Clonal hematopoiesis and risk of nonmyeloid subsequent malignant neoplasms after autologous hematopoietic cell transplantation

Abstract

Background: The association between clonal hematopoiesis (CH) and nonmyeloid subsequent malignant neoplasms (SMNs) after autologous hematopoietic cell transplantation (HCT) has not been explored. Methods: This was a retrospective cohort study of 1931 consecutive patients who underwent HCT between 2010 and 2016 at a single center. DNA from pre-HCT mobilized blood products was sequenced to identify CH variants (variant allele frequency [VAF] ≥2%). The primary outcome was 8-year(y) cumulative incidence of nonmyeloid SMNs. Multivariable regression analysis was used to evaluate the association between CH and nonmyeloid SMNs, as well as cause-specific mortality. Results: Median age at HCT was 58.8 y (range ¼ 18.4-78.1 y); 389 patients (20.1% of the cohort) had at least 1 CH variant and 94 (4.9%) had ≥2 variants. The 8 y cumulative incidence of nonmyeloid SMNs was significantly higher in patients with CH compared with those without (15.1% vs 7.2%, P < .001), and increased by VAF: 7.2% (VAF <2%), 14.0% (VAF 2% to <10%), 19.4% (VAF ≥10%); P ¼ .001. Patients with CH had a 2-fold increased risk of nonmyeloid SMNs (standardized incidence ratio ¼ 1.9), compared with the general population. In multivariable analysis, CH was an independent and significant risk factor for nonmyeloid SMNs (hazard ratio [HR] ¼ 1.72, 95% confidence interval [CI] ¼ 1.15 to 2.59). Finally, patients with CH had significantly worse survival, primarily due to the higher risk of nonrelapse mortality (HR ¼ 2.97, 95% CI ¼ 1.90 to 4.64). Conclusions: CH was significantly associated with the risk of nonmyeloid SMNs after HCT, and the magnitude of association increased by VAF. Clonal hematopoiesis may serve as a biomarker for identifying HCT survivors at higher risk for developing nonmyeloid SMNs.