Pharmacogenomics and ALL treatment: How to optimize therapy

Abstract

Inherited genetic variations may alter drug sensitivity in patients with acute lymphoblastic leukemia, predisposing to adverse treatment side effects. In this review, we discuss evidence from children and young adults with acute lymphoblastic leukemia to review the available pharmacogenomic data with an emphasis on clinically actionable and emerging discoveries, for example, genetic variants in thiopurine methyltransferase and NUDT15 that alter 6-mercaptopurine dosing. We also highlight the need for ongoing pharmacogenomic research to validate the significance of recent findings. Further research in young adults, as well as with novel therapeutics, is needed to provide optimal therapy in future trials.

Keywords: Acute lymphoblastic leukemia; Pharmacogenomics; Precision medicine.

Figure 1:

TPMT and NUDT15 inactivate thiopurines As prodrugs, thiopurines (mercaptopurine [6MP] and thioguanine [TG]) are enzymatically metabolized to TGTP that is incorporated into DNA resulting in DNA damage and cytotoxicity. TPMT reduces MP cytotoxicity by converting it to inactive methyl-MP, whereas NUDT15 dephosphorylates TGTP and converts it to inactive TGMP. TPMT and NUDT15 are highlighted in red ovals, while MP/TG and their active metabolites (TGTP and DNA.TG) are shown in red text.

Figure 2:

Genotype guided dose of 6-MP Starting 6-MP doses in Total 17 (NCTgg03117751) vary by phase of therapy. Patients with one known inactivating variant in TPMT (i.e. *3A, *3C, *2) or NUDT15 (i.e. *2, *3, *9) are considered intermediate metabolizers for the respective enzyme, while patients with two inactivating alleles are considered poor metabolizers. All other patients are considered normal metabolizers. Phases of therapy include late induction (1b), consolidation with high-dose methotrexate (HD), and continuation (Maint). All doses are given daily with the exception of patients with TPMT poor metabolizer genotypes who receive 6-MP only 3 of 7 days each week.