The Promise of Pharmacogenomics in Reducing Toxicity during Acute Lymphoblastic Leukemia Maintenance Treatment

Abstract

Pediatric acute lymphoblastic leukemia (ALL) affects a substantial number of children every year and requires a long and rigorous course of chemotherapy treatments in three stages, with the longest phase, the maintenance phase, lasting 2–3 years. While the primary drugs used in the maintenance phase, 6-mercaptopurine (6-MP) and methotrexate (MTX), are necessary for decreasing risk of relapse, they also have potentially serious toxicities, including myelosuppression, which may be life-threatening, and gastrointestinal toxicity. For both drugs, pharmacogenomic factors have been identified that could explain a large amount of the variance in toxicity between patients, and may serve as effective predictors of toxicity during the maintenance phase of ALL treatment. 6-MP toxicity is associated with polymorphisms in the genes encoding thiopurine methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), and potentially inosine triphosphatase (ITPA), which vary between ethnic groups. Moreover, MTX toxicity is associated with polymorphisms in genes encoding solute carrier organic anion transporter family member 1B1 (SLCO1B1) and dihydrofolate reductase (DHFR). Additional polymorphisms potentially associated with toxicities for MTX have also been identified, including those in the genes encoding solute carrier family 19 member 1 (SLC19A1) and thymidylate synthetase (TYMS), but their contributions have not yet been well quantified. It is clear that pharmacogenomics should be incorporated as a dosage-calibrating tool in pediatric ALL treatment in order to predict and minimize the occurrence of serious toxicities for these patients.

Pathway genes and metabolites in thiopurine therapy in Korean children with acute lymphoblastic leukaemia

“…However, adverse effects of 6‐MP, including myelotoxicity which can lead to life‐threatening infection, and hepatotoxicity often lead to decreased thiopurine dosage or treatment interruption . The pharmacokinetic and pharmacogenetic characteristics of thiopurine drugs are complicated (Figure S1), with high intra‐ and inter‐individual variability …”

“…Despite a lower frequency of TPMT variant alleles in Asians, the incidence of thiopurine‐induced leukopenia is higher in Asians than in individuals of European descent . Studies have found an association between several genetic polymorphisms and toxicity in paediatric ALL patients, but the association varies among ethnic groups . For example, thiopurine‐related toxicity is frequently observed in Asian populations, with importance of the Nudix hydrolase 15 ( NUDT15 ) genotype rather than the thiopurine methyltransferase ( TPMT ) genotype …”

“…It has been suggested that pharmacogenomics should be incorporated as a dosage‐calibrating tool in the treatment of paediatric ALL in order to predict and minimize the occurrence of serious toxicity in these patients . However, to the best of our knowledge, there is a lack of pharmacogenetic studies focused on the various genetic polymorphisms in association with thiopurine metabolism and toxicity in Korean paediatric ALL patients.…”

Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia

“…The antitumor activity of MTX depends on its inhibition of dihydrofolate reductase (DHFR). 11 Inter-individual differences in MTX pharmacokinetics can largely be attributed to the genetic polymorphisms of transporters and enzymes involved in folate metabolism. 12 It may be valuable to identify genetic polymorphisms associated with serum MTX concentrations to optimize the treatment outcome of pediatric patients with ALL.…”

Homozygous mutation in NUDT15 in childhood acute lymphoblastic leukemia with increased susceptibility to mercaptopurine toxicity: A case report

“…Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, accounting for 25-30% of all childhood malignancies (1,2). Pediatric patients with ALL are classified into standard-, intermediate-or high-risk categories based on age, white blood cell count, existing central nervous system leukemia or testicular leukemia, immunophenotype, cytogenetic and molecular characteristics, prednisone response, morphological remission at the end of induction therapy, and the different expression of minimal residual disease (MRD) (3,4). Newly diagnosed patients with ALL require a rigorous, standardized and long-course chemotherapy treatment strategy, which includes induction, consolidation, intensification and maintenance therapy (5).…”