Adam Lamble, MD, at the Cancer and Blood Disorders Center, Seattle Children’s Hospital, discusses a new study showing that pathogenic TP53 mutations, while rare, are associated with a poor prognosis in pediatric acute myeloid leukemia (AML). These findings were recently presented at this year’s American Society of Hematology Meeting & Exposition (ASH 2022).
AML is a rare progressing blood cancer that most often occurs in people over the age of 40 years but can also occur in children. Signs and symptoms can vary but for many patients, the cancer can be very aggressive and may require intensive treatment.
As Dr. Lamble explains, mutations in the gene, TP53, are the most common mutations in human cancer and occur in almost every cancer subtype. In adult AML, TP53 mutations are associated with a poor prognosis. However, given the rarity of these mutations in pediatric AML, less is known about its prognostic significance in this age group.
In this investigation, TP53 variant status was determined in children with AML enrolled on four clinical trials (NCT00002798, NCT00070174, NCT01407757, NCT01371981). Next generation sequencing was retrospectively employed on diagnostic specimens to screen for variants.
Of 1790 patients (median age 10.48 years), 68 (3.8%) had TP53 variants. Of these, 26 (38.2%) were considered likely pathogenic or pathogenic, 33 (48.5%) were considered likely benign or benign, and the remaining nine (13.2%) were of unknown significance.
Disease characteristics and clinical outcomes were compared between patients with likely pathogenic or pathogenic TP53 mutations and patients without any TP53 variant.
While there were no differences in complete remission rates (TP53 mutation: 85% vs. no TP53 mutation: 77.6%; p=0.426) or their ability to clear minimal residual disease (TP53 mutation: 55% vs. no TP53 mutation: 71.6%; p=0.132), patients with TP53 mutations had a lower event-free survival (EFS) compared to patients without any TP53 variant (5yr: 13.3% vs. 46.3%; p <.0001), which was largely driven by a higher relapse risk (5yr: 76.5% vs. 42.1%; p <.0001). Salvageability following an event was largely unsuccessful for patients with TP53 mutations, including only 1 long-term survivor following an event, which contributed to a lower overall survival compared to patients without any TP53 variant (5yr: 15.9% vs. 64.7%; p < .0001).
Overall, these findings suggest TP53 pathogenic mutations should be considered high-risk defining lesions in pediatric AML. Given the poorer outcomes, clinical trials and novel targeted agents should be prioritized for relapsed patients with TP53 pathogenic mutations.
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