurine dosage range for patients with TPMT and/or NUDT15 deficiency on mercaptopurine maintenance therapy (as a percentage of the planned dosage) was as follows: heterozygous for either TPMT or NUDT15, 50-90%; heterozygous for both TPMT and NUDT15, 30- 50%; homozygous for either TPMT or NUDT15, 5-10%.

Approximately 0.3% (1:300) of patients of European or African ancestry have two loss-of-function alleles of the TPMT gene and have little or no TPMT activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function TPMT allele leading to intermediate TPMT activity (heterozygous deficient or intermediate metabolizers). The TPMT*2, TPMT*3A, and TPMT*3C alleles account for about 95% of individuals with reduced levels of TPMT activity. NUDT15 deficiency is detected in <1% of patients of European or African ancestry. Among patients of East Asian ancestry (i.e., Chinese, Japanese, Vietnamese), 2% have two loss-of-function alleles of the NUDT15 gene, and approximately 21% have one loss-of-function allele. The p.R139C variant of NUDT15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function NUDT15 alleles have been observed.

Consider all clinical information when interpreting results from phenotypic testing used to determine the level of thiopurine nucleotides or TPMT activity in erythrocytes, since some coadministered drugs can influence measurement of TPMT activity in blood, and blood from recent transfusions will misrepresent a patient’s actual TPMT activity.

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Warnings

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Evaluate patients with repeated severe myelosuppression for thiopurine S-methyltransferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency. TPMT genotyping or phenotyping (red blood cell TPMT activity) and NUDT15 genotyping can identify patients who have reduced activity of these enzymes. Patients with homozygous TPMT or NUDT15 deficiency require substantial dosage reductions. Bone marrow suppression could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine, or sulphasalazine.

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Laboratory Tests

Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated episodes of myelosuppression.

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Drug Interactions

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As there is in vitro evidence that aminosalicylate derivatives (e.g., olsalazine, mesalazine, or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent thioguanine therapy.

Dosage and Administration

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Patients with homozygous deficiency of either TPMT or NUDT15 enzyme typically require 10% or less of the standard thioguanine dosage. Reduce initial dosage in patients who are known to have homozygous TPMT or NUDT15 deficiency. Most patients with heterozygous TPMT or NUDT15 deficiency tolerate recommended thioguanine doses, but some require dose reduction based on toxicities. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reductions. Reduce the dosage based on tolerability.

Please review the complete therapeutic recommendations that are located here: (1).

TPMT recommendation

If starting doses are already high (e.g., 75 mg/m² of mercaptopurine), as is true in some ALL treatment regimens, lower than normal starting doses should be considered in TPMT intermediate metabolizers and markedly reduced doses (10-fold reduction) should be used in TPMT poor metabolizers. This approach has decreased the risk of acute toxicity without compromising relapse rate in ALL. Even at these markedly reduced dosages, erythrocyte TGN concentrations in TPMT poor metabolizers remain well above those tolerated and achieved by the majority of patients (who are TPMT normal metabolizers).

In some nonmalignant conditions, alternative agents may be chosen for TPMT intermediate or poor metabolizers rather than reduced doses of thiopurines; if thiopurines are used, full starting doses are recommended for TPMT normal metabolizers, reduced doses (30–80% of target dose) in TPMT intermediate metabolizers, and substantially reduced doses (or use of an alternative agent) in TPMT poor metabolizers.

Some of the clinical data upon which dosing recommendations are based rely on measures of TPMT phenotype rather than genotype; however, because TPMT genotype is strongly linked to TPMT phenotype, these recommendations apply regardless of the method used to assess TPMT status.

NUDT15 recommendation

Similar to TPMT, tolerated mercaptopurine dosage is also correlated with the number of nonfunctional alleles of the NUDT15 gene. In fact, the degree of thiopurine intolerance (e.g., for mercaptopurine) is largely comparable between carriers of TPMT vs. NUDT15 decreased function alleles, there remains a paucity of multi-ethnic studies examining both TPMT and NUDT15 variants.

