Effects of radiation therapy on clonal hematopoiesis.

Abstract

12062 Background: Clonal hematopoiesis (CH), characterized by recurrent somatic mutations in blood, is a common age-associated condition that portends an increased risk of myeloid neoplasms and cardiac disease. Oncologic therapies appear to promote CH, including ionizing radiation therapy (RT) (OR = 1.4, p < 10−6) and systemic DNA-damaging agents (OR = 1.2, p = 8x10−4). How various RT parameters (e.g. target site, dose, fractionation, modality) may influence CH is unknown. Methods: CH mutations were identified via targeted, deep-coverage next-generation sequencing from paired peripheral blood and tumor samples (MSK-IMPACT). CH was defined as a somatic blood mutation with a minimum variant allele frequency of 2%. Putative driver mutations (CH-PD) were identified from OncoKB and other published sources. Clinical and RT characteristics were abstracted from medical records. To account for differences in RT dose and fractionation, equivalent radiation dose in 2 Gy fractions (EQD2) with an α/β ratio of 3 for late effects was calculated. Univariate and logistic regression modeling for associations between clinical and treatment parameters and CH were performed. Results: We identified 2,195 patients who received RT before blood draw and 7,832 who did not, encompassing 57 histologies. A median of 267 days elapsed between the end of RT and blood draw. After RT, 22% of patients had at least one CH-PD mutation (n = 486). The most common single anatomic sites radiated were pelvis, chest wall/breast, and head and neck. Conventional RT was used in 2% (n = 46), 3D-conformal in 14% (n = 308), intensity modulated RT in 36% (n = 787), volumetric modulated arc RT in 12% (n = 263), multiple techniques in 26% (n = 560), and unknown in 11% (n = 231). There was no association between RT modality and presence of CH-PD (p > 0.05 for all between group comparisons of modality). On multivariate regression after controlling for age, race, time from diagnosis to blood draw, smoking status, and for chemotherapy class, cytotoxic, immune, or targeted therapies in the entire cohort, EQD2 was associated with CH-PD (p = 0.012x10−3). Evaluating EQD2 by irradiated anatomic site, total pelvic dose by EQD2 in 10 Gy increments remained significantly associated with CH-PD (OR = 1.07, p = 0.0046), as was head and neck EQD2 (OR = 1.046, p = 0.032). Conclusions: CH-PD was associated with higher radiation dose for pelvic or head and neck RT, but not other anatomic sites after controlling for systemic therapies. RT modality was not associated with CH-PD. Ongoing work will directly evaluate the bone marrow dosimetry of various treatment approaches using phantom-based modeling.