The Role of SLC22A1 and Genomic Ancestry on Toxicity during Treatment in Children with Acute Lymphoblastic Leukemia of the Amazon Region.

In Brazil, Acute lymphoid leukemia (ALL) is the leading cause of cancer deaths in children and adolescents. Treatment toxicity is one of the reasons for stopping chemotherapy. Amerindian genomic ancestry is an important factor for this event due to fluctuations in frequencies of genetic variants, as in the NUDT15 and SLC22A1 genes, which make up the pharmacokinetic and pharmacodynamic pathways of chemotherapy. This study aimed to investigate possible associations between NUDT15 (rs1272632214) and SLC22A1 (rs202220802) gene polymorphism and genomic ancestry as a risk of treatment toxicities in patients with childhood ALL in the Amazon region of Brazil. The studied population consisted of 51 patients with a recent diagnosis of ALL when experiencing induction therapy relative to the BFM 2009 protocol. Our results evidenced a significant association of risk of severe infectious toxicity for the variant of the SLC22A1 gene (OR: 3.18, p = 0.031). Genetic ancestry analyses demonstrated that patients who had a high contribution of African ancestry had a significant protective effect for the development of toxicity (OR: 0.174; p = 0.010), possibly due to risk effects of the Amerindian contribution. Our results indicate that mixed populations with a high degree of African ancestry have a lower risk of developing general toxicity during induction therapy for ALL. In addition, individuals with the SLC22A1 variant have a higher risk of developing severe infectious toxicity while undergoing the same therapy.

Low ABCB1 and high OCT1 levels play a favorable role in the molecular response to imatinib in CML patients in the community clinical practice.

Despite the favorable clinical evolution of patients with chronic myeloid leukemia (CML), resistance or intolerance to imatinib is present in approximately 35% of patients. Sokal score is a widely used risk factor, however efflux and influx transporters are provisional risk factors implicated in imatinib resistance. This study analyzed Sokal score, ABCB1, ABCG2 and OCT1 mRNA transporter expression levels as well as P-glycoprotein expression and efflux transporters activity to seek a possible correlation between these factors and the molecular response at 12 months from imatinib start as well as 8-year overall survival (OS). Low plus intermediate Sokal score correlated to optimal imatinib responses, as well as OS at 8-years, thus confirming the established role of Sokal score as a prognostic factor in CML patients. Low ABCB1 and high OCT1 mRNA levels were associated with an optimal molecular response, while the inverse levels were associated with non-responders (warning and failure) patients. Our results suggest that ABCB1 and OCT1 mRNA expressions may present biological relevance to identify responder and non-responder patients to imatinib treatment.

Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia.

Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second-generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients.

Pretherapeutic expression of the hOCT1 gene predicts a complete molecular response to imatinib mesylate in chronic-phase chronic myeloid leukemia.

In this retrospective study we evaluated the pretherapeutic mRNA expression of the hOCT1 (human organic cation transporter 1) gene in patients with chronic-phase (CP) chronic myeloid leukemia (CML) who varied in terms of their response to imatinib (IM). hOCT1 mRNA was quantified by real-time PCR. Patients were classified as expressing either high (n = 44) or low hOCT1 mRNA (n = 44). The complete cytogenetic response rates observed at 6, 12 and 18 months were 47.7, 84.1 and 91%, respectively, in patients with high hOCT1 mRNA and 47.5, 81.8 and 86.3%, respectively, in patients with low hOCT1 transcripts. The major molecular response rates were not significantly different between patients with high and low hOCT1 mRNA after 6 months of therapy (22.7 vs. 9.1%; p = 0.07), but they were significantly different after 12 months (54.5 vs. 31.8%; p = 0.026) and 18 months (77.2 vs. 56.8%; p = 0.034). Complete molecular responses were observed in 5 patients with low and 17 patients with high hOCT1 mRNA (p = 0.003). The 5-year event-free and overall survival analyses revealed no significant differences between the groups. These data imply that knowledge of the pretherapeutic level of hOCT1 could be a useful marker to predict IM therapy outcome in treatment-naïve CP CML patients.