Clinical Implications of Treatment-Related Clonal Hematopoiesis in Adolescent and Young Adult Survivors of Acute Lymphoblastic Leukemia

Children and young adults with acute lymphoblastic leukemia (ALL) are exposed to intensive cytotoxic chemotherapy early in life, which increases the risk of developing long-term complications such as cardiovascular disease (CVD), bone loss, and subsequent malignancies. These genotoxic therapies may induce or select for therapy-related clonal hematopoiesis (CH), characterized by mutations in hematopoietic cells in the absence of an overt hematologic malignancy. CH has been associated with risk for blood cancers, CVD, osteoporosis, and other inflammatory disorders, all of which are complications that are routinely monitored for in ALL survivors. Therefore, we investigated the prevalence of CH and its association with long-term treatment-related complications in ALL survivors.

We prospectively evaluated 66 consecutive ALL survivors seen at the Childhood, Adolescent and Young Adult Survivor Clinic at the University of Chicago, who underwent comprehensive clinical assessment for treatment-related toxicities. All participants were treated with intensive pediatric or pediatric-inspired young adult chemotherapy regimens. For CH assessment, DNA was extracted from whole peripheral blood and sequenced using a hybrid capture-based targeted gene panel, covering for 22 genes and 95% of CH mutations found in the general population, reaching a depth of 2000x coverage and allelic frequency (AF) sensitivity of 0.01%. We defined presence of CH (CH+) when a variant was identified at AF >0.1%.

Among the 66 survivors studied, the median age was 25.8 years (range, 4–48 years), 53% were female. Participants were 52% White, 26% Hispanic, 11% Black, and 11% did not report race. The interval between ALL diagnosis and assessment of CH in survivors was 6.1 years (range, 0.1 – 30 years). None of the survivors had CH with AF >1%, similarly to historically reported CH frequency in age-matched healthy controls (Jaiswal et al., NEJM 2014). Therefore, we looked at CH clones with AF 0.1–1%. 64% of survivors had at least one CH clone: 41% in one gene, 17% in two genes, 6% in three genes. Most frequently mutated genes included TP53 (58%, median AF 0.1%), DNMT3A (11%, median AF 0.2%), SF3B1 (11%, median AF 0.1%) and KRAS (9%, median AF 0.1%).

When CH+ vs CH- survivors were compared, we did not observe any differences in median age (23 vs 26 years respectively, p= 0.88) or female sex (45% vs 66%, p= 0.12). Among hematologic parameters, platelet count at the time of sample collection was lower in CH+ survivors vs CH- survivors (210 vs 267 x10⁹/L, p= 0.01). We observed a trend towards increased frequency of osteopenia (12% vs 0), osteoporosis (10% vs 0), and avascular necrosis (17% vs 8%), in CH+ survivors when compared to those with CH-. However, none of these comparisons reached statistical significance.

In this ongoing prospective study of CH in ALL survivors, we did not observe an appreciable increase in prevalence of CH at 1% AF when compared to healthy individuals without genotoxic treatment exposure. However, we identified a high prevalence of TP53 clones at low AF, which is expected with therapy-related CH. We report for the first time on the CH landscape in ALL survivors and show that CH in our studied population did not correlate with age. This is likely due to the treatment-related selection of clones harboring mutations in DNA damage repair genes. Additional samples and timepoints are being studied to better understand the impact of CH on long-term complications of therapy.