Abstract Introduction: Hematopoietic stem and progenitor cells with preleukemic mutations (mutns), collectively termed clonal hematopoiesis (CHIP) serve as the cellular origin of myeloid neoplasms (MN). While risk of MN development varies, its natural history and transformation potential remain poorly defined. We present findings from our ongoing 10-year CHIP protocol using serial NGS to monitor clonal evolution and MN in cancer survivors. Methods: Retrospective analysis of 210 prospective pts from March 2020 to June 2024. Mutns were classified CHIP+ if they had a variant allele frequency (VAF) ≥2% (or ≥1% for IDH1, IDH2, and JAK2). Clonal evolution was evaluated by annual VAF changes adjusted for age-related increases (e.g. DNMT3A increases by ∼2%/yr based on published data). Mutns were classified as slow (≤5%/yr: DNMT3A, TET2, ASXL1), intermediate (5-10%/yr: TP53, PPM1D, IDH1/2, KRAS, NRAS, SF3B1), or fast-growing (10%/yr: JAK2, SRSF2). BPearson's Chi-squared, Fisher’s exact, and Wilcoxon rank-sum tests were used. Results: Of 210 pts, 42 (20%) had at least one CHIP+ mutn. Median age was higher in CHIP+ vs. CHIP- pts (66 vs. 59 years, p0.001). CHIP+ was not significantly associated with sex, race, family history, smoking, alcohol use, prior cancer types (e.g., breast, head and neck) or treatment (chemo, radiation, surgery). Of 487 samples, 56 had detectable somatic mutns. The most frequent mutn were DNMT3A (n=27), PPM1D (n=10), and TET2 (n=9). By expected growth kinetics, 37 (66%) mutn were slow-growing, 12 (21.4%) intermediate, 2 (3.5%) fast-growing, and 4 (7.14%) of unknown kinetic category. Beyond VAF-kinetics-based progression, 12 pts developed new mutn in subsequent years - DNMT3A (n=8), PPM1D (n=2). Some later became undetectable, suggesting transient clones. In total, 12 pts (1 by VAF kinetics, 11 by new mutn acquisition) clonally progressed over 5 years of this study (5.7%). 6 pts regressed by year 2, with gene mutn VAFs becoming undetectable. These included mutn in PPM1D (n=2), CBL (n=2), TP53 (n=1), and DNMT3A (n=1). Three more pts regressed in year 3, and 1 in year 4. In all, 10 pts showed regression over 5 years (17.8%). Notably, 5 of 10 had received interventions for cardiac comorbidities. Overall, ∼94% pts had clonal stability/regression. Slow-growing mutns - DNMT3A and TET2 had median rates of 0.83% and 2.11%, (historical rates ≤5%). Intermediate mutns like TP53 and PPM1D had median rates of 1.64% and -0.625%, below the expected 5-10% annual rise. JAK2, a fast-growing mutn, also showed a lower rate of 0.19%. Conclusion: Despite being a high-risk population due to prior solid malignancy and exposure to chemo/radiation, most pts in our five-year longitudinal study showed clonal stability. Even among those who progressed, VAF kinetics remained stable post-detection. CHIP’s inflammatory link to cardiovascular disease suggests preventive cardiology may impact clonal behavior. Citation Format: Anmol Goyal, Akriti Jain, Salendra Singh, Ying Ni, Emmett Samsa, Kristen Sykes, Sujata Patil, Abhay Singh. Clone wars: Evidence of clonal stability in a longitudinal prospective cohort of cancer survivors with serial NGS analysis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5227.
Goyal et al. (Fri,) studied this question.