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Thymidylate synthase polymorphism increases risk for bony morbidity in pediatric ALL
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ORLANDO, Fla. — Homozygosity for the 2R tandem repeat thymidylate synthase polymorphism appeared associated with increased risk for bone morbidity among children undergoing treatment for acute lymphoblastic leukemia, according to study results presented at the ASH Annual Meeting and Exposition.
Peter D. Cole, MD, associate professor in the department of pediatrics at Albert Einstein Medical College, as well as attending physician in the division of hematology-oncology in the department of pediatrics and director of the hematologic malignancy service at Montefiore, and colleagues from Dana-Farber Cancer Institute and Hospital for Sick Children in Toronto, also found that the impact of this polymorphism differed among children aged at least 10 years — who appeared at greater risk for facture — than children aged younger than 10 years, who were more at risk for osteonecrosis.
Bone fractures and osteonecrosis are associated with exposure to components of leukemia therapy such as corticosteroids, asparaginase and methotrexate, according to study background. “Age is a very important predictor and we know that children over the age of 10 have a much higher frequency of bone toxicity,” Cole said at a press conference. “We’re not very good at predicting within age categories. We’re trying to understand why — if we’re giving all children the same therapies — some children develop these toxicities while others do not. We hypothesized that interindividual genetic variation plays a key role.”
Rather than use a genome-wide approach to look for invariances, the researchers selected a list of common genetic variants a priori that may be related to bone metabolism or risk for drug-induced toxicity. They selected 19 common polymorphisms that occurred in more than 15% of the population.
The investigators evaluated data from 637 patients with ALL. From that group, 627 patients (98.4%) achieved complete remission and received post-induction therapy. Sixty-one of those patients (9.7%) experienced osteonecrosis while 138 (22%) experienced one or more fractures. As has been observed on most leukemia protocols, a greater proportion of children aged older than 10 years experienced osteonecrosis (22.9% vs. 5.5%; P < .0001) and fracture (30.7% vs. 19.2%; P = .002) than children aged younger than 10 years.
Homozygosity for the 2R polymorphism in the thymidylate synthase promoter occurred in 20.6% of all patients. This genetic feature was associated with greater cumulative incidence of osteonecrosis (11.6%; 95% CI, 6.1-18.9) compared with patients with the 2R/3R or 3R/3R genotypes (4.1%, 95% CI, 2.4-6.5; P = .0037) among children aged younger than 10 years, but not among older children.
This association remained significant in a multivariable risk regression model (adjusted HR = 2.92; 95% CI, 1.36-6.28).
Among children older than 10 years, homozygosity for this polymorphism appeared to increase the risk for bony fracture (adjusted HR = 2.13; 95% CI, 1.13-3.99), but not for osteonecrosis.
The researchers found no significant association between bony morbidity and the other polymorphisms tested, including those that have been previously linked to osteonecrosis risk such as PAI-1 (rs6092), ABCB1 (rs1045642) and Fok1 restriction site (rs228570).
There also did not appear to be any associations between thymidylate synthase genotype and serum or red blood cell folate. The researchers are currently investigating the intersection of these two factors, asking whether children who have both the 2R/2R TS genotype and low folate stores are at even greater risk of bone toxicity during leukemia therapy.
“Patients who have this variant should have increased surveillance for bony toxicity,” Cole said. “Our findings also suggest the importance of the chemotherapy drug methotrexate in the pathogenesis of the toxicity. It interestingly suggests that the pathophysiology may be different between the younger and the older patients.” – by Anthony SanFilippo
Reference:
Cole PD, et al. Abstract 251. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: One researcher reports research funding from Seattle Genetics.
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Rachel Kobos, MD
The abstracts presented at the ASH Annual Meeting by Cole and colleagues and Karol and colleagues were on similar topics.Cole and colleagues from the Dana-Farber Cancer Institute Childhood ALL Consortium looked at their trials of childhood leukemia and those patients who developed bone toxicities, and researchers were able to identify a factor in their germline associated with this risk.
Karol and colleagues looked at data from recently completed Children’s Oncology Group leukemia trials and identified additional genetic alterations associated with development of osteonecrosis. OS rates are high in leukemia, so researchers are trying to find ways to prevent long-term toxicities, and this might be one way.
There have been other reports in the past few years about markers for vincristine toxicity, and then going back even farther, toxicity from mercaptopurine. Mercaptopurine is the only therapy we have some idea how to change based on risk for toxicity; however, it is not clearly defined how best to do that. As we learn about these germline biomarkers, the goal is to eventually put that all into a trial and say, “If you have these biomarkers, you’ll get this dose of vincristine, this dose of steroids and this dose of mercaptopurine.” But, if you have certain other biomarkers, you may not be able to get that high of a dose, and you will get your dose reduced. However, we are not there yet.
First, we need to figure out what the landscape is and how many of these biomarkers are important, and that is going to take a little bit more time. Ultimately, the goal would be to have an entire platform that each newly diagnosed patient gets, so not only are you sequencing their leukemia, but you are sequencing their germline to evaluate their risk. Some centers are moving toward that concept, but again, we still do not know how yet to incorporate these markers into a clinical trial.
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