We began our study by assessing all survivors with solid tumor chemo who eventually developed cytopenias and underwent bone marrow evaluation for the cytopenias. The most prevalent mutations that were found in therapy-related CHIP were TET2, DNMT3A, and TP53. This is in some contrast to the classical or canonical CH mutations, which include DNMT3A, TET2, and ASXL1, mostly found in seemingly healthy populations...
We began our study by assessing all survivors with solid tumor chemo who eventually developed cytopenias and underwent bone marrow evaluation for the cytopenias. The most prevalent mutations that were found in therapy-related CHIP were TET2, DNMT3A, and TP53. This is in some contrast to the classical or canonical CH mutations, which include DNMT3A, TET2, and ASXL1, mostly found in seemingly healthy populations. So we had noted that there was an inferior overall survival for patients with a therapy-related CHIP compared to de novo or just age-related CHIP. We also modeled the clonal dynamics of therapy-related CHIP to assess patterns of progression. And finally, we identified four key gene mutations that imparted a significantly heightened risk for progression from a therapy-related CHIP to a therapy-related myeloid neoplasm. And those mutations were JAK2, RUNX1, ECH2 and TET2. Some of those mutations are also confirmed to be high-risk mutations based on the clonal hematopoiesis risk score published in the New England Journal of Medicine Evidence in 2023. We found that higher variant allele frequency was noted in progressors compared to non-progressors.
So, I think our study has some important implications in risk assessment for therapy – related CHIP, and it brings to light the fact that chemo and radiation can sometimes contribute to the selective outgrowth of pre-existing clones that harbor mutations within DNA damage response genes, and thereby, that can result in a more aggressive secondary hematologic malignancy many years down the road after treatment of a primary cancer. So the scientific and clinical impact of these findings may influence monitoring of patients who are survivors of chemotherapy or radiotherapy. Patients with high-risk myeloid mutations might need closer surveillance. They might need active surveillance so that we can detect these conditions at an earlier time point in the course of the condition. And at the current time, the general paradigm involves just routine labs and physical exams, usually every 3 to 12 months, depending on genomic risk. But it’s not really standardized. Risk stratification in therapy-related CHIP hasn’t really been materialized across different studies, and consensus data is somewhat limited. So, it’s worthwhile to perform multi-institutional collaborations, ideally through the lens of CHIP clinics across the country and across the nation, to help validate the findings in larger cohorts that represent more diverse patient populations, with these pre-leukemic states. And I think collaboration is really key to implementing practical recommendations based on the highest level of evidence.
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