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ASH 2015: Genetic Variants Discovered in Acute Lymphocytic Leukemia That Indicate Higher Risk for Osteonecrosis, Avascular Necrosis

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Key Points

  • Patients with osteonecrosis are 8 to 15 times more likely to possesses genetic variants near a gene important to bone development (BMP7) and between 3 to 6 times more likely to have variants near a gene important to fat levels in the blood (PROX1).
  • In patients with avascular necrosis, 20.6% had a specific genetic variant (2R/2R) in a promoter of thymidylate synthase, an enzyme that is often linked to treatment resistance.

Two new studies to be reported at the 57th American Society of Hematology (ASH) Annual Meeting highlighted new insights on genetic mutations in children with acute lymphocytic leukemia (ALL) that indicate a higher risk for debilitating chemotherapy-associated bone damage. The study findings were presented at a press conference held during the ASH meeting.

“We all have thousands of small variants in our genomes, some of which may predispose an individual to greater toxicity to a particular drug or alter the response to a specific treatment. Identification of these genetic variations using DNA sequencing provides a powerful and increasingly accessible tool to help predict which patients may be at risk for adverse treatment-related outcomes,” said Wendy Stock, MD, Professor of Medicine in Hematology/Oncology and Director of the Leukemia Program at the University of Chicago. “The exciting research presented today provides new information on specific genetic risk factors that could lead to more personalized therapeutic approaches to improve outcomes for children with devastating diseases.” 

Osteonecrosis

In a study to be presented by Karol et al, researchers identified genetic variants that indicate increased risk of osteonecrosis in children under 10 years old with ALL (Abstract 250).

Osteonecrosis is a significant side effect of chemotherapy in children with ALL, especially in patients aged 10 to 20 years. As previous research has focused on patients older than 10, this study sought to evaluate whether genetic risk factors for osteonecrosis differ for younger children.

Investigators performed a genome-wide association study in 1,186 children, including an initial discovery group of 82 patients with osteonecrosis and 287 without it, to identify genetic variants that are most common among those with the bone disease. Researchers observed that patients with osteonecrosis are 8 to 15 times more likely to possess genetic variants near a gene important to bone development (BMP7) and between 3 to 6 times more likely to have variants near a gene important to fat levels in the blood (PROX1).

This study increases understanding of the development of osteonecrosis, which may lead to better treatments in the future. The researchers concluded: “These data provide new insights into osteonecrosis with implications for patients of all ages.

Avascular Necrosis

A study to be presented by Cole et al identified a genetic variant that signified higher risk for avascular necrosis in children with acute leukemia (Abstract 251).

Bone fractures and avascular necrosis can frequently complicate therapy for children with ALL, resulting in significant pain and physical disability. These treatment-related side effects have been seen most commonly in ALL patients diagnosed in their early teenage years but can occur in children of any age.

The study sought to determine if any of 19 common genetic variants are associated with an increased risk of bone damage in children with ALL. Investigators collected blood or bone marrow from 627 children in remission and sequenced their DNA. They then observed the children for signs of bone damage during postinduction therapy. The researchers found that 61 patients (9.7%) developed avascular necrosis and 138 (22%) suffered one or more fracture.

Of the patients tested, 20.6% had a specific genetic variant (2R/2R) in a promoter of thymidylate synthase, an enzyme that is often linked to treatment resistance. Compared to those with other thymidylate synthase variants, researchers estimate that patients 10 and younger with the 2R/2R genotype have a nearly threefold higher risk of developing avascular necrosis. Among older children, this variant was associated with a twofold increased risk of bony fractures.

The investigators concluded: “This is the first report identifying a genetic risk factor for [avascular necrosis] specifically among children younger than 10 years, a group where [avascular necrosis] is significantly less frequent. This result suggests young children with ALL and the 2R/2R genotype should be monitored more closely for the development of [avascular necrosis] during therapy for ALL.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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