Clonal Hematopoiesis and Risk of Heart Failure After Autologous Hematopoietic Cell Transplantation for Lymphoma

Abstract

Background: Patients with lymphoma are at high risk for developing heart failure (HF) after autologous hematopoietic cell transplantation (HCT). More accurate risk determination pre-HCT may facilitate screening and prevention of HF.

Objectives: The aim of this study was to examine the association between clonal hematopoiesis of indeterminate potential (CHIP) and the risk for HF after HCT for lymphoma.

Methods: This was a retrospective cohort study of 861 patients who underwent autologous HCT for lymphoma between 2010 and 2016 at City of Hope Comprehensive Cancer Center. Targeted DNA sequencing was performed to determine the presence of CHIP (variant allele frequency ≥ 2%). The primary outcome of interest was the 5-year cumulative incidence of de novo HF. Other outcomes of interest included overall and cause-specific mortality.

Results: Overall, 186 patients (21.7% of the cohort) had at least 1 CHIP variant, and 59 (6.9%) had ≥2 variants. DNMT3A, PPM1D, and TET2 were the most frequently mutated genes. The 5-year incidence of HF was significantly higher in patients with CHIP compared with those without CHIP (13.8% vs 4.7%; P < 0.001; sub-distribution hazard ratio [sHR]: 2.48; 95% CI: 1.32-4.68); the HF incidence increased by variant allele frequency: 0-2% (4.7%), 2-10% (11.7%), and >10% (18.5%), P < 0.001. Patients with CHIP had significantly worse overall survival after HCT, compared with those without (63.4% vs 80.3%; P < 0.001), due primarily to the higher risk for nonrelapse mortality (subdistribution HR: 5.37; 95% CI: 2.34-12.35).

Conclusions: CHIP was highly prevalent and associated with risk for HF and nonrelapse mortality after HCT. These findings highlight the role of CHIP as a novel biomarker and potential target for intervention to improve outcomes after autologous HCT.

Keywords: CHIP; autologous hematopoietic cell transplantation; biomarkers; heart failure; lymphoma; nonrelapse mortality.

Graphical abstract

Figure 1

Characteristics of CHIP Mutations (A) Number of patients harboring clonal hematopoiesis of indeterminate potential (CHIP) mutations in 1, 2, and 3 or more different genes. (B) Prevalence of CHIP according to age groups at transplantation. (C) Spectrum of variant allele frequencies (VAFs) in genes. (D) Number of patients with specific gene mutations. (E) Percentages of the different mutation subtypes for 4 of the most prevalent CHIP genes. Red denotes missense, green denotes nonsense, blue denotes frameshift, and yellow denotes splicing variants. (F) Comutation plot showing mutations present in all 186 patients: each column represents a single patient. Solid green denotes a single mutation, green with a white slash denotes double mutations, and solid red denotes triple mutations in the same gene. The VAF cutoff used to call mutations was 0.02. Max = maximum.

Figure 2

Five-Year Cumulative Incidence of Heart Failure Five-year cumulative incidence of heart failure according to (A) the presence of CHIP and (B) CHIP VAF categories (no CHIP, VAF ≤ 10%, and VAF > 10%). HCT = hematopoietic cell transplantation; other abbreviations as in Figure 1.

Figure 3

Modifiable Cardiovascular Risk Factors, CHIP, and the Risk for Heart Failure Subdistribution HRs (sHRs) and 95% CIs for heart failure outcomes according to the prespecified categories on the basis of clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular risk factor status (A, hypertension [HTN]; B, diabetes mellitus [DM]; C, dyslipidemia [HLD]), adjusted for age, sex, HCT-specific comorbidity index, diagnosis, conditioning regimen, and respective cardiovascular risk factors. ref = reference.

Figure 4

Survival Outcomes (A) Cumulative incidence of all-cause mortality following HCT. (B, C) Cumulative incidence of cause-specific mortality following HCT according to the relapse status: (B) relapse-related mortality and (C) nonrelapse mortality. Abbreviations as in Figure 1.

Central Illustration

CHIP and Risk of Heart Failure and Nonrelapse Mortality After Hematopoietic Cell Transplantation DNA was extracted from cryopreserved mobilized peripheral blood stem cells of 861 patients who underwent autologous hematopoietic cell transplantation (HCT) for lymphoma. Targeted gene sequencing of isolated DNA revealed a rate of pre-HCT clonal hematopoiesis of indeterminate potential (CHIP) of 21.7%. The 5-year incidence of heart failure after HCT was significantly higher in patients with CHIP compared with those without CHIP (13.8% vs 4.7%; P < 0.001; subdistribution HR [sHR]: 2.48; 95% CI: 1.32-4.68). Patients with CHIP also had significantly worse overall survival after HCT, due primarily to the higher risk for nonrelapse mortality (sHR: 5.37; 95% CI: 2.34-12.35). ∗Created using BioRender.com.