Clonal hematopoiesis and risk of non-myeloid subsequent malignant neoplasms after autologous hematopoietic cell transplantation

Purpose Examine the association between clonal hematopoiesis (CH) and non-myeloid subsequent malignant neoplasms (SMNs) after autologous hematopoietic cell transplantation (HCT). Methods This was a retrospective cohort study of 1,931 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 (CI) of non-myeloid SMNs. Multivariable regression analysis was used to evaluate the association between CH and non-myeloid SMNs, as well as cause-specific mortality. Results Median age at HCT was 58.8 y (range 18.4-78.1y); 389 patients (20.1% of the cohort) had at least one CH variant and 94 (4.9%) had ≥2 variants. The 8 y CI of non-myeloid SMNs was significantly higher in patients with CH compared to those without (15.1% vs 7.2%, p < .001), and increased by VAF: 7.2% (VAF <2%), 14.0% (VAF 2– <10%), 19.4% (VAF ≥10%); p = .001. Patients with CH had a two-fold increased risk of non-myeloid SMNs (standardized incidence ratio = 1.9), compared with the general population. In multivariable analysis, CH was an independent and significant risk factor for non-myeloid SMNs (hazard ratio [HR]=1.72, 95%CI 1.15–2.59). Finally, patients with CH had significantly worse survival, primarily due to the higher risk of non-relapse mortality (HR: 2.97, 95%CI: 1.90-4.64). Conclusions CH was significantly associated with risk of non-myeloid SMNs after HCT, and the magnitude of association increased by VAF. CH may serve as a biomarker for identifying HCT survivors at higher risk for developing non-myeloid SMNs.