 | The AlloMap™ molecular expression test for heart transplantation rejection is considered experimental/investigational and, therefore, not covered because the safety and/or efficacy of this service cannot be established by review of the available published peer-reviewed literature.
While the Company considers this test to be experimental/investigational, there are clinical trials available through XDx Laboratories, the proprietor of AlloMap™, for members who wish to enroll and participate.
For more information on clinical trials for AlloMap™, go to:
http://www.clinicaltrials.gov/ct2/show/NCT00962377?term=AlloMap&recr=Open&rank=2.
Routine services associated with some experimental/investigational services may be covered when they are performed in a qualified clinical trial. For more information, refer to the Company policy on qualifying clinical trials.
To report Allomap™, use the following CPT codes:
Also use the following ICD 9 codes:
- 996.83: Complications of transplanted heart
- V42.1: Heart replaced by transplant (not a primary code)
About AlloMap™ molecular expression test for heart transplantation rejection
Many cardiac transplant recipients experience at least one episode of rejection in the first year after transplantation. The highest incidence of rejection is within the first six months after transplantation, when acute cellular rejection is most likely to occur; there is a significant decline in the incidence of rejection after that time.
Post-transplant recipients require the lifelong use of immunosuppressant drugs, with dosing adjusted on the basis of graft function and the grade of acute cellular rejection, which is determined by histopathology. Endocardial biopsies are typically taken from the right ventricle via the jugular vein on a weekly basis for the first month, and once or twice monthly for the following six months. Following stabilization, surveillance biopsies are performed on a yearly basis.
In August 2008, the US Food and Drug Administration (FDA) cleared the AlloMap™ (XDx Laboratories, Brisbane, CA), a commercially available molecular expression test that has been developed to detect acute heart transplantation rejection or graft dysfunction. AlloMap™ is a noninvasive test that involves polymerase chain reaction (PCR) expression measurement of a panel of genes derived from peripheral blood cells, and applies an algorithm to the results. The algorithm produces a single score that considers the contribution of each gene in the panel.
Patterns of gene expression were studied in the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, which included eight US cardiac transplantation centers enrolling 650 cardiac transplant recipients encompassing over 5,000 clinical encounters. Blood samples were obtained at the time of endomyocardial biopsy, and the expression levels of over 7,000 genes known to be involved in immune responses were assayed and compared to the biopsy results. A subset of 200 candidate genes were identified that showed promise as markers that could distinguish transplantation rejection from quiescence. From there, a panel of 11 genes was selected that could be evaluated using PCR assays. A proprietary algorithm was applied to the results of the analysis, producing a single score that considers the contribution of each gene in the panel.
The third phase in the development of the AlloMap™ test was a pivotal validation study designed to further evaluate the algorithm and establish performance characteristics of the test. This phase of the study was prospective, blinded, and enrolled 270 individuals.
Results of the CARGO study were presented at the 2005 annual meeting of the International Society for Heart Lung Transplantation and published in 2006. Primary validation was conducted using samples from 63 individuals independent of the discovery phases of the study and enriched for biopsy-proven evidence of rejection. A prospectively defined test cutoff value of 20 resulted in correct classification of 84 percent of patients with moderate/severe rejection but just 38 percent of patients without rejection. Of note, in the “training set” used in the study, these rates were 80 percent and 59 percent, respectively. The authors evaluated the 11-gene expression profile on 281 samples collected at one year or more from 166 individuals representative of the expected distribution of rejection in the target population (and not involved in discovery or validation phases of the study). When a test cutoff of 30 was used, the negative predictive value (no moderate/severe rejection) was 99.6 percent; however, only 3.2 percent of specimens had grade 3 or higher rejection. In this population, grade 1B scores were found to be significantly higher than grade 0, 1A, and 2 scores but similar to grade 3 scores. The sensitivity and specificity for determining quiescent versus early stages of rejection was not addressed.
Post-CARGO clinical observations have also been published. The multicenter workgroup identified a number of factors that can affect AlloMap™ scores, including the time post-transplant, corticosteroid dosing, and transplant vasculopathy. Scores of 34 and above were considered positive, potentially indicating rejection, whereas scores below that threshold were considered negative with no evidence of rejection. Analysis of data from a number of centers collected post-CARGO showed that, at one year or more post-transplantation, an AlