Defining the Landscape of Mutations Present in Pediatric Acute Lymphoblastic Leukemia

Researchers defined the landscape of mutations that preexist and arise after commencement of acute lymphocytic leukemia (ALL) therapy in pediatric patients, and demonstrated that relapse may be transmitted from ancestral, major, or minor clones at initial diagnosis, according to a study published in the American Association for Cancer Research’s latest journal, Blood Cancer Discovery.¹

A subset of cases was also found to display hypermutation that results in expression of neoepitopes that may be substrates for immunotherapeutic intervention.

“ALL is one of the most common causes of death from cancer for children in the United States,” study author Charles G. Mullighan, MD, member of the Department of Pathology and deputy director of the St. Jude Children’s Research Hospital Comprehensive Cancer Center, said in a press release.² “Our study provides a tapestry of the genetic changes in pediatric ALL and how these genetic changes alter over time as the patient is treated and as the leukemia relapses. This information has the potential to be translated into new strategies for early detection of relapse and the development of treatments to prevent clinical occurrence.” 

In this cohort of 92 children with relapsed ALL, 67 with B-cell ALL, and 25 with T-cell ALL, researchers incorporated multimodal DNA and RNA sequencing, deep digital mutational track, and xenografting to formally define clonal structure, from which they identified 50 significant targets of mutation with distinct patterns of mutational acquisition or enrichment. 

From this analysis, it was indicated that CREBBP, NOTCH1, and RAS signaling mutations derived from diagnosis subclones, whereas variants in NCOR2, USH2A, and NT5C2 were solely observed at relapse. Furthermore, over time an increase in RAS pathway mutations was observed in B-cell ALL relapse. RAS pathway mutations made up 17.9% of the mutations in patients at diagnosis, and 31.3% of the mutations at relapse. In patients with T-cell ALL, PI3K-AKT pathway mutations were common at diagnosis and infrequently detected at relapse.

Evolutionary modeling and xenografting determined that relapse-fated clones were minor (50%), major (27%), or multiclonal (18%) at diagnosis. Putative second leukemias, including those with lineage shift, were shown to most often represent relapse from an ancestral clone rather than a truly independent second primary leukemia. A subset of leukemias prone to repeated relapse exhibited hypermutation driven by at least 3 distinct mutational processes, resulting in heightened neoepitope burden and possible vulnerability to immunotherapy. 

Additionally, relapse-driving sequence mutations were detected prior to relapse using droplet digital polymerase chain reaction (PCR) at levels corresponding to orthogonal approaches to monitor levels of measurable residual disease. Altogether, these results provide a genomic framework to anticipate and circumvent relapse by earlier detection and targeting of relapse-fated clones. 

In regard to next steps, the authors wrote, “It will now be of great interest to formally document the presence of autoreactive T-cell clones directed at neoepitopes induced by hypermutation, as we have described at diagnosis in ALL, and to formally test, in experimental models, whether immunomodulatory approaches can augment or restore antitumor reactivity in hypermutated ALL.” 

According to the study, relapsed ALL is the second leading cause of cancer-related death in children. The early identification and genetic characterization of relapse fated clones provide the opportunity to enhance treatment outcomes by preparing for relapse and adjusting therapy accordingly, or by targeting relapse-fated clones before the receipt of additional mutations facilitating leukemic progression. 

References:

1. Waanders E, Gu Z, Dobson SM, et al. Mutational Landscape and Patterns of Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia. Blood Cancer Discovery. doi:10.1158/0008-5472.BCD-19-0041.

2. New AACR Journal, Blood Cancer Discovery, Publishes Its First Paper [news release]. Philadelphia, Pennsylvania. Published January 16, 2020. Accessed January 16, 2020.