Pharmacogenetics of Outcome in Children with Acute Lymphoblastic Leukemia.

Abstract

The acquired genetic characteristics of acute lymphoblastic leukemia (ALL) blasts are often used to guide the intensity of therapy, whereas the germline host genetic characteristics of the patient generally have not been considered. Multiple common, functionally important polymorphisms affect genes whose products determine the pharmacokinetics and pharmacodynamics of antileukemic agents. It is not yet known how genetic polymorphisms may interact to affect the outcome of antileukemic therapy. Combining classification and regression tree with failure time analysis, we assessed whether 16 genetic polymorphisms, alone or in combination, predicted relapses in 246 children with ALL, 116 of whom were treated on the lower-risk (LR) and130 on the higher-risk (HR) arms of the St Jude protocol Total XIIIB. Genotyping was performed for the following polymorphic loci: CYP3A4*1B and CYP3A5*3; GSTP1 313A>G, GSTM1 and GSTT1 deletions; MDR1 exon 21 (2677G>T/A) and MDR1 exon 26 (3435C>T); MTHFR 677C>T and MTHFR 1298A>C; NR3C1 1088A>G; SLC19A1 80G>A; TPMT 238G>C, 460G>A and 719A>G; TYMS enhancer repeat; UGT1A1 promoter repeat polymorphism; VDR intron 8 G>A and VDR FokI (start-site) T>C. In all children with available RNA in their diagnostic ALL blasts, gene expression levels of prognostic genotypes were analyzed using the Affymetrix genechip array HG_U95Av2. Among the HR group, the glutathione S-transferase M1 (GSTM1) non-null genotype was associated with the risk of hematological relapse (5-year cumulative incidence, 17.1%±4.5% compared to 5.1%±2.9% for GSTM1 null genotype, p = 0.03), and among the non-null genotypes, the thymidylate synthetase (TYMS) 3/3 genotype was associated with a further increase in hematologic relapse risk (5-year cumulative incidence, 29.2%±9.5% compared to 10.9%±4.7% for TYMS 2/3 or 2/2 genotypes, p = 0.02). Increased expression levels of these two target genes (p < 0.0001 and p = 0.09, respectively) were consistent with resistance to the drugs interacting with these gene products. For central nervous system relapse, among the HR group, the vitamin D receptor (VDR) start site (p = 0.02) and intron 8 genotypes (p = 0.04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (p = 0.04). The genotypes associated with outcome have pharmacologic plausibility: e.g., high GST activity (GSTM1 non-null) could cause anticancer drug resistance; high TYMS activity (TYMS 3/3) would be less inhibited by antifolates. In conclusion, germline polymorphisms influence the outcome of antileukemic therapy, and therefore represent determinants of response that can be used to optimize therapy.

The impact of CYP3A5*3 on risk and prognosis in childhood acute lymphoblastic leukemia

“…Thus, CYP3A5*3 may play a role in both the risk of developing ALL (because CYP3A5 is involved in the metabolism of endogenous metabolites and of environmental xenobiotics) and in the outcome for children with ALL (because the enzyme modifies activity of chemotherapeutics). This is supported by some studies (12, 16, 17), but not others (18–21). In this study, we investigate the impact of CYP3A5*3 on risk of developing childhood ALL and on outcome in a large Danish/Norwegian childhood ALL population.…”

“…However, in their study, only IR childhood patients with ALL were included, and of those, only three were T‐ALL. In a more recent study of 246 (low‐ and high risk) childhood patients with ALL, it was also not possible to find any significant associations between CYP3A5*3 and outcome (19). Again, there was no distinction between BCP‐ALL and T‐ALL in their analysis.…”

Evaluating glutathione S‐Transferase (GST) null genotypes (GSTT1 and GSTM1) as a potential biomarker of predisposition for developing leukopenia

“…, 1995; Nedelcheva Kristensen et al. , 1998; Lourenco et al ., 2005; Mondal et al ., 2005; Rocha et al . 2005; Ye & Song., 2005).…”

Pharmacogenetics of Childhood Acute Lymphoblastic Leukemia

“…Whether ALL patients with intermediate TPMT activity would need dose reduction is less clear. Some authors found an association between TPMT heterozygosis and increased toxicity [16][17][18][19][20][21] while others found no association [22][23][24][25][26][27][28]. It has been proposed that hetero zygous TPMT patients treated with higher doses (75 mg/m 2 per day) are more likely to benefit from dose reduction because of hematopoietic toxicity [16], while those treated with lower doses [23] may not have higher risk of hematologic toxicity and might not need a dose reduction [29].…”