Gene Variant Linked With Increased Bony Toxicity in Pediatric ALL

Researchers have identified a genetic variant, 2R thymidylate synthase (TS) polymorphism, that is associated with an increased risk for avascular necrosis (AVN) in children with acute lymphoblastic leukemia (ALL), according to the results of a study (abstract 251) presented at the American Society of Hematology (ASH) 57th Annual Meeting and Exposition.

“Interestingly, we saw a difference by age category. Young patients with this variant had almost a threefold increased risk of osteonecrosis, while older patients with this variant had almost a twofold increased risk for fracture,” said Peter D. Cole, MD, of Albert Einstein College of Medicine, who presented the results during a press conference.

According to the presentation, TS is a folate-dependent enzyme necessary for DNA synthesis, and methotrexate, commonly used in the treatment of leukemia, inhibits TS function.

“Patients who were homozygous for the 2R variant have less expression of the TS protein which we would predict would lead to increased sensitivity to methotrexate,” Cole said.

Fractures and AVN in children with ALL result in significant pain and loss of function. Although previous research has shown that risk for bony toxicity is associated with older age and exposure to drugs such as corticosteroids, asparaginase, and methotrexate, Cole and colleagues sought to identify additional risk factors for AVN.

In this study, the researchers isolated genomic DNA from peripheral blood or bone marrow taken from 637 patients between 2005 and 2010, and tested it for 19 common polymorphisms targeting variants within genes related to glucocorticoid metabolism, oxidative damage, and folate physiology.

The rate of AVN among these patients was 9.7% with 22% of patients having one or more fractures.

Because incidence of bony morbidity was significantly different between children older and younger than 10, the researchers looked at the relationship between polymorphisms and bony morbidity separately in these age groups.

They found that about one in five patients (20.6%) had homozygosity for the 2R TS polymorphism. Among children younger than 10, patients with the 2R/2R variant had an increased 5-year estimated incidence of AVN compared with patients with the 2R/3R or 3R/3R genotypes (11.6% vs 4.1%).

A multivariable risk regression model estimated that children younger than 10 with this polymorphism had about a threefold increased risk for osteonecrosis (adjusted hazard ratio [HR], 2.92; P < .01) compared with those without it. In children 10 or older, the 2R polymorphism was associated with about twice the risk for bony fracture (HR, 2.13; P < .01).  

“Going forward patients who have this variant should probably have increased surveillance for bone toxicity,” Cole said during the press conference. “[The data] supports the importance of the chemotherapy drug methotrexate in the pathogenesis of bone toxicity, but, interestingly, suggests that the pathophysiology may be different between younger and older patients.”