The emphasis on precision medicine continues as health care providers discover the value of using information about a patient’s particular disease to inform treatment approaches. Genetic testing and personalized medicine are extremely valuable tools that represent the future of health care. They also serve a valuable purpose as risk assessors that can be used to help physicians strategize and plan treatment courses. Thus, it has become increasingly necessary to diagnosis not only the patient’s disease but also the genetics of the patient’s disease.
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During a session at the ASH meeting, presenters reported on research revealing how some genetic variants are associated with disease severity and treatment-related complications in children with blood diseases. In a presentation titled “Genetic Risk Factors for the Development of Osteonecrosis in Children Under Age 10 Treated for ALL,” Seth E Karol, MD (St Jude Children’s Research Hospital, Memphis, TN), shared new research identifying genetic risk factors associated with acute lympocytic leukemia (ALL). Osteonecrosis is a disease associated with chemotherapy treatment for ALL and is especially common in children between the ages of 10 and 20 years. The disease causes severe pain in the joints and decreased mobility, which may require surgery. Prior research on the subject of osteonecrosis has focused primarily on children older than 10 years; therefore, Dr Karol and his team chose to analyze whether genetic risk factors might differ for children younger than 10 years. Dr Karol explained that, to determine whether differences in genentic associations exist between the age groups, he and his team performed a genome-wide association study (GWAS) with 1186 patients, including 82 with osteonecrosis and 287 without.
After analysis, Dr Karol and his team observed that patients with osteonecrosis were 15 times more likely to have mutations near BMP7, an important gene in bone development. In addition, they also observed that patients were between 3 and 6 times more likely to have genetic variants near PROX1, a gene involved in regulating fat levels in the blood. Ultimately, researchers concluded that these mutations were highly associated with osteonecrosis in children under the age of 10 years. There seemed to be less of an association between the glutamate receptor-signaling gene (GRID2) and osteonecrosis, leading researchers to believe that this particular mutation is more important in older children.
In another study of treatment-related side effects associated with ALL, Peter D Cole, MD (Albert Einstein College of Medicine, Bronx, NY), and his team evaluated whether patients presenting with any of 19 common genetic variants are at a greater risk of bone fractures and avascular necrosis (AVN), the death of bone tissue due to lack of blood.
The investigators drew bone or bone marrow samples from 627 children in remission and sequenced their DNA while also looking for signs of bone damage during post-induction therapy. Dr Cole reported that 61 patients (9.7%) developed AVN and 138 (22%) experienced one or more fractures. Problems were most commonly reported in patients who tested positive for the genetic variant 2R/2R in a promoter of thymidylate synthase, an enzyme that is often linked to treatment resistance. Compared to other variants, Dr Cole explained that patients 10 years and younger with the 2R/2R variant have a 3 times higher risk of developing AVN and a 2 times higher risk of bone fractures, indicating that these patients should be monitored with greater attention.
Finally, Elizabeth Raetz, MD (Huntsman Cancer Institute and Primary Children’s Hospital, University of Utah, Salt Lake City, UT) reported on results from a Children’s Oncology Group study on how cytogenetic abnormalities can be associated with better or worse outcomes in ALL patients. Newly diagnosed B-cell lymphocytic leukemia patients between the ages of 1 and 30 years receive either standard- or high-risk chemotherapy regimens based on how the National Cancer Institute (NCI) defines these risks. The researchers looked at 5,104 NCI standard-risk patients and 2,791 NCI high-risk patients and reclassified them as low-, standard-, high-, or very high–risk groups based on cytogenetic findings and early treatment response after induction therapy.
Dr Raetz stated that 5-year event-free survival varied according to genetic subsets. Those with unfavorable cytogenetic profiles had a ~70% chance of surviving at least 5 years, whereas those with more favorable profiles had a 95% likelihood of being alive after 5 years. Further, patients with standard- or high-risk disease but favorable cytogenetic findings had a 98% likelihood of being alive 5 years after diagnosis. Therefore, it was concluded that real-time genetic analysis could identify high-risk patients who still have excellent opportunities to be cured of symptoms or have them reduced.
