Clonal hematopoiesis of indeterminate potential (CHIP), treatment outcomes and adverse events in gastrointestinal cancers: A pooled analysis of clinical trial and real-world data.

Abstract

169 Background: Clonal hematopoesis of indeterminate potential (CHIP) is the acquisition of somatic mutations leading to clonal expansion of hematopoietic stem cells and is a common incidental finding in circulating tumor DNA (ctDNA). Inflammation from these cells or a reduced marrow reserve may impact treatment outcomes or adverse events. We investigated the incidence of CHIP in ctDNA from patients with gastrointestinal (GI) cancers and explored its association with outcomes and adverse events (AEs). Methods: We collected ctDNA results from a local prospective metastatic colorectal cancer (mCRC) cohort (PREDICT-L) and ctDNA data from two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care [BSC] in mCRC) and CCTG PA.7 (gemcitabine and nab-paclitaxel [GN] with or without D+T in metastatic pancreatic adenocarcinoma [mPDAC]). CHIP+ was defined as the presence of a variant of ≥2% variant allele frequency annotated in the ctDNA report in any of the genes DNMT3A, TET2, ASXL1 and ATM, and not annotated as germline by respective sequencing platforms. The first line of treatment after ctDNA was reviewed, and grade ≥3 or dose-limiting adverse events were documented. Results: The prevalence of CHIP varied from 10% to 18% (see table). CHIP+ patients were older than CHIP- in the CO.26 cohort (p=0.011), and ECOG was higher in CHIP+ patients in the PREDICT-L cohort. There was no difference between CHIP+/- patients with regards to sex. DNMT3A was the gene most frequently mutated in all three cohorts. There was no significant difference in PFS or OS between the CHIP+/- groups, both in those treated with chemotherapy (Chemo) or immunotherapy (IO). The most common AEs were rash, GI toxicities and bleeding/clotting abnormalities. There was no significant difference in the rates of AEs between the CHIP+/- groups for those treated with Chemo or IO. Conclusions: CHIP is a common alteration in ctDNA but did not impact PFS, OS, or the chance of developing an AE. [Table: see text]