A study published in the Annals of Hematology attempted to characterize the role of specific gene variants in the development of therapy-related myeloid neoplasms (t-MN) and found that clonal hematopoiesis of indeterminate potential (CHIP)-driver genes not only conferred a variable risk for progression to t-MN, but also modeled the features of the subsequent t-NM.
Currently available CHIP risk scores are not designed to account for the risk of therapy-related neoplasms, according to Maria Teresa Voso, MD, of the University of Rome Tor Vergata. In this study, Dr. Voso and colleagues attempted to fill that knowledge gap by analyzing data from 10 published reports with matching information from 109 patients with a primary malignancy and a t-MN.
The patients had primary tumors classified as lymphoid malignancies (58%), solid tumors (26%), and plasma cell dyscrasias (16%). More than half (61%) of these patients developed myelodysplastic syndromes as the t-MN; 38% developed acute myeloid leukemia.
Of the 109 patients, 43% had at least one somatic mutation at the time of their primary malignancy.
“In particular, we observed a significant increase of TET2 and TP53 mutation burden when comparing the CHIP versus the t-MN timepoints,” Dr. Voso said.
At the time of primary malignancy, the most common mutations were TP53 (16%), TET2 (12%), DNMT3A (12%), and ASXL1 (4%). At t-MN, the most frequently mutated genes were TP53 (45%), DNMT3A (20%), TET2 (15%), and NRAS (14%).
There was a significant increase from primary malignancy to t-MN in TET2 (median variant allele frequency [VAF] = 3.5% vs. 21.2%; p=0.019) and TP53 (median VAF = 5% vs. 31.95%; p=0.005).
Dr. Voso and colleagues also analyzed correlations between mutations at primary malignancy and t-MN. They found that ASXL1-driven CHIP was correlated with the emergence of TET2 (odds ratio [OR] = 16.667; p=0.024) and CEBPA mutations (OR not available; p=0.046) at t-MN. Additionally, U2AF1-driven CHIP was correlated with the emergence of EZH2 (OR=106.00; p=0.037), and IDH2- (OR=106.00; p=0.037) and SRSF2-driven (OR not available; p=0.001) CHIP was correlated with the emergence of FLT3 mutations.
However, DNMT3A-driven CHIP was correlated with a lower incidence of TP53 mutation.
“Furthermore, when compared to other gene mutations, TP53-driven t-MNs were characterized by the acquisition of karyotype abnormalities, rather than additional gene mutations,” Dr. Voso said.
Dr. Voso and colleagues listed several limitations to this study. First, the researchers were not able to analyze specific therapy-related effects or deep gene-specific mutational patterns. In addition, PPM1D, a gene whose mutations are “a known hematopoietic driver in response to DNA damage,” was excluded from most gene panels in the study.
Dr. Voso said that in an ideal world, CHIP testing in patients with cancer in which a cytotoxic treatment is planned would help to refine the risk of t-MN and support the choice of tailored versus cytotoxic treatment.
“In general, the prevalence of t-MN is less than 1% of patients with cancer, and this probably does not justify large-scale screening outside of dedicated research projects,” Dr. Voso said. “CHIP testing may be, on the other hand, recommended for those treatments at high leukemogenic potential, such as PARP inhibitors as maintenance for ovarian cancer.”
If CHIP is diagnosed, Dr. Voso said that follow-up should include regular complete blood counts and that clinicians might also consider “monitoring with a myeloid next-generation sequencing panel at a frequency tailored to the type of CHIP mutation (i.e., more frequently for TP53), the entity of the original clone, and the expansion with time.”
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Guarnera L, Pascale MR, Hajrullaj H, et al. The role of clonal progression leading to the development of therapy‑related myeloid neoplasms. Ann Hematol. 2024;103(9):3507-3517.
