228 - Impact of Radiotherapy Site, Modality, and Dose on Subsequent Clonal Hematopoiesis
Presenter(s)
A. G. Goglia1, G. R. Mustion2, L. A. Modlin1, R. L. Levine3, K. Bolton2, and L. Z. Braunstein1; 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 2Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, 3Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Purpose/Objective(s): Clonal hematopoiesis (CH) is the premalignant clonal outgrowth of blood stem and progenitor cells harboring somatic mutations, and carries an increased risk of leukemia and all-cause mortality. Exposure to radiotherapy (RT) can promote expansion of CH clones, particularly those carrying mutations in DNA damage response (DDR) genes like TP53. Notably, TP53-mutant CH is the most common precursor to therapy-related myeloid neoplasms (tMN) and understanding how RT impacts CH can provide insights into its relationship with tMN risk. However, RT is not a uniform treatment and can be delivered with variable doses and techniques to distinct anatomic compartments. It remains unknown how these parameters affect CH and subsequent risk of tMN.
Materials/Methods: We identified CH among patients who underwent targeted, deep-coverage sequencing from paired blood and tumor samples (MSK IMPACT). CH was defined as a somatic putative-driver mutation with a minimum variant allele frequency of 2%. CH mutations in the DDR genes TP53, PPM1D, ATM, and CHEK2 were defined as DDR-CH. Equivalent radiation dose in 2 Gy fractions (EQD2) was calculated with an a/ß of 3 for late effects. We used logistic regression adjusted for age, race, time from diagnosis to blood draw, smoking status, and chemotherapy class to test for association between RT parameters and CH.
Results: We identified 2,195 patients who previously received RT, encompassing 57 primary tumor histologies. After RT, 22% had =1 CH mutation (n=486) and 6.4% had =1 DDR-CH mutation (n=140). EQD2 was associated with the presence of CH across all samples (OR=1.3 per 10Gy; p=1.2×10-5), with a stronger association for DDR-CH (OR=1.5; p=6×10-6) than non-DDR-CH (OR=1.2; p=1.4×10-2). We found no association between RT modality and either CH overall or DDR-CH. We then quantified EQD2 within irradiated anatomic sites and identified site-dependent differences in the strength of association between RT and DDR-CH. Total dose to the head and neck (OR=2.2; p=9×10-3), pelvis (OR=2.2; p=5×10-2), brain (OR=1.7; p=2×10-2), and thorax (OR=1.5; p=3×10-2) was significantly associated with DDR-CH.
Conclusion: RT late effects are defined largely by the site treated and the dose/fractionation delivered. While RT has been linked to risk of CH, this is the first study to assess this risk with respect to technique, dose, and site. The four anatomic sites associated here with DDR-CH account for 60-70% of adult bone marrow, suggesting that CH risk may depend on total marrow dose and not secondary systemic effects. RT modality was not associated with CH, allaying concerns regarding low-dose exposure from IMRT. Our findings carry implications for informed decision-making in several malignancies with frequent long-term survivorship following RT (e.g., breast, prostate, head and neck). Future work to characterize the relationship between RT, CH evolution, and progression to tMN is needed to evaluate the potential of CH screening to identify those at high risk of RT-related CH and tMN.