Presence of Clonal Hematopoiesis and Cardiac Events After Allogeneic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been associated with serious cardiotoxicity, including atrial fibrillation (AF) and other cardiac events. In preclinical models, posttransplant clonal hematopoiesis (CH) frequently parallels or precedes clinical AF, yet whether this is seen in patients or has implications for cardiotoxic risk in long-term follow-up is unknown.

Leveraging consecutive patients treated with alloHSCT, genotyped using deep-amplicon sequencing to detect the presence of CH, we assessed the development of new (incident) AF, by CH status. Secondary outcomes were the occurrence of major adverse cardiac events, defined as heart failure, myocardial infarction, AF, symptomatic ventricular arrhythmias, and cardiovascular death after alloHSCT. We also assessed the relation between CH and post-alloHSCT cancer survival outcomes. Observed incident AF rates were compared with Framingham heart predicted rates. Multivariable regression and survival analyses were used to define the relation between CH and incident AF, major adverse cardiac events, progression-free survival, and overall survival. We also explored these relationship by specific mutation and by varying variant allele frequency.

Overall, 201 patients with deep sequencing after alloHSCT were identified (median age, 59 years; 46.3% with hypertension; and 42.3% with CH, including 29.5% with ≥2 mutations). Over a median follow-up of 35 months, 11.5% of patients developed incident AF, and 29.9% experienced major adverse cardiac events. In those without prior AF, the weighted-average incidence was 407 per 10 000 person-years compared with the Framingham-predicted 63 per 10 000 person-years (risk ratio, 6.4; P<0.001; absolute excess risk, 344). In follow-up, increased CH burden was associated with higher risk of incident AF (hazard ratio [HR], 4.0 [95% CI, 1.2-14.1]; P=0.03), cancer-progression (HR, 2.6 [95% CI, 1.3-5.2]; P=0.006), and death (HR, 2.1 [95% CI, 1.0-4.3]; P=0.047). There was no difference in non-AF major adverse cardiac events.

Collectively, these data suggest among patients treated with alloHSCT, the presence of CH appears to portend increased AF risk, though validation in larger prospective studies is needed.