IN THE LITERATURE
CHIP-Associated Mutations Linked With
Comorbidities in MDS
The presence of clonal hematopoiesis of indeterminate poten-
tial (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 authors 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 indepen-
dent 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 sig-
nificant association with any of the comorbidity systems,” they
commented.
Those with mutations in the TP53 gene, compared with
TET2 mutations, had a higher likelihood of having a prior his-
tory 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 muta-
tions 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 import-
ant 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]
Continued on page 17
May 2019
7