Clonal hematopoiesis of indeterminate potential (CHIP) and its association with treatment outcomes and adverse events in patients with solid tumours.

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) is the clonal expansion of hematopoietic stem cells from somatic mutations. It is a common incidental finding in cell-free DNA (cfDNA). We investigated the incidence of CHIP in cfDNA from patients with solid tumours and explored its association with treatment outcomes and adverse events. We reviewed cfDNA results from a local prospective solid tumour cohort (PREDiCT-l) and two randomized trials: CCTG CO.26 (durvalumab + tremelimumab [D+T] or best supportive care in metastatic colorectal cancer) and CCTG PA.7 (gemcitabine and nab-paclitaxel +/- D+T in metastatic pancreatic adenocarcinoma). CHIP+ was defined as any mutation in DNMT3A, TET2 or ASXL1 with a variant allele frequency (VAF) ≥2% Presumed germline variants (VAF>40%) were removed. The first line of treatment after cfDNA was reviewed for grade 3 and dose-limiting toxicities. The prevalence of CHIP in the 465 included patients was 10-30% and it was more common as age increased (p=0.003). DNMT3A was the gene most frequently mutated in all cohorts. Patients with CHIP in PA.7 treated with immunotherapy showed an improved progression-free survival (PFS) versus CHIP- (HR 0.55 [0.28-1.07], p=0.079, p-interaction=0.098 [multivariable]). However, patients with CHIP treated with chemotherapy in PREDiCT-l showed a trend towards worse PFS (HR 1.82 [0.98-3.38], p=0.059). There was no difference in adverse event rates between CHIP+/- groups for those treated with chemotherapy or immunotherapy. CHIP is common in patients with solid tumours. Although not appearing to impact rates of adverse events, CHIP may impact outcomes from immunotherapy or chemotherapy.