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 2-3years. 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.

Keywords: 6-Mercaptopurine; Acute lymphoblastic leukemia; Maintenance therapy; Methotrexate; Pharmacogenomics.

Figure 1

Diagram of the treatment phases of pediatric acute lymphocytic leukemia

Figure 2

Structures of 6-MP and thioguanine in comparison to adenine and guanine Thiopurines are metabolized into thiopurine nucleotides that substitute regular adenine and guanine nucleotides, leading to cytotoxicity in cells treated with those drugs. The key differences between each molecule are shown in red. 6-MP, 6-mercaptopurine.

Figure 3

6-MP metabolism 6-MP is converted by HPRT to 6-TGNs, which are methylated by TPMT. Methyl-TGNs block DNA and RNA synthesis. 6-MP is also methylated directly by TPMT, producing methylmercaptopurine (methyl-MP). MTX-PG blocks the conversion of 6-MP to its inactive metabolite thiouric acid. MTX-PG, methotrexate polyglutamate; 6-MP, 6-mercaptopurine; TGN, thioguanine nucleotide; TPMT, thiopurine methyltransferase; ITPA, inosine triphosphatase; TYMS, thymidylate synthetase; HPRT, hypoxanthine phosphoribosyl transferase; DPK, diphosphate kinase; XO, xanthine oxidase.

Figure 4

Structures of MTX and folic acid The molecular structures of MTX and folic acid. The key differences between MTX and folic acid are shown in red. MTX, methotrexate.

Figure 5

Cellular pathway and action of MTX MTX enters cells through SLC19A1 and SLCO1B1 transporters, and leaves cells through the ABCC protein. Inside cells, MTX is converted by FPGS into its active form, MTX-PG, which then inhibits TYMS and DHFR. SLCO1B1 is almost exclusively found on hepatocytes in the liver. MTX, methotrexate; MTX-PG, methotrexate polyglutamate; SLC19A1, solute carrier family 19 member 1; SLCO1B1, solute carrier organic anion transporter family member 1B1; ABCC, ATP-binding cassette transporter subfamily C; FPGS, folylpolyglutamate synthase; TYMS, thymidylate synthetase; MTHFR, methylenetetrahydrofolate reductase; DHFR, dihydrofolate reductase.