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Summary: Recursive partitioning of healthy consortia led to the development of the Clonal Hematopoiesis Risk Score (CHRS) for clonal haematopoiesis (CH); however, in the practical setting, most cases of CH are diagnosed after patients present with cytopenias or related symptoms. To address this real‐world population, we characterize the clinical trajectories of 94 patients with CH and distinguish CH harbouring canonical DNMT3A/TET2/ASXL1 mutations alone ('sole DTA') versus all other groups ('non‐sole DTA'). TET2, rather than DNMT3A, was the most prevalent mutation in the real‐world setting. Sole DTA patients did not progress to myeloid neoplasm (MN) in the absence of acquisition of other mutations. Contrastingly, 14 (20.1%) of 67 non‐sole DTA patients progressed to MN. CHRS assessment showed a higher frequency of high‐risk CH in non‐sole DTA (vs. sole DTA) patients and in progressors (vs. non‐progressors). RUNX1 mutation conferred the strongest risk for progression to MN (odds ratio [OR] 10.27, 95% CI 2.00–52.69, p = 0.0053). The mean variant allele frequency across all genes was higher in progressors than in non‐progressors (36.9% ± 4.62% vs. 24.1% ± 1.67%, p = 0.0064). This analysis in the post‐CHRS era underscores the natural history of CH, providing insight into patterns of progression to MN. [ABSTRACT FROM AUTHOR]

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL., Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status., Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1 ) in one of the 42 assessed genes versus those with only non-FS mutations., Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes., Competing Interests: M. Ramanathan: Spouse owns stock options in Smith & Nephew: Current equity holder in publicly-traded company; spouse owns stocks in Alcon, Biogen, Boston Scientific, Dexcom, Gilead, Intuitive Surgical, Moderna, Medtronic, Novartis, Tandem Diabetes, Ocular Therapeutics, Pfizer, Sanofi, Vertex, and Viatris: Current equity holder in publicly-traded company; spouse has divested stocks in Abbvie, Jansenn and BMS: Divested equity in a private or publicly-traded company in the past 24 months. J. Cerny: MERIT CRO: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Actinium Pharmaceuticals: Current holder of stock options in a privately-held company; BlueBird Bio, Inc.: Current holder of stock options in a privately-held company; Cellectar Sciences: Current holder of stock options in a privately-held company; Dynavax Technologies: Current holder of stock options in a privately-held company; Gamida Cell: Current holder of stock options in a privately-held company; Atyr Pharma: Current holder of stock options in a privately-held company; Novavax Inc.: Current holder of stock options in a privately-held company; Ovid Therapeutics Inc.: Current holder of stock options in a privately-held company; Sorreto Therapeutics: Current holder of stock options in a privately-held company; Veru Inc.: Current holder of stock options in a privately-held company; Viridian Therapeutics: Current holder of stock options in a privately-held company; Vaxart Inc.: Current holder of stock options in a privately-held company; 2Seventy Bio Reg SHS: Current holder of stock options in a privately-held company; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; ICON-Prolacta: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; ICON-Allovir: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. S.A. Patel: UMass Center for Clinical and Translational Science (CCTS) Pilot Project Program grant (NIH/NCATS Grant UL1TR001453: Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees., (Copyright 2024, Cammann et al.)