Children's Health UT Southwestern Medical Center (Children's Medical Center) Archives

2019

Scholar Grant

Kathryn Dickerson

Dallas, TX

Title: Defining Clonal Hematopoiesis in Childhood Cancer Survivors: A Novel Approach to Predicting Therapy-Related Myeloid Neoplasms

Executive Summary:
Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) occur as the result of a patient’s cancer treatment and represent the therapy-related myeloid neoplasms (tMN) that plague the survivor community. Although tMNs affect just 1% of childhood cancer survivors, they confer an even poorer prognosis than that of primary AML/MDS with an overall survival (OS) of 32% and require aggressive treatment with a hematopoietic stem cell transplant (HSCT) for cure. tMN patients have been heavily treated for their initial diseases, therefore treatment modalities are extremely limited and the abundance of leukemic blasts directly impacts the success of HSCT. The ability to detect tMNs prior to leukemic transformation or prior to the development of a significant disease burden would lead to significant improvement in cure rates for this patient population.
Clonal hematopoiesis is widely accepted as a consequence of aging and it has been well established as a precursor to AML/MDS. With the improvement of cure rates in childhood cancer, there is a growing survivor cohort and a need to study the late effects of chemoradiotherapy. The Childhood Cancer Survivor Study (CCCS) has demonstrated across tumor types a phenomenon of accelerated aging in childhood cancer survivors culminating in subsequent neoplasms, stroke, and cardiac events. In the CCCS, 24-year old survivors of childhood cancer had the same cumulative incidence of grade 3-5 health conditions as a 50-year old sibling.
The study of the structure and dynamics of clonal hematopoiesis at the single cell level has never been performed in children and childhood cancer survivors. Hence, this represents a critical gap in knowledge in identifying the genetic basis of clonal hematopoiesis in childhood cancer survivors, which when elucidated will allow for improvement in decision of timing to HSCT or the discovery of new targeted therapies for this high-risk disease that would mitigate the need for HSCT for cure.
We hypothesize that childhood cancer survivors are at increased risk of clonal hematopoiesis from accelerated aging and thus they are at an increased risk of leukemia/myelodysplasia, a risk augmented further by their exposure to mutagenic chemo/radiotherapy.
• Aim 1 will define the incidence of clonal hematopoiesis in childhood cancer survivors and yield a list of mutations to be evaluated for malignant potential.
• Aim 2 will define the structure and dynamic of clonal hematopoiesis at the single cell level, which will help to better understand the cooperative nature and burden of mutations that tip a patient from clonal hematopoiesis to tMN.
This proposal will not only confirm that clonal hematopoiesis occurs at a higher rate in pediatric cancer survivors, but also identify cooperative mutations that can be evaluated for greatest leukemic potential. This discovery will allow for active surveillance for tMN in cancer survivors.