TP53 Variants Increase Risk for Pediatric ALL, Adverse Treatment Outcomes

Jun J. Yang, PhD

Children with TP53 pathogenic variants were more likely to both develop acute lymphoblastic leukemia (ALL), as well as secondary cancers later on, according to an analysis of 3801 Children with newly diagnosed B-cell ALL enrolled in 2 consecutive Children’s Oncology Group trials.

Investigators performed a comprehensive screening of TP53 germline variation in children who were enrolled in the frontline AALL0232 and P9900 trials to identify leukemia risk variants in this gene and evaluate their association with clinical features and treatment outcomes. Overall, 26 patients carried 22 pathogenic variants, 51 patients carried variant of unknown significance (VUS), and 3724 patients carried wild-type variants.

Children who were positive for TP53 pathogenic variants were significantly more likely to develop ALL compared with non-ALL control patients (OR, 5.2; P <.001). Carrying germline TP53 pathogenic variants was associated with inferior event-free survival (EFS; HR, 4.2; P <.001) and overall survival (OS; HR, 3.9; P <.001).

Five-year cumulative incidence for secondary cancers was 25.1% for children with TP53 pathogenic variants compared with just 0.7% for those without pathogenic variants (P <.001).

“These germline variations are a double whammy for carriers,” corresponding author Jun J. Yang, PhD, an associate member of the St. Jude Department of Pharmaceutical Sciences and Department of Oncology, said in a press release. “Not only is their risk of developing leukemia very high, they are also more likely to relapse or develop a second cancer.”

Yang said the association between the high-risk variants and second cancers is so significant that St. Jude researchers are exploring ways to help patients and families manage the risk.

“The ALL treatment might have added to that risk but we do not know for sure. Maybe these patients should avoid certain ALL therapies in order to reduce their risk of developing another cancer,” he said. “I believe this finding may change treatment and follow-up for these high-risk patients.”

ALL is the most common cancer in children, though the disease is highly curable with contemporary risk-stratified combination chemotherapy. However, up to 20% of patients experience relapse, and most of those who relapse eventually die of ALL despite salvage chemotherapy and/or hematopoietic stem cell transplant. Even for children who achieve long-term remission, ALL therapy is associated with acute and late toxicities, including the development of treatment-related secondary cancers.

Because the importance of TP53 in tumor suppression and tumor drug response, investigators initiated this study based on the hypothesis that function-altering genetic variants in the TP53 gene would predispose children to adverse outcomes from ALL therapy.

Children with TP53 pathogenic variants were significantly older at ALL diagnosis (15.5 vs 7.3 years; P <.001) and were more likely to have hypodiploid ALL (65.4% vs 1.2%; P <.001). Hypodiploid ALL was only present in 3.9% of children with TP53 VUS and 1.2% of those with wild-type genotype. The prevalence of TP53 pathogenic variants did not differ by genetic ancestry (P = .9).

Carriers of the pathogenic variants also had significantly lower leukocyte count at presentation than did those with a VUS or wild-type genotype (P = .006).

When investigators examined the relationship between germline TP53 variants and treatment outcomes of ALL therapy, they found that the presence of a TP53 pathogenic variant was associated with a significantly lower EFS and OS compared with patients without pathogenic variants. The association remained significant on multivariable analyses even after adjusting for ancestry, age and leukocyte count at diagnosis, and minimal residual disease at the end of remission induction therapy for both EFS (HR, 3.4; 95% CI, 1.8-6.3; P = .0002) and OS (HR, 2.9; 95% CI, 1.3-6.2; P = .007). Adding hypodiploidy to this regression model diminished the prognostic value of germline TP53 risk variants for EFS (P = .2) and OS (P = .9).

Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children [published online January 4, 2018]. J Clin Oncol doi: 10.1200/JCO.2017.75.5215.