Four alleles in three genes identified in research in the upcoming issue of the journal Blood may serve as powerful prognostic markers for children with acute lymphoblastic leukemia following chemotherapy, while possibly providing drug makers with a new way to stratify clinical trials.
The suspect alleles are a non-null GSTM1 allele, the TYMS 3/3 allele, as well as two alleles of the VDR gene — the FokI and intron 8 polymorphisms.
The genes identified were linked to CNS and hematological relapses, and it's "certainly possible" that the four polymorphisms will make their way into prognostic test products, although there is not yet a company that is unambiguously interested, Mary Relling, the study's lead author and a St. Jude Children's Hospital faculty member, told Pharmacogenomics Reporter. "The two most-important polymorphisms are relatively easy to analyze," but neither the GSTM1 allele or the TYMS allele has yet been featured in a commercial diagnostic to Relling's recollection.
The alleles could likely also prove useful to pharma for clinical trial stratification, said Relling. "I think there's a precedent for this TYMS polymorphism" being used as a stratification parameter for a phase I drug targeting the thymidylate synthase, she said. However, no pharmas have contacted her in more than a "general way" about the using the genes, although "they might be" interested, she said.
Teams from St. Jude Children's Hospital, the University of Tennessee, and the University of Chicago assigned 246 children with ALL to high- and low-risk trial arms, with 130 and 116 children in each, respectively, based on conventional prognostic factors. They genotyped patients for loci known to be involved in the metabolism or activity of chemotherapy drugs, and looked for genes associated with hematological relapse and central nervous system relapse.
The re-emergence of cancer in the blood and bone marrow, called hematological relapse, is the most common type of ALL relapse. In CNS relapse, cancer cells invade central nervous tissue. The ability of drugs to cross the blood-brain barrier is highly influenced by genotype, so CNS relapse can be influenced by a patient's genotype as well.
In the high-risk group, a GSTM1 non-null allele conferred a greater chance of hematological relapse, while a TYMS 3/3 genotype increased that risk, according to a statement from the American Society of Hematology. The low-risk arm of the study had no genotype associated with relapse, the organization said.
The genetic markers are about the best that the field has to offer for ALL prognosis. "We compared the effect of these two genotypes with the other most important prognostic factors for ALL in a multivariate analysis, and they were on par with [the additive prognostic power of] two other very poor prognostic features," the presence of a translocation in leukemic blasts, and the presence of minimal residual disease after six weeks of therapy, said Relling. "In terms of their quantitative importance, in this study it was pretty impressive," she said.
The chances of CNS relapse in the high-risk arm were significantly higher for patients carrying the VDR FokI genotype, and the presence of a VDR intron 8 was found to amplify the chances of a poor outcome. Members of the low-risk group carrying TYMS 3/3 tended to have a poorer prognosis for CNS relapse as well.
According to the American Society of Hematology, ALL is the most common form of childhood cancer, and approximately 80 percent of treated children recover from the disease.
— Chris Womack ([email protected])