Unraveling clonal hematopoiesis of indeterminate potential (CHIP) in cancer: Prevalence, clonal dynamics, and prognostic significance.

Abstract

e22524 Background: CHIP prevalence in cancer (CA) patients (pts) is estimated at 30%, its presence being associated to higher risk of therapy-related myeloid neoplasms (TRMN). We hypothesized CHIP may not only predispose to TRMN but also impact primary malignancy prognosis and treatment (tx)-related toxicity. This study aimed to prospectively characterize CHIP prevalence and dynamics in tx-naïve CA pts and assess its impact on outcomes. Methods: This study included pts ≥60 years with a 1st CA diagnosis and eligible for tx. Peripheral blood samples were collected pre-tx(T0), 6 months (m,T1), and 1 year (T2) after tx completion. A custom NGS panel targeting 13 most common CHIP genes was used to identify CHIP (VAF ≥1%) and CHIP-negative pts (CHIP neg ). Clonal dynamics were traced using the formula: (VAF T1 -VAF T0 ) / VAF T0 . VAF changes >20% were classified as clonal growth or reduction, while smaller changes indicated stability. Results: In our cohort (n=113), CHIP prevalence was 36%. Breast CA pts had higher CHIP prevalence (55%), while no CHIP was found in bladder CA pts (n=8), likely due to sample size (Table 1). DNMT3A , TET2 , and PPM1D mutations accounted for 75% of variants, followed by TP53 . Among 26 CHIP pts with NGS at T1, clonal growth occurred in 41%, reduction in 27%, and stability in 32%. No new clones emerged post-tx, and clonal evolution was unrelated to tumor type, tx modality, or gene involved. We assessed response in 66 pts (neoadjuvant/non-surgical tx). Complete response rates were comparable between CHIP and CHIP neg pts (70% vs. 63%), as was relapse incidence (13% vs. 24%). Tx-related complications showed no differences. With a median follow-up of 29m (95% CI, 26–30), 24m overall survival was 81% for CHIP and 77% for CHIP neg pts (p=0.3). One DLBCL pt with CHIP (ASXL1, PPM1D and TP53) developed MDS-MD with del20q seven m post-R-CHOP. Conclusions: CHIP prevalence in our newly diagnosed CA pts cohort was 36%, with enrichment of mutations in DNA damage repair gene mutations ( PPM1D and TP53 , 20%). Notably, bladder CA pts showed no CHIP before tx, whereas breast CA pts had a higher CHIP prevalence (55%, though non significant). These results should be cautiously interpreted given the sample size. In contrast to our initial hypothesis, we found no evidence of impaired outcomes in the CHIP population. These results emphasize the need for further longitudinal follow-up. Baseline characteristics. Characteristics Total cohort (n=113) CHIP (n=41) CHIPneg (n=72) p-value Age, median(range), y 70 (64-77) 75 (68-78) 70 (64-76) 0,04 Sex (female), n (%) 63 (56%) 27 (66%) 36 (50%) 0,21 Type of neoplasm  Lymphoma, n (%) 25 (22%) 11 (44%) 14 (56%) 0,36  Multiple myeloma, n (%) 9 (8%) 3 (33%) 6 (67%) 0,79  Bladder, n (%) 8 (7%) 0 8 (100%) 0,02  Breast, n (%) 20 (18%) 11 (55%) 9 (45%) 0,06  Colorectal n (%) 21 (19%) 6 (29%) 15 (71%) 0,41  Head & neck, n (%) 12 (11%) 4 (33%) 8 (66%) 0,98  Ovarian, n (%) 17 (15%) 5 (29%) 12 (71%) 0,52