ATLANTA – It doesn’t get more personal than this: genetic studies of individual patients can predict who is at increased risk for treatment-related toxicity or death, reported investigators at the annual meeting of the American Society of Hematology.
For example, a single nucleotide polymorphism (SNP) in the Wilms tumor gene (WT1) appears to predict lower risk for treatment-related mortality in children of African American and Asian ancestry with acute myeloid leukemia, reported Dr. Phoenix A. Ho from the University of Washington and Fred Hutchinson Cancer Center, both in Seattle.
Dr. Phoenix Ho
Other recently identified polymorphisms appear to increase the risk of cardiotoxicity from exposure to anthracyclines in chemotherapy regimens, reported Dr. Smita Bhatia from the City of Hope Comprehensive Cancer Center in Duarte, Calif.
Protection from toxicity
Dr. Ho and his colleagues had previously identified mutations in the exon 7 region of WT1, a tumor suppressor and transcription factor gene that is over-expressed in an estimated 81% of AML cells compared with normal hematopoietic cells. Mutations in WT1 found in about 8% of children with AML are associated with worse prognosis, Dr. Ho said.
But during their investigation of mutations, the researchers also found apparently favorable single-nucleotide polymorphisms (SNPs), specifically a normal variant labeled rs16754, in cancer samples from children with AML or myelodysplastic syndrome enrolled in the Children’s Oncology Group CCG-2961 trial comparing combination chemotherapy with or without bone marrow transplantation.
"Normally, in our work looking at changes in leukemia DNA, we ignore these polymorphisms, but we were surprised to find that patients that carry this SNP, which is present in about one-third of the American population, had a significantly improved overall survival," Dr. Ho said at a media briefing.
They found that the SNP was present in 25% of white patients, 21% of African Americans, 34% of Hispanics, and 53% of Asians in CCG-2961.
When they then looked at differences in toxicity-related deaths by ethnic group and SNP status, they found that the African American patients who were positive for rs16754 had no toxicity-related deaths, compared with 25% of African American patients who were SNP negative. Among patients of Asian background, the difference was even more pronounced, with none of the SNP-positive patients dying from treatment toxicity, compared with 43% of Asians who were SNP-negative.
Although the numbers of patients were small, there was evidence hinting that treatment-related mortality was higher among SNP-negative patients assigned to an experimental arm with a consolidation regimen containing the then-investigational agent fludarabine, Dr. Ho said.
He and his colleagues plan to validate the ethnicity-specific associations they found, and explore biologic mechanisms for the association of WT1 SNPs and patient outcomes, Dr. Ho said.
Heart failure markers
Dr. Bhatia presented data from a study led by Dr. Saro Armenian, a researcher in her laboratory. The investigators looked at polymorphisms that may contribute to anthracycline-related heart failure 1 or more years after a hematopoietic cell transplant (HCT).
Dr. Smita Bhatia
They investigated candidate genes for anthracycline metabolism, iron homeostasis, antioxidant defense, and myocardial remodeling in a nested case-control study of all transplant patients at City of Hope from 1988 through 2008, including 77 HCT survivors with heart failure, and 178 without it.
They found that in addition to risk factors known to be associated with heart failure in transplant survivors such as female gender (odds ratio [OR], 3.0; P less than .01), radiation to the chest (OR, 5.6; P less than .05), and hypertension (OR, 3.5; P less than .05), three SNPs were significantly associated with risk. The suspect SNPs were in genes for the multidrug resistant protein (MRP2 –rs8187710; OR, 3.7; P less than .05), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit (RAC2 –rs13058338; OR, 3.0; P less than .01), and hemochromatosis (HFE2-rs1799945; OR, 2.4; P less than .05).
In multivariate analysis controlling for age at transplant, ethnicity, donor source, anthracycline dose, and follow-up time, the investigators saw that combinations of the risk factors increased the likelihood that survivors would develop heart failure. For example, females with two or more of the SNPs had a 17-fold greater risk (P less than .01), and males with two or more SNPs had a fivefold higher risk (P less than .05).
"There is biological plausibility to the genes that we have identified, and we are pretty certain this conglomeration of genes, along with the clinical factors, can predict a patient developing congestive heart failure," Dr. Bhatia said.
Dr. Ho’s and Dr. Bhatia’s studies were supported by the National Institutes of Health. Dr. Ho and Dr. Bhatia declared no relevant conflicts of interest.