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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4151-4157.
Prepublished online as a Blood First Edition Paper on January 30, 2007; DOI 10.1182/blood-2006-10-054528.
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CLINICAL TRIALS AND OBSERVATIONS
Ancestry and pharmacogenetics of antileukemic drug toxicity
Shinji Kishi1,
Cheng Cheng2,3,
Deborah French1,
Deqing Pei2,
Soma Das4,
Edwin H. Cook4,
Nobuko Hijiya3,5,6,
Carmelo Rizzari7,
Gary L. Rosner8,
Tony Frudakis9,
Ching-Hon Pui3,5,6,
William E. Evans1,3,6, and
Mary V. Relling1,3,6
1 Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN;
2 Department of Biostatistics, St Jude Children's Research Hospital, Memphis, TN;
3 Hematologic Malignancies Program, St Jude Children's Research Hospital, Memphis, TN;
4 Department of Psychiatry, Pediatrics, and Human Genetics, University of Chicago, IL;
5 Oncology, St Jude Children's Research Hospital, Memphis, TN;
6 University of Tennessee, Memphis;
7 Clinica Pediatrica, Università di Milano, Milan, Monza, Italy;
8 Biostatistics, M. D. Anderson Cancer Center, Houston, TX;
9 DNAPrint Genomics, Sarasota, FL
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.
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