Researchers at St. Jude Children's Research Hospital have discovered inherited variations in certain genes that make children with acute lymphoblastic leukemia ( ALL ) susceptible to the toxic side effects caused by chemotherapy medications. The researchers showed that these variations, called polymorphisms, occur in specific genes known to influence pharmacodynamics.

The findings, made during a study of 240 children, are important because these side effects in acute lymphoblastic leukemia can be life-threatening and interrupt delivery of treatment, increasing the risk of relapse. The new insights gained in this study could help individualize ALL chemotherapy according to a patient’s inherited tendencies to develop toxic reactions to specific drugs.

The study is published in Blood.

The St. Jude team extracted DNA from healthy white blood cells of patients and looked for 16 polymorphisms previously known to be present in genes linked to drug pharmacodynamics. Using a variety of statistical analyses, the investigators identified links between specific polymorphisms and gastrointestinal, infectious, hepatic, and neurologic toxicities during each phase of treatment.

The study showed that some of the 16 genetic polymorphisms are linked to toxic side effects during more than one treatment phase; and some caused more than one type of toxicity. Certain polymorphisms were linked to the pharmacokinetics of specific drugs.Variations in pharmacokinetics can alter the levels of drugs in the body, leading to ineffective or toxic levels in individual patients.

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 ) and cytochrome P4503A5 ( OR, 4.61 ) 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 ) as it also did during continuation ( OR, 2.01 ).
In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia and Methotrexate clearance, which was also independently associated with hyperbilirubinemia.

Source: St. Jude Children's Research Hospital, 2007

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