Prevalence of clonal hematopoiesis of indeterminate potential across different systemic cancer therapies in gastrointestinal malignancies: An analysis from the All of Us registry.

828 Background: Clonal hematopoiesis of indeterminate potential (CHIP) refers to the presence of somatic mutations in hematopoietic stem cells that confer an increased risk of hematologic malignancies in the absence of cytopenias or dysplasia. CHIP has been recognized as a predictive marker for the future development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Exposure to cancer therapeutics accelerates CHIP development. However, the prevalence of therapy-induced CHIP remains poorly characterized. We aim to investigate the rate of CHIP in patients with gastrointestinal (GI) malignancies who received commonly used cancer therapeutics. To our knowledge, this is the first study to investigate CHIP prevalence across different cancer therapy regimens using data from the All of Us registry. Methods: We conducted a retrospective cohort analysis using data from the National Institutes of Health All of Us Research Program. Adult participants with a diagnosis of GI malignancy and documented exposure to cancer therapeutics were included. CHIP was identified using genomic testing by peripheral blood samples. The primary outcome is the prevalence of CHIP among patients with GI malignancies treated with commonly used cancer therapeutics. Results: From 243,751 individuals in the All of Us registry, 9,506 (3.9%) were diagnosed with CHIP. Among patients with GI malignancies exposed to systemic therapy, the highest prevalence of CHIP was seen with temozolomide (10.3%), pembrolizumab (9.8%), and lutetium (9.1%), while the lowest was noted with oxaliplatin (3.2%) and irinotecan (2.6%). Notably, agents commonly used in the management of neuroendocrine tumors (NETs) were associated with the highest rates (temozolomide 10.3% vs. lutetium 9.1%). Conclusions: The highest prevalence of CHIP among drugs commonly used for GI malignancies was observed in NET patients. Given that NETs are typically slow-growing and require prolonged treatment exposure, patients may be particularly susceptible to CHIP development, which can then give rise to MDS or AML, underscoring the need for vigilant surveillance and risk-adapted therapeutic strategies. Prevalence of CHIP by treatment type in GI malignancies (All of Us Registry). Drug NETs Pancreatobiliary Hepatic Colorectal Esophagogastric Temozolomide 10.3% — — — — Pembrolizumab — — 7.6% 11.5% — Lutetium 9.1% — — — — Paclitaxel — 5.5% 3.2% 4.7% 6.9% Cisplatin — 5.7% 2.4% 3.7% 5.9% 5-Fluorouracil — 4.9% — 5.8% 4.4% Capecitabine — 3.8% — 5.3% 7.1% Oxaliplatin — 3.8% — 3.2% 3.7% Irinotecan — 1.5% — 3.2% —