2011 - Transplantomics and Biomarkers in Transplantation

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Biomarkers to Improve Patient Management in Solid Organ Transplantation

2.4 - Application of Gene-expression Profiling in Heart Transplantation

Presenter: Michael, Pham, Stanford, CA, USA
Authors: Michael Pham

Application of Gene-expression Profiling in Heart Transplantation

Michael Pham, Stanford University School of Medicine, Stanford, CA, USA

Learning Objectives:

1. Summarize the development and validation of a peripheral blood gene-expression profiling test (AlloMap®) used to monitor heart transplant recipients for acute rejection.

2. Identify the appropriate candidates for gene-expression testing in heart transplantation.

3. Describe the impact of a rejection surveillance protocol utilizing gene-expression profiling on clinical outcomes.

Acute cellular rejection (ACR) is observed at a diminishing frequency throughout the first three years after heart transplantation and is responsible for significant morbidity and mortality despite advances in immunosuppression. Owing to the asymptomatic nature of many rejection episodes and the lack of sensitivity or specificity of previous biomarkers, the endomyocardial heart biopsy (EMB) has remained the gold standard for rejection monitoring in heart transplant recipients since its introduction in 1973.Peripheral blood gene-expression profiling (GEP) was developed to provide a non-invasive alternative to the EMB in patients at low risk for acute rejection. The assay is based on the analysis of peripheral blood mononuclear cell mRNA using real-time PCR technology. In the multicenter Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, a multi-gene algorithm based on the expression of 11 informative and 9 control genes was developed and validated.

The 11 informative genes in the AlloMap® test are involved in pathways hypothesized to play a role in immune activation during ACR, including T cell priming, platelet activation, proliferation and mobilization of immature erythrocytes, and steroid responsiveness. In the CARGO study, AlloMap® scores below 34 were associated with a negative predictive value of 98.9% for moderate or severe ACR among stable outpatients who were at least 6 months post-transplantation. The use of GEP testing as part of a non-invasive rejection monitoring approach was compared with the standard approach of routine EMB in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study. IMAGE was a multi-center, randomized clinical trial conducted among 602 heart transplant recipients who were at least 6 months post-transplantation and considered at low risk for rejection. The study randomized patients to either conventional surveillance EMB or to GEP testing, in conjunction with clinical and echocardiographic assessment of graft function in both arms. During a median follow-up of 19 months, patients randomized to GEP testing underwent significantly fewer biopsies, reported higher satisfaction scores, and had similar 2-year rates of death or re-transplantation, rejection with hemodynamic compromise, or graft dysfunction due to other causes. Based upon the combined knowledge gained in the CARGO and IMAGE studies, the use of GEP testing has been incorporated into the rejection monitoring practices at many heart transplant centers in the United States.

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