Pharmacogenetic Predictors of Treatment-Related Toxicity Among Children With Acute Lymphoblastic Leukemia

Abstract

Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.

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

“…However, in kidney transplant recipients receiving azathioprine, there was no association between this polymorphism and azathioprine dose requirements . Although the mechanisms of these SNPs have not been fully explained by previously published studies, these genetic polymorphisms in candidate genes with potential effects on the pharmacokinetics of thiopurine metabolism should be considered and validated with further studies …”

“…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 …”

Seizures during treatment of childhood acute lymphoblastic leukemia: A population-based cohort study

“…Several chemotherapeutic agents used in ALL treatment are also associated with neurotoxicities and seizures (9)(10)(11)(12)(13)(14)(15)(16) . Treatment of seizures is symptomatic but awareness of possible etiologies, such as PRES, infections or SVT, is important for timely diagnosis and optimal treatment (8,17,18) .…”

ITPA, TPMT, and NUDT15 Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia

“…6-Mercaptopurine (6-MP) is concomitantly given with Methotrexate (MTX) during consolidation and maintenance. It is a purine antimetabolite, and it is frequently associated with life threatening myelosupression, though with major individual variability (Al-Mahayri et al, 2017; Maxwell and Cole, 2017; Rudin et al, 2017; Koutsilieri et al, 2019).…”

“…Driven by this inter-individual variability, a number of investigators have extensively evaluated germline pharmacogenetic (PGx) markers with a focus on candidate pharmacokinetic and pharmacodynamic targets to predict 6-MP toxicity (Al-Mahayri et al, 2017; Maxwell and Cole, 2017; Rudin et al, 2017; Koutsilieri et al, 2019). The oldest and most robust evidence is currently for genetic variants in thiopurine-S-methyltransferase (TPMT), an enzyme that inactivates the drug.…”