826 Background: Oxaliplatin (OXA) is a cornerstone therapy for gastrointestinal (GI) cancers, but chemotherapy-induced peripheral neuropathy (CIPN) is its most common dose-limiting toxicity, impairing quality of life and limiting efficacy. While mechanisms of CIPN remain incompletely defined, inflammation has been implicated in its development. Clonal hematopoiesis (CH)—the expansion of mutated hematopoietic clones without overt malignancy—is linked to systemic inflammation and adverse clinical outcomes. We evaluated the association between CH and CIPN in older patients with GI cancers treated with OXA. Methods: Using the Moffitt Cancer Analytics Platform, we identified patients >65 years with GI cancers treated with OXA between 2020–2022 who also had tissue or blood-based next-generation sequencing (NGS). CH was defined by the presence of somatic mutations in canonical myeloid genes in blood or tissue. For variants such as TP53 , CH was suspected if detected only in blood in patients with both blood and tissue NGS, or when variant allele frequency was significantly lower than known tumor mutations in tissue. Results: Among 486 patients with colorectal (n=173, 35.6%), esophageal (n=74, 15.2%), gastric (n=66, 13.6%), pancreatic (n=161, 33.1%), or unknown primary (n=14, 2.9%) cancers, CIPN was reported in 110 (25%). CH was identified in 109 patients (22.4%), including 21 (21.6%) with multiple CH mutations. The most frequent mutations were DNMT3A (47.4%), TET2 (25.8%), and TP53 (24.7%), with less common alterations in ASXL1 (9.3%), SF3B1 (7.2%), and others. Mutation prevalence varied by cancer type, with DNMT3A enriched in gastric, pancreatic, and colorectal cancers, TP53 in unknown primary, and ATM largely restricted to esophageal cancer. No significant association was observed between CH and CIPN (p=0.917). Multigene CH did not differ by CIIP status (2.5% vs 4.9%, p=0.312), and neither TET2 nor DNMT3A , individually or grouped as an epigenetic CH category, was linked to CIPN (all p≥0.99). In the subset of 82 patients with diabetes-independent PN, CH was not associated with increased risk (CH– 17.5% vs CH+ 14.7%; RR 0.84; p=0.583). Conclusions: CH was common among older adults with GI cancers but was not associated with CIPN or diabetic independent PN. While CH reflects a pro-inflammatory state, it does not appear to influence oxaliplatin-related neurotoxicity.
Xie et al. (Sat,) studied this question.