Abstract P037

Impact of Clonal hematopoiesis of indeterminate potential in classical Hodgkin lymphoma

Background: Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with an increased risk of cardiovascular diseases (CVD) in addition to developing myeloid neoplasias. Long-term survivors of classical Hodgkin lymphoma (cHL) have a risk of cardiovascular side effects. The aim of this study was to examine the prevalence and clinical impact of CHIP in patients with cHL in relation to CVD.

Material/Methods: Blood samples were collected in cHL patients at diagnosis before treatment in a cohort diagnosed from 2010-2020 (n=61) (Cohort 1) and after treatment (mean time from diagnosis 25 years) in a cohort of long-time survivors (n=266) diagnosed between 1965-1995 (Cohort 2). Next generation sequencing (NGS) on DNA extracted from blood, with a targeted gene panel covering either full coding region or hotspot region of 33 genes with a sensitivity of a variant allele frequency (VAF) down to 2% was performed.

Results: Mutations classified as pathogenic (P)/likely pathogenic (LP) were detected in 39 (15%) long-term survivors compared to 5 (8%) in cHL patients in Cohort 1. An inferior overall (OS, Fig 1A) and event-free survival (EFS) was observed in cHL patients in Cohort 1 with mutations at diagnosis compared to those with no variants (n=41) and/or variants of unknown significance (VUS) (n=15). There were no survival differences in Cohort 2 of long-term survivors with P/LP mutations vs no variants/VUS (Fig 1B). In 111/266 (42%) long-term survivors a CVD was diagnosed (hypertension (n=58), valvular disease (n=44), angina pectoris (n=31), ischemic myocardial infarction (n=19), stroke (n=8) and other (n=38). There was no difference in frequencies of CVD side effects between patients with P/LP or no variants in cohort 2 of long-term survivors, whereas patients with VUS had a lower frequency (17%). The mutational landscape varied, with the most commonly mutated genes in the P/LP categories being DNMT3A (n=12), TET2 (n=9) and PPM1D (n=9), and in the VUS category, ZRSR2 (n=10), CEBPA (n=9), KDM6A (n=8) and ASXL1 (n=8).

Conclusions: Detection of P/LP mutations in cHL patients at the time of diagnosis seems to affect survival. For long-time survivors, mutations detected after treatment does not affect survival and CHIP mutations does not seem to play a major role in the development of cardiovascular side effects.