CHIP Present Before HCT Linked With Later CVD Risk in Multiple Myeloma

In patients with multiple myeloma, clonal hematopoiesis of indeterminate potential (CHIP) seen at the time of hematopoietic stem transplant (HCT) was independently and significantly associated with the risk of cardiovascular disease (CVD) in the years following HCT, according to a study published in JAMA Cardiology. The findings suggest CHIP could potentially be a biomarker for CVD among this patient population.

“Research into survivorship issues during the past 2 decades has highlighted the high risk for developing CVD following autologous HCT, especially among patients with lymphoma attributed to pre-HCT exposures to cardiotoxic chemotherapies, HCT-associated conditioning exposures, and de novo modifiable cardiovascular risk factors (eg, hypertension, diabetes, dyslipidemia) that emerge after HCT,” the authors wrote. “Yet, there is a paucity of information on the risk of CVD after HCT for patients with MM, including the role of emerging biologic modifiers of CVD risk in the general population.”

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CHIP, which entails the clonal expansion of hematopoietic stem cells driven by a leukemogenic mutation in patients who do not have leukemia, has been associated with coronary artery disease (CAD), heart failure, and stroke in patients without cancer.

The study aimed to fill knowledge gaps around the association of pre-HCT CHIP and post-HCT CVD in patients with multiple myeloma. The primary end point was cumulative incidence and the risk for developing CVD—heart failure, coronary artery disease, or stroke—at 5 years after HCT.

The retrospective cohort study included 1036 consecutive patients with multiple myeloma who underwent HCT at City of Hope Comprehensive Cancer Center in Duarte, California, between 2010 and 2016. All patients included had cryopreserved pre-HCT mobilized peripheral blood stem cell (PBSC) samples available, and CHIP was detected via targeted DNA sequencing, with patients considered positive if the variant allele frequency was 2% or more.

Of the overall patient population, 201 patients (19.4%) had at least 1 CHIP variant, and 35 (3.4%) showed 2 or more variants before their first autologous HCT.

In patients with CHIP, the 5-year CVD incidence was 21.1%, compared with 8.4% in those without CHIP (P < .001). There was a graded association, and patients with 2 or more variants had a 5-year CVD incidence of 25.6%. Having CHIP before HCT remained associated with an increased CVD risk in a multivariable model (HR, 2.72; 95% CI, 1.70-4.39).

The presence of CHIP prior to HCT was also associated with other individual outcomes within the realm of CVD. Those with CHIP were at higher risks of heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52).

Other CVD risk factors were Black race, older age at the time of HCT, a high HCT Comorbidity Index score, hypertension, and dyslipidemia.

Patients who had both CHIP and preexisting hypertension or dyslipidemia were at substantially higher risk of CVD. Patients with preexisting hypertension and CHIP were at almost 7 times the risk of CVD (HR, 6.64; 95% CI, 2.97-14.83) compared with patients with no CHIP and no hypertension; those with CHIP and dyslipidemia were at almost 4 times the risk of CVD (HR, 3.87; 95% CI, 2.02-7.44) compared with those with no CHIP and no dyslipidemia.

The study was limited by a lack of serial blood sampling after HCT to determine the course of CHIP variants after HCT, although the authors noted that recent research shows that once CHIP is acquired, it is persistent. The researchers also did not have data on post-HCT therapies that may lead to cardiovascular risk.

However, the findings suggest that CHIP before HCT may influence CVD risk after HCT in patients with multiple myeloma.

“These findings may inform more targeted approaches to screening for CVD risk, allowing for improved CVD risk prediction prior to HCT and to guide the implementation of personalized preventive measures to improve health outcomes in at-risk patients,” the authors wrote. “Additional studies are needed to further delineate if the association between CHIP and CVD exists in other cancer populations (eg, solid tumors, nonleukemic hematologic cancers) and to interrogate the specific gene-environment interactions that modulate long-term CVD risk.”

Reference

Rhee JW, Pillai R, He T, et al. Clonal hematopoiesis and cardiovascular disease in patients with multiple myeloma undergoing hematopoietic cell transplant. JAMA Cardiol. Published online November 8, 2023. doi:10.1001/jamacardio.2023.4105