For patients with lymphoma who underwent autologous hematopoietic cell transplantation (AHCT), clonal hematopoiesis of indeterminate potential (CHIP) was highly prevalent before AHCT and was associated with an increased risk for heart failure (HF) after AHCT, more so in patients with hypertension. This is according to a study published in JACC: CardioOncology, which also found that patients with CHIP had poorer survival outcomes than those without CHIP, mainly due to an increased risk for non-relapse mortality (NRM).
“Our findings suggest that CHIP detected at the time of HCT may serve as a biomarker for stratifying patients’ risk of heart failure and NRM,” said first author June-Wha Rhee, MD, of City of Hope Comprehensive Cancer Center in Duarte, California. “This information can guide clinical decision-making prior to HCT by identifying high-risk patients and supporting consideration of alternative treatments, such as chimeric antigen receptor T-cell (CAR-T) therapy, which is emerging as a viable option for some patients. Additionally, recognizing CHIP as a risk factor may support the implementation of enhanced post-HCT surveillance and early interventions aimed at reducing cardiovascular complications. However, further prospective research is needed to determine how best to incorporate CHIP screening into clinical practice and assess its impact on patient outcomes.”
This retrospective cohort study included 861 patients (median age at AHCT = 55.7 years, range = 18.4-87.1; 63.3% male; 46.1% with AHCT-specific comorbidity index ≥3; 78.0% with non-Hodgkin lymphoma) who underwent AHCT for lymphoma between 2010 and 2016. The researchers examined the association between pre-AHCT CHIP (variant allele frequency [VAF] ≥ 2% as per targeted DNA sequencing) and HF. The primary outcome was the five-year cumulative incidence of de novo HF. The researchers also looked at the relationship between modifiable cardiovascular risk factors and CHIP in curbing HF risk and the impact of CHIP on survival after AHCT.
At least one CHIP variant was present in 21.7% of patients, and 6.9% presented with two or more CHIP variants. The prevalence of CHIP increased with age as follows: 4.2% for patients younger than 50 years, 20.4% for 50 to 59 years, 36.8% for 60 to 69 years, and 52.2% for those 70 years or older. The most frequently mutated genes included DNMT3A, PPM1D, and TET2. The five-year cumulative incidence of de novo HF struck more patients with CHIP (13.8%) than without CHIP (4.7%; p<0.001). The HF incidence increased with VAF: no CHIP (4.7%), VAF 10% or less (11.7%), and VAF greater than 10% (18.5%). Patients with CHIP had worse five-year overall survival (63.4%) after AHCT compared with those without CHIP (80.3%; p<0.001), mainly due to the higher risk for NRM.
Hypertension (32.1%) was the most prevalent cardiovascular risk factor at AHCT, followed by dyslipidemia (24.5%) and diabetes (14.2%). Moreover, an incremental increase in HF incidence occurred across the following categories: no CHIP and no hypertension (3.2%), no CHIP and hypertension (8.5%), CHIP and no hypertension (11.2%), and CHIP and hypertension (17.6%; p<0.001).
“I’d like to emphasize the important role of modifiable cardiovascular risk factors, such as hypertension, diabetes, and dyslipidemia, in shaping outcomes for patients with CHIP,” Dr. Rhee said. “Our findings highlight that patients with both CHIP and hypertension have a five-fold increased risk of developing heart failure, and the five-year cumulative incidence of heart failure in patients with CHIP and diabetes exceeds 20%. These results underscore the need for personalized risk management strategies, including early screening and targeted interventions, such as intensive blood pressure control and optimized glycemic management. Addressing these modifiable risk factors may be a critical step in reducing the cardiovascular burden in this high-risk population.”
A limitation of the study is the fact that some CHIP mutations may overlap with lymphoma-related circulating tumor DNA. However, the authors noted that most mutations were not lymphoma specific, and no significant link was found between remission status at AHCT and CHIP risk. Other limitations included the lack of longitudinal blood sampling to determine the extent to which clonal expansion of CHIP contributed to HF. The researchers also cited missing data on blood pressure, smoking history, and coronary artery disease, which could influence HF risk. Additionally, the absence of left ventricular ejection fraction data restricted classification of HF subtypes.
“Our findings will need to be further examined in the context of patients with lymphoma with varying therapeutic exposures (e.g., without HCT) and also validated in an independent cohort, setting the stage for broader integration of CHIP during and after lymphoma treatment,” the researchers noted.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Rhee JW, Pillai R, Chen S, et al. Clonal hematopoiesis and risk of heart failure after autologous hematopoietic cell transplantation for lymphoma. JACC CardioOncol. 2025;7(1):20-33.
