Ancestry and pharmacogenetics of antileukemic drug toxicity

Abstract

Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.

Figure 1

The interactions of antileukemic agents with gene products. Antileukemic agents (dashed boxes) interact with gene products typed in this study (genes italicized, with their functions indicated in the colored boxes). Bidirectional arrows indicate that the drugs are both substrates for and competitive inhibitors of the indicated gene products; dashed arrow indicates inductive effect of steroids on CYP3A enzymes; flat-headed arrows indicate inhibitory effects. Genotypes were determined at loci in the indicated genes and analyzed individually; they were also pooled into 1 of 3 major groups: glucocorticoid (green), phase II conjugating (blue), and antimetabolite related (red).

Figure 2

Concordance of self-reported and AIMs-determined race. Percentage of Sub-Saharan African, European, Native American, and East Asian ancestry as determined by AIMs (y-axes) plotted by self-reported race categories (x-axes); black, n = 44; white, n = 167; Asian, n = 1; and other, n = 28. Boxes indicate quartiles, horizontal bars indicate medians, and whiskers indicate the range after excluding outliers (circles).

Figure 3

Odds ratios of experiencing toxicity during therapy. Median (95% confidence intervals) odds ratios of experiencing the indicated toxicity for the 3 phases of therapy for the most predictive genotypes. Odds ratios resulting from multivariate analyses using self-declared race. The genotypes depicted were significantly associated with more than one toxicity or with toxicity in more than one phase of therapy.

Figure 4

Incidence of toxicity based on specific genotypes. Cumulative incidence of the first episode of grade 3 to 4 gastrointestinal (GI) toxicity differing (P = .014) by RFC genotypes during therapy (top). Cumulative incidence of the first episode of grade 3 to 4 hyperbilirubinemia differing (P < .001) by UGT1A1 genotypes, during therapy (bottom).