Abstract A018: Association of clonal hematopoiesis and diabetes with mortality after autologous hematopoietic cell transplantation
Authors: Bhandari Rusha , Rhee June-Wha , Chen Sitong , Pillai Raju , Bosworth Alysia , Oganesyan Artem , Atencio Liezl , Estrada Caitlyn , Kassabian Mareen , Lindenfeld Lanie , Goldsmith Scott , Rosenzweig Michael , Herrera Alex , Mei Matthew , Nakamura Ryotaro , Natarajan Rama , Wong F Lennie , Forman Stephen , Armenian Saro 
Published: February 2025

Abstract
Background: Clonal hematopoiesis of indeterminate potential (CHIP) and diabetes mellitus (DM) are aging-related phenomena associated with risk of premature mortality in the general population. CHIP is highly prevalent in patients undergoing HCT, but its association with DM and survival after HCT is unknown. Methods: This single-center study included 1,931 consecutive patients who underwent autologous HCT for lymphoma or myeloma between 2010-2016. Demographic and clinical data were abstracted from the medical record. Panel-based DNA sequencing was performed on 92 pre-defined genes (sequencing depth: 1000x) to detect CHIP variants (variant allele frequency [VAF] ≥2%). Socioenvironmental vulnerability was measured using the Centers for Disease Control Environmental Justice Index (EJI), with scores derived using patient addresses at time of HCT. The primary outcome was 5-year (y) cumulative incidence of non-relapse mortality (NRM). Multivariable Fine-Gray regression was used to examine the association between CHIP and pre-HCT DM, and the combined impact of CHIP and DM (pre- or post-HCT) on NRM (model adjusted for demographics, diagnosis, EJI). We also examined outcomes by body mass index (BMI), given the relationship between BMI, DM, and NRM risk. Results: Median age at HCT was 58.8y, 59.1% were male, 51.5% were non-Hispanic White, 25.4% were Hispanic, and 53.2% had lymphoma. Overall, 17.5% had DM at HCT; 20.1% had &gt;1 CHIP variant and 4.9% had ≥2 variants. Among identified CHIP variants, 78.1% had calculated VAFs 2-&lt;10% and 21.9% had VAFs ≥10%. The most frequent mutations were DNMT3A (36.6%), TET2 (15.2%), PPM1D (13.1%), and ASXL1 (8.0%). In multivariable analyses, CHIP was independently associated with odds of having pre-HCT DM (OR 1.5, 95%CI 1.1-2.0). Gene-specific analysis revealed a significant association between ASXL1 and DM; 28.6% of patients with the ASXL1 mutation had DM, vs 16.3% in those without the mutation (p=0.05). There was an incremental increase in 5y cumulative incidence of NRM across categories (no CHIP/no DM: 3.2%; no CHIP/DM: 8.5%; CHIP/no DM: 11.2%; CHIP/DM: 17.6%; p&lt;0.001). In multivariable analysis, patients with both DM and CHIP had a fifteen-fold risk (HR: 14.9; 95%CI 7.2-30.9) of NRM (reference: no CHIP/no DM). Patients who were non-overweight/obese (BMI&lt;25 Kg/m2) with CHIP and DM had an especially high risk of NRM (HR 21.4, 95%CI 9.5-58.2, ref: no CHIP, no DM, BMI ≥25 Kg/m2). Conclusions: CHIP was significantly and independently associated with DM in HCT patients. Those with both CHIP and DM had a very high risk of NRM, and there was a noticeably higher risk among those who were non-overweight/obese by BMI. Additionally, ASXL1, which is associated with risk of DM in the general population, was significantly associated with DM in our cohort. This finding underscores the need for future mechanistic studies to investigate the interplay between CHIP, DM, and outcomes after HCT, and the importance of phenotypically distinct approaches to risk stratify patients for screening and intervention prior to HCT.
Citation Format: Rusha Bhandari, June-Wha Rhee, Sitong Chen, Raju Pillai, Alysia Bosworth, Artem Oganesyan, Liezl Atencio, Caitlyn Estrada, Mareen Kassabian, Lanie Lindenfeld, Scott Goldsmith, Michael Rosenzweig, Alex Herrera, Matthew Mei, Ryotaro Nakamura, Rama Natarajan, F Lennie Wong, Stephen Forman, Saro Armenian. Association of clonal hematopoiesis and diabetes with mortality after autologous hematopoietic cell transplantation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr A019.