CHIP-Associated Mutations Linked With Comorbidities in MDS

The presence of clonal hematopoiesis of indeterminate potential (CHIP) mutations, particularly DNMT3A and JAK2 mutations, was associated with a higher likelihood of prior myocardial infarction (MI), thrombotic events, and other comorbidities in patients with myelodysplastic syndromes (MDS), according to findings published in Cancer.

“Individuals with CHIP have an increased risk of developing MDS and also comorbidities, such as cardiovascular disease,” corresponding author Guillermo Garcia-Manero, MD, from MD Anderson Cancer Center in Houston, told ASH Clinical News.

“We previously reported the frequency and clinical impact of comorbidities in MDS. This was important because patients with MDS, as with CHIP, tend to be older [and at high risk for these comorbidities],” he explained. “In that analysis, we were able to develop a prognostic model incorporating disease-specific characteristics and also presence of comorbidity as an independent prognostic factor, suggesting a potential interplay between disease and comorbidity.”

With the present study, researchers from MD Anderson retrospectively collected data from 566 consecutive patients with MDS who presented to their center between 2013 and 2016.

The 27-item Adult Comorbidity Evaluation (ACE-27) was used to extract comorbidity data for each patient and, using next-generation sequencing, the researchers identified the presence of the CHIP-associated mutations in bone marrow aspirates. In the final cohort, mutations were identified in the following genes:

  • TET2: 20%
  • ASXL1: 18%
  • DNMT3A: 9%
  • JAK2: 2%
  • TP53: 21%

According to their analysis, the authors reported that individuals with DNMT3A and JAK2 mutations were more likely to have a prior history of MI (odds ratio [OR] = 2.62; 14% vs. 6%; p=0.03) and veno-occlusive disease (OR=6.48; p=0.02), compared with other mutations.

“Despite being the second most frequently mutated gene observed in this cohort of patients, TET2 failed to show a significant association with any of the comorbidity systems,” they commented.

“Despite being the second most frequently mutated gene observed in this cohort of patients, TET2 failed to show a significant association with any of the comorbidity systems.”

—Guillermo Garcia-Manero, MD

Those with mutations in the TP53 gene, compared with TET2 mutations, had a higher likelihood of having a prior history of diabetes mellitus (27% vs. 16%; p=0.01) and respiratory disorders (16% vs. 9%; p=0.02).

Not surprisingly, given the high frequency of TP53 mutations in therapy-related MDS, the presence of a TP53 mutation also correlated with a greater proportion of patients with a prior history of malignancy, including solid tumor (44% vs. 21%; p<0.001), myeloma (9% vs. 3%; p=0.003), and lymphoma (17% vs. 3%; p<0.001).

To determine the prognostic significance of these mutations, the researchers developed a model that incorporated TP53 mutation status, revised International Prognostic Scoring System (IPSS-R) classification, and ACE-27 comorbidity score. They found that inclusion of TP53 mutation status and comorbidities improved outcome prediction; both TP53 mutations and higher comorbidity scores were independently associated with worse outcomes. Across the five risk categories (very good, good, intermediate, poor, and very poor), survival curves by this new classification system showed better separation between cohorts, compared with patients classified according to the IPSS-R.

“The associations between mutations and comorbidities are not random,” Dr. Garcia-Manero explained. “We did not observe an association between TET2 and cardiovascular disease, for example. This may be related to the facts that our cohort was relatively small, follow-up was short, or that there are other pathophysiological factors contributing to cardiovascular disease in MDS.”

Other limitations of the study include the lack of adjustment for transfusion burden, the retrospective nature of the analysis, the inclusion of a heterogenous population, and the reliance on only five gene-associated mutations.

Dr. Garcia-Manero added that larger, prospective studies are needed to elucidate the connection between comorbidities and clonal hematopoiesis in myeloid malignancies. These data could have important implications for treatment and study of patients with MDS.

“As with CHIP, perhaps the presence of these mutations in MDS should alert the hematologist to [potential] comorbidities, [which] could have an impact on the well-being and survival of our patients,” he concluded. “Also, I believe it will be important to incorporate comorbidities as an endpoint, and not as an exclusion, in the design of clinical trials [because], potentially, treatment of MDS may not only affect evolution of MDS but also may influence associated comorbidities.”

The authors report no relevant conflicts of interest.

Reference

Naqvi K, Sasaki K, Montalban-Bravo G, et al. Clonal hematopoiesis of indeterminate potential-associated mutations and risk of comorbidities in patients with myelodysplastic syndrome. Cancer. 2019 March 12. [Epub ahead of print]

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