Pediatric patients with acute lymphocytic leukemia (ALL) and chemotherapy-induced osteonecrosis are significantly more likely to possess certain genetic variants near genes essential to bone development and adipogenesis, according to results from a study of 82 ALL patients younger than 10 years old presented at the ASH annual meeting last month.
Osteonecrosis, which is caused by reduced blood flow to bones in the joints that results in pain and decreased mobility, is a significant toxicity of ALL, limiting the ability to intensify treatment in young ALL patients – particularly among patients 10 to 20 years of age.
The risk of osteonecrosis is lower among younger patients but, despite the lower risk, children under 10 years of age make up 40 percent of cases of osteonecrosis. While prior studies on the genetic determinants of osteonecrosis have focused primarily on patients older than 10 years, the current study included patients younger than 10 years, marking "the first evaluation of genetic risk factors for osteonecrosis" in these patients, according to the authors, led by Seth E. Karol, MD, from the Department of Oncology at St. Jude Children's Research Hospital in Memphis, Tennessee.
"The genetic risk factors for the larger group of children with ALL less than 10 years old [are] incompletely understood," the authors added. "Genetic risk factors may account for a greater proportion of risk of osteonecrosis or involve differing mechanisms in younger [patients] versus older patients."
The researchers performed genome-wide association studies (GWAS) in a discovery cohort of 82 cases of osteonecrosis and 287 controls (all with standard-risk ALL), then tested the findings for replication in 817 children with high-risk ALL.
Within the discovery cohort, the top-ranked variants associated with osteonecrosis were rs76599360 and rs77556622 (p=1.13×10-9; odds ratio [OR]=22.0; 95% CI 8.15-59.6). These variants were located near bone morphogenic protein 7 (BMP7).
The top replicated non-synonymous SNP, rs34144324, was in a glutamate receptor gene (GRID2): p=8.65×10-6 (OR=3.46; 95% CI 2.00-5.98) and p=0.0136 (OR=10.8; 95% CI 1.63-71.4) in the discovery and replication cohorts, respectively. "Genotyping of this variant was verified in the whole-exome sequencing data," the authors noted, with the GWAS results further supported by pathway and enhancer enrichment analyses.
Glutamate receptor signaling was the top enriched pathway (p=9.91×10-4) with six genes present; the adipogenesis pathway was the only other non-overlapping pathway (p=0.02), with seven genes present (including BMP7).
"Variants in genes important to bone and fat differentiation from mesenchymal stem cells were associated with osteonecrosis in children younger than 10 years old," Dr. Karol and colleagues concluded, suggesting that the balance of bone and fat may be important in these patients and affect osteonecrosis through an effect on cholesterol levels.
"Recent pediatric ALL trials have been amended to decrease osteonecrosis," Dr. Karol noted, "precluding us from using more intensive regimens involving steroids and asparaginase â€” drugs that have acute toxicities but have fewer long-term side effects than many of our other alternatives." The results of the current study increase the understanding of the development of osteonecrosis, which may lead to better treatments in the future, he added.
Karol SE, Yang W, Mattano LA, et al. Genetic risk factors for the development of osteonecrosis in children under age 10 treated for acute lymphoblastic leukemia. Abstract #250. Presented at the 2015 ASH Annual Meeting, December 6, 2015; Orlando, Florida.