Ontogeny and Natural History of Therapy‐Related Clonal Hematopoiesis From a Multidisciplinary <scp>CHIP</scp> Clinic

Age-related changes in human hematopoietic stem cells (HSCs) often form the basis for clonal hematopoiesis (CH), which presages the development of overt myeloid neoplasm with variable risk. CH can also arise after exposure to chemotherapy, radiotherapy, or immune interventions. In this study, we performed clinico-genomic profiling of therapy-related CH (t-CH) (n = 67) versus de novo CH (n = 123) from a multidisciplinary CHIP Clinic. The most enriched mutations in t-CH were TET2 (26.2%), DNMT3A (22.4%), and TP53 (8.4%). Median latency period from the time of initial exposure to the diagnosis of t-CH was 6.96 ± 1.10 years. Patients with t-CH had inferior event-free survival compared to de novo CH (median 29.9 months versus 122.1 months, p = 0.0045). Overall survival was also shorter in t-CH versus de novo CH (median 55.3 months vs. 129.2 months, p = 0.043). Genes that imparted significantly increased risk for progression from t-CH to overt therapy-related myeloid neoplasm (t-MN) included JAK2 (relative risk (RR) 9.42, p = 0.0001), RUNX1 (RR 7.11, p = 0.001), EZH2 (RR 7.11, p = 0.001), and TET2 (RR 13.4, p = 0.01). Clonal dynamic modeling of patients with t-CH who progressed to overt t-MN showed an increase in the relative clonal fraction and new clonal outgrowth. In the t-CH cohort, higher mean variant allele frequency was observed in progressors versus non-progressors (77.1% vs. 30.6%, p = 0.017). This study sheds light onto outcomes for CH based on differing clinical ontogeny and has implications for previvorship for secondary malignancies.