Therefore, our NUDT15 recommendations parallel those for TPMT. For NUDT15 normal metabolizers (NUDT15*1/*1), starting doses do not need to be altered. For NUDT15 intermediate metabolizers (e.g., NUDT15*1/*3), reduced starting doses should be considered to minimize toxicity, particularly if the starting doses are high (e.g., 75 mg/m²/day for mercaptopurine). For NUDT15 poor metabolizers (e.g., NUDT15*3/*3), substantially reduced doses (e.g.,10 mg/m²/day of mercaptopurine) or the use of an alternative agent should be considered.

As for TPMT, there is substantial variability in the tolerated thiopurine dosages within NUDT15 intermediate metabolizers, with a minority of individuals who do not seem to require significant dose reduction. Therefore, genotype-guided prescribing recommendations apply primarily to starting doses; subsequent dosing adjustments should be made based on close monitoring of clinical myelosuppression (or disease-specific guidelines). In contrast, a full dose of mercaptopurine poses a severe risk of prolonged hematopoietic toxicity in NUDT15 poor metabolizers and pre-emptive dose reductions are strongly recommended.

The NUDT15 poor metabolizer phenotype is observed at a frequency of about 1 in every 50 patients of East Asian descent, which is more common than the TPMT poor metabolizer phenotype in Europeans, and, thus, genotyping NUDT15 in the Asian populations may be of particular clinical importance. NUDT15 deficiency is also more prevalent in individuals of Hispanic ethnicity, particularly those with high levels of Native American genetic ancestry.

Please review the complete therapeutic recommendations, which include CPIC’s recommended course of action if both TPMT and NUDT15 genotypes are known, located here: (2).

TPMT Intermediate Metabolizer

The risk of serious adverse events such as myelosuppression is increased. The genetic variation increases the concentration of the active metabolites of thioguanine.

IMMUNOSUPPRESSION

• Start with 75% of the standard dose
• Adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.

LEUKEMIA

• start with 75% of the standard thioguanine dose, or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction
• It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity.The initial dose should be adjusted based on toxicity (monitoring of the blood counts) and efficacy.

Note: more stringent dose reductions are necessary if the patient is also NUDT15 IM or NUDT15 PM.

TPMT Poor Metabolizer

The risk of serious, life-threatening adverse events such as myelosuppression is strongly increased. The genetic variation increases the concentration of the active metabolites of thioguanine.

• Choose an alternative or use 6-7% of the standard doseAny adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and effectiveness.
• If the dose is decreased: advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) develop.

NUDT15 Intermediate Metabolizer

Grade ≥ 2 leukopenia occurs in an estimated 40% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of thioguanine.

IMMUNOSUPPRESSION

• start with 75% of the standard dose
• Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy.
• Monitoring should be performed at an increased frequency.

LEUKEMIA

• start with 75% of the standard thioguanine dose or start with the standard dose and reduce to 75% if side effects necessitate a dose reduction
• It is not known whether dose reduction in advance results in the same efficacy as dose reduction based on toxicity.
• Adjustment of the initial dose should be performed based on toxicity (monitoring of the blood counts) and efficacy.
• Monitoring should be performed at an increased frequency.

Note: more stringent dose reductions are necessary if the patient is also TPMT IM.

NUDT15 Poor Metabolizer

Grade ≥ 2 leukopenia occurs in an estimated 95% of these patients with standard therapy. The genetic variation increases the concentration of the fully activated metabolite of thioguanine.

• avoid thioguanine
• if it is not possible to avoid thioguanine: use 10% of the standard dose and advise patients to seek medical attention when symptoms of myelosuppression (such as severe sore throat in combination with fever, regular nosebleeds and tendency to bruising) occur
• Any adjustment of the initial dose should be guided by toxicity (monitoring of blood counts) and efficacy.
• Monitoring should be performed at an increased frequency.

For more information about TPMT and NUDT15 phenotypes: see the general background information about TPMT and NUDT15 on the KNMP Knowledge Bank or on www.knmp.nl (search for TPMT or NUDT15).

Please review the complete therapeutic recommendations that are located here: (3, 4).