Clonal Hematopoiesis Is Associated with Cardiovascular Disease Risk and Worse Survival after Autologous Hematopoietic Cell Transplantation for Lymphoma

Introduction: Autologous hematopoietic cell transplantation (HCT) is an effective treatment for patients with relapsed or refractory lymphoma, and use of HCT has contributed to a growing number of survivors. Despite these improvements in outcomes, long-term survivors of lymphoma are at high risk of developing clinically significant cardiovascular disease (CVD) which, to date, has largely been attributed to pre-HCT cardiotoxic therapeutic exposures (e.g. anthracyclines, radiation) and modifiable risk factors (e.g. hypertension, diabetes, dyslipidemia) after HCT. In the general population, clonal hematopoiesis of indeterminate potential (CHIP), which refers to clonal expansion of hematopoietic stem cells with somatic mutations, has been associated with aging-related health conditions including CVD. Accumulating data suggests CHIP is more prevalent in cancer patients compared to age-matched controls, due in part to clonal selection after genotoxic stressors. There is a paucity of information about the association between CHIP and CVD after HCT, including its interaction with modifiable risk factors and subsequent impact on survival after HCT.

Methods: This was a retrospective cohort study of 861 consecutive patients who underwent autologous HCT for lymphoma between 2010 and 2016, with available pre-HCT DNA obtained from peripheral blood stem cells. We performed targeted exome sequencing of DNA (92 pre-defined gene panel with 1000x sequencing depth) to determine the presence of CHIP (variant allele frequency ≥2%). CVD outcomes of interest included de novo heart failure, coronary artery disease and stroke after HCT. Five-year cumulative incidence of CVD was calculated taking into consideration competing risk of death. Fine-Gray multivariable regression was used to evaluate the association between CHIP and CVD, adjusting for demographic, clinical and therapeutic factors. The Kaplan-Meier method was used to examine the effect of CHIP on overall survival after HCT.

Results: Median age at HCT was 55.7 years (range 18.4-78.1 years); 63.3% were male; race/ethnicity: non-Hispanic White (56.9%), Hispanic (26.1%), Asian (10.8%), Black (5.1%); 78.0% had non-Hodgkin lymphoma; comorbidities at HCT: hypertension (32.1%), dyslipidemia (16.4%), diabetes (10.1%), high (≥3) HCT-comorbidity index (CI) score (46.1%). Nearly all patients (94.3%) had received anthracycline-based chemotherapy prior to HCT, and 63.3% were treated with cumulative dose ≥300mg/m ²; 6% had chest radiotherapy. Overall, 186 patients (21.7% of the cohort) had at least one CHIP variant and 57 (6.6%) had ≥2 variants. DNMT3A, PPM1D, TET2 and TP53 were the most frequently mutated genes. In total, 74 patients developed CVD within five years from HCT. The 5-year cumulative incidence of CVD was significantly higher in patients with CHIP (20.9% vs 9.1%, p<0.001), compared to those without CHIP, and there was a graded relationship between number of CHIP variants and incidence of CVD. In the adjusted (age, cancer diagnosis, HCT-CI, modifiable cardiovascular risk factors) multivariable model, CHIP was significantly and independently associated with a nearly two-fold (HR: 1.8, 95% CI=1.1-3.1; P=0.020) risk of CVD, as well as the individual outcome of heart failure (HR: 2.3, 95%CI=1.3-4.3; P=0.008). Patients who had both CHIP and hypertension had a 3-fold (HR: 3.0, 95%CI=1.4-6.5, p=0.006) risk of CVD (reference: no CHIP, no hypertension). Overall 5-year survival after HCT was significantly worse in patients with CHIP, compared to those without CHIP (47.2% vs 68.2%, p<0.001; adjusted HR: 1.9, 95%CI=1.4-2.6), attributed to the higher burden of non-relapse mortality in patients with CHIP.

Conclusions: In this well-characterized and demographically diverse cohort of lymphoma patients undergoing HCT, CHIP was highly prevalent and associated with a significantly higher risk of CVD after HCT, with the highest risk among those with CHIP and hypertension. We confirmed the poor overall survival rate in patients with CHIP, independent of patient and disease-related risk factors. These findings highlight the potential role of CHIP as a novel biomarker to better define CVD risk in patients with lymphoma prior to HCT, setting the stage for better screening and implementation of interventions (e.g., aggressive management of modifiable risk factors) to reduce the risk of CVD and to ultimately improve long-term health outcomes after HCT.