Ancestry and pharmacogenetics of antileukemic drug toxicity.
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.
Kishi
Shinji
S
Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
Cheng
Cheng
C
French
Deborah
D
Pei
Deqing
D
Das
Soma
S
Cook
Edwin H
EH
Hijiya
Nobuko
N
Rizzari
Carmelo
C
Rosner
Gary L
GL
Frudakis
Tony
T
Pui
Ching-Hon
CH
Evans
William E
WE
Relling
Mary V
MV
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000145:classification; D002648:Child; D064420:Drug-Related Side Effects and Adverse Reactions / Q000145:classification / Q000208:ethnology / Q000235:genetics; D005838:Genotype; D006801:Humans; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use; D008954:Models, Biological; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D044469:Racial Groups; D012074:Remission Induction
D000970:Antineoplastic Agents; D008727:Methotrexate