Clonal Hematopoiesis of Indeterminate Potential — Associated Mutations and Risk of Comorbidities in Patients with Myelodysplastic Syndrome

Introduction:

Comorbidities have a significant impact on the prognosis and survival of patients with myelodysplastic syndrome (MDS) (Naqvi et al, JCO. 2011). Recent studies have indicated the role of clonal hematopoiesis of indeterminate potential (CHIP) - associated mutations (TET2, ASXL1, DNMT3A and JAK2) and atherosclerotic cardiovascular disease (Ebert et al. NEJM. 2017). The objective of this study was to evaluate the association of these CHIP - associated mutations as well as TP53 mutations and comorbidities in patients with MDS.

Methods:

We conducted a retrospective study of 566 consecutive patients with MDS who presented to MD Anderson Cancer Center from August 2013 to December 2016. The Adult Comorbidity Evaluation-27 (ACE-27) scale, a validated 27-item comorbidity index for cancer patients was used to assess the severity of comorbid conditions. We used next-generation sequencing to detect the presence of CHIP mutations in the bone marrow samples. Data on demographics, international prognostic scoring system (IPSS) were collected. Wilcoxon's rank-sum test and chi-squared test were used to determine the association between genes and comorbidities.

Results:

Of the 566 patients included in this study, 66% were male, and 82% white; median age at presentation was 69 years (range: 22-93). A total of 350 (62%) patients had an IPSS of Intermediate-1 and low; complex karyotype was noted in 128 (23%) patients. The ACE-27 comorbidity scores were as follows: none, 101 (18%); mild, 214 (38%); moderate, 146 (26%); and severe, 105 (19%). Mutations in DNMT3A, ASXL1, TET2, JAK2 and TP53 were noted in 9%, 18%, 20%, 2% and 21% patients respectively. One hundred and seventy (30%) patients had no mutations. With respect to the cardiovascular system, patients harboring DNMT3A were noted to have a higher incidence of myocardial infarction than those without DNMT3A mutation (14% vs 6%; p= 0.03). As expected, patients with a JAK2 mutation had higher number of venous thromboembolic events (18% vs 4%; p= 0.013). TET2, ASXL1 and TP53 mutationshowever were not associated with increased cardiovascular events in our patients. TP53 mutations were highly associated with history of prior malignancy: solid tumors, 44% vs 21%; p= <0.001; myeloma, 9% vs 3%; p= 0.003; lymphoma, 17% vs 3%; p= <0.001. Patients with renal disease and diabetes mellitus were also noted to most likely harbor TP53 mutations: 16% vs 9%; p= 0.016 and 27% vs 16%; p= 0.009 respectively. Patients with ASXL1 were less likely to have prior malignancy (18% vs 27%; p= 0.057). Additionally, IDH1, IDH2 and RUNX1 mutations were also noted in 3%, 6% and 9% of the patients respectively but without any association with the comorbidities. A trend towards higher ACE-27 comorbidity scores and increased number of mutations was noted (p= 0.075).

Conclusion:

CHIP associated mutations namely DNMT3A was noted to be associated with higher number of cardiovascular events. Contrary to what is previously reported, we didn't find this association with TET2. TP53 mutations were highly prevalent in patients with therapy related MDS. Further work is ongoing studying the variant allele frequency of these mutations and impact on comorbidities.