Older Patients With Clonal Hematopoiesis and Non-DT Mutations at Higher Risk of Mortality

For patients aged 80 and older, those with clonal hematopoiesis (CH) and mutational spectra other than isolated DNMT3A and TET2 (DT) variants may have a higher risk of mortality, compared with patients carrying other gene mutations. This is according to results published in Blood Advances.

While CH does not appear to be associated with an increased risk of mortality in adults ≥80 years, the reasons are unknown. Previous research using whole-exome sequencing shows CH is practically nonexistent in people younger than 30. Over time, somatic mutations accumulate, ultimately increasing the prevalence of CH with advancing age. In the general population, CH may progress to hematologic malignancy and may also be associated with other age-related comorbidities, such as inflammatory conditions and cardiovascular disease.

In this study, researchers led by Isabelle A. van Zeventer, MD, of the University Medical Center Groningen in the Netherlands, assessed the clinical implications of CH in a cohort of adults aged 80 years and older who participated in the prospective population-based LifeLines study. This cohort includes 167,729 individuals across three generations who live in the northeast region of the Netherlands.

The investigators assessed CH in DNA samples from 621 participants in the LifeLines study, performing targeted next-generation sequencing for 27 myeloid and lymphoid malignancy-associated driver genes. Sensitive error-corrected sequencing of these driver genes at a variant allele frequency of 1% and greater showed CH was present in 62% of participants.
The presence of CH at older age was associated with a higher prevalence of carrying a mutated DNMT3A clone (35%) and mutated TET2 clones (27%). Approximately 27% of participants carried multiple somatic variants in DT.

Regarding age-related comorbidities, the investigators uncovered an association between CH and a history of chronic obstructive pulmonary disease (odds ratio = 2.26; 95% CI 1.09-5.18; p=0.038).

There were 241 deaths reported in participants (39%) over the median follow-up study period. In a multivariable model with age and sex as covariables, there was no association between the presence of CH and a higher risk of mortality (hazard ratio [HR] = 0.91; 95% CI 0.70-1.18; p=0.48).

Overall survival rates were subsequently compared for participants with mutational spectra confined to the DT variants versus other variants. The investigators found a higher risk of mortality in people who carried mutational spectra other than isolated DT variants, which was validated in a multivariable analysis (HR=1.48; 95% CI 1.06-2.08; p=0.025). A univariable analysis likewise found an association between spliceosome variants and a higher mortality risk (HR=1.84; 95% CI 1.05-3.23; p=0.033).

A total of six people with baseline CH developed a hematologic malignancy during the follow-up period. Death associated with these hematologic malignancies was only observed in people who had CH at baseline.

The multivariable analysis found no significant differences between individuals with and without CH in terms of the probabilities of death from cardiovascular disease (p=0.29), solid malignancies (p=0.66), or respiratory disorders (p=0.43).

Data regarding estimated exposures to DNA-damaging toxicities found a significantly higher prevalence of spliceosome (6% vs. 1%; p=0.014) and ASXL1 (7% vs. 2%; p=0.035) variants, which was shown for three investigated potential DNA damaging exposures (smoking, a history of cancer, and job-related pesticide exposure).

The researchers noted that while there was a higher prevalence of DNMT3A variants in people who smoked, there did not appear to be an enrichment of DT variants in individuals who had an increased risk of prior exposure to DNA-damaging toxicities. “This suggests that exposures may differentially affect the emergence of specific CH-associated gene mutations, which deserves validation in a larger cohort,” the investigators wrote.

The authors report no relevant conflicts of interest.

Reference

van Zeventer IA, Salzbrunn JB, de Graaf AO, et al. Prevalence, predictors, and outcomes of clonal hematopoiesis in individuals aged ≥80 years. Blood Adv. 2021;5(8):2115-2122.