Determinants of mercaptopurine toxicity in paediatric acute lymphoblastic leukemia maintenance therapy

Abstract

Aims: 6-mercaptopurine (6-MP) is used in the treatment of childhood acute lymphoblastic leukaemia (ALL). Its red blood cell (RBC) metabolite concentrations (6-thioguanine [6-TGN] and 6-methylmercaptopurine nucleotides [6-MMPN]) are related to drug response. We investigated the impact of non-genetic covariates and pharmacogenetic polymorphisms affecting thiopurine methyltransferase (TPMT) and inosine triphosphate pyrophosphatase (ITPA) on 6-MP metabolism and response.

Methods: Sixty-six children with ALL treated according to EORTC 58951 protocol were included in this study. Six patients had a heterozygous genotype for the most common TPMT polymorphisms, nine for ITPA 94 C > A and 17 for ITPA IVS2+21 A > C. 6-MP metabolites concentrations were analyzed by mixed model analysis.

Results: During maintenance, steady-state RBC 6-TGN concentrations were lower in patients aged 6 years or younger (493 pmol/8 × 10(8) RBC) than in older children (600 pmol/8 × 10(8) RBC). 6-MMPN concentrations were low in patients with TPMT variant/wild-type ITPA (1862 pmol/8 × 10(8) RBC), intermediate in wild-type patients and high (16468 pmol/8 × 10(8) RBC) in patients wild-type TPMT/variant ITPA. A 6-MMPN threshold of 5000 pmol/8 × 10(8) RBC was associated with an increased risk of hepatotoxicity.

Conclusion: In this study, age and both TPMT and ITPA genotypes influenced 6-MP metabolism. High 6-MMPN was associated with hepatotoxicity. These pharmacological tools should be used to monitor ALL treatment in children.

Figure 1

A) RBC 6-TGN concentrations during maintenance therapy according to TPMT genotype. n number of patients without/with TPMT variant is indicated for each cycle. B) RBC 6-TGN concentrations during maintenance therapy according to patients' age. n number of patients below 6 years or over 6 years is indicated for each cycle. represent median concentrations and bars include data between the 25th and 75th percentiles excluding the outliers. Grey lines are shifted slightly to the right compared with black lines so that error bars do not overlap. (A) Variant TPMT (n = 6) (); Wild-type TPMT (n = 60) (); (B) Age > 6 years (n = 29) (); Age ≤ 6 years (n = 37) ()

Figure 2

A) RBC 6-MMPN concentrations during maintenance therapy according to TPMT genotype. n number of patients without/with TPMT variant is indicated for each cycle. B) RBC 6-MMPN concentrations during maintenance therapy according to ITPA genotype. n number of patients without/with ITPA variant is indicated for each cycle. Boxes represent median concentrations and bars include data between the 25th and 75th percentiles excluding the outliers. Grey lines are shifted slightly to the right compared with black lines so that error bars do not overlap. C) Mean RBC 6-MMPN concentrations during maintenance therapy according to the combined TPMT/ITPA C94A genotype. Boxes include data between the 25th and 75th percentiles, and bars represent the 5^th and 95^th percentiles. (A) Variant TPMT (n = 6) (); Wild-type TPMT (n = 60) (); (B) Variant ITPA (n = 9) (); Wild-type ITPA (n = 56) ()

Figure 3

A) Boxes represent median level and the 25th and 75th percentiles, n number of patients without/with hepatotoxicity, P value of the statistical test are indicated for each cycle. B) Boxes represent median level and the 25th and 75th percentiles and bars include data between the 5^th and 95^th percentiles. This graph represents the dispersion of mean 6-MMPN concentrations in RBC for each patient depending on the occurrence of hepatotoxicities The black line indicates the threshold of RBC 6-MMPN concentrations at 5000 pmol/8 × 10⁸ RBC. C) Specificity and sensibility curves of ROC analysis. Hepatotoxicity (); No hepatotoxicity ()