790 - Higher Gene Expression Profiling Scores Are Associated with Subsequent Elevations in Donor Derived Cell-Free DNA

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Author Block: C. A. Bravo¹, M. Urey², N. Uriel³, B. Mackie⁴, A. van Bakel⁵, C. Fan⁶, J. Kobulnik⁶, K. Oreschak⁶, L. Shen⁶, E. M. DeFilippis³, ¹UCSF, San Francisco, CA, ²UCSD, La Jolla, CA, ³Columbia University Irving Medical Center, New York, NY, ⁴Tampa General Medical Group, Tampa, FL, ⁵MUSC, Charleston, SC, ⁶CareDx, Brisbane, CA
*Purpose: The clinical relevance of an elevated gene expression profiling (GEP) score in the absence of current graft injury, as measured by donor-derived cell-free DNA (dd-cfDNA), remains unclear. We sought to assess whether elevated GEP scores with normal dd-cfDNA levels predict future abnormalities in dd-cfDNA in patients enrolled in the Surveillance HeartCare Outcomes Registry (SHORE).
*Methods: This analysis included SHORE patients with at least one GEP/dd-cfDNA result in the first 6-months post-heart transplant (HT). Simultaneous GEP/dd-cfDNA drawn 55-days to 2-years post-HT were considered. We applied conditional logistic regression (CLR) to assess the association of the GEPs collected in the absence of rejection on biopsy (acute cellular rejection ≥2R and/or ≥pAMR1) and with negative dd-cfDNA (<0.20%) with subsequent dd-cfDNA positivity. Subsequent dd-cfDNA levels were required to be collected between 3 and 26 weeks after the initial GEP result.
*Results: We identified 15594 GEP/dd-cfDNA results collected in the absence of rejection on biopsy and with negative dd-cfDNA results in 2355 patients [73% male, 68% White, median (IQR) age at HT 57 (47-64)]. The results of CLR suggested a significant curvilinear association between GEP and subsequent dd-cfDNA positivity (p <0.001; Figure). Specifically, the likelihood of dd-cfDNA positivity became elevated when GEP scores were ≥25. With the GEP score of 25 as a reference, the estimated odds ratios (ORs) of subsequent dd-cfDNA positivity for a GEP score of 30 and 36 were 1.44 [1.27 - 1.64] and 1.49 [1.27 - 1.74], respectively. Two sensitivity analyses for [1] dd-cfDNA results drawn between 4 and 26 weeks and [2] those drawn anytime within 26 weeks after the initial GEP/dd-cfDNA result showed similar results.
*Conclusions: Despite being paired with negative dd-cfDNA and biopsies that did not demonstrate rejection, elevated GEP scores are associated with future dd-cfDNA positivity. This may be explained by GEP scores indicating immune activation prior to graft injury or biopsy evidence of rejection. Closer monitoring, including immunosuppression optimization in patients with elevated GEP scores, even without current evidence of graft injury, may be warranted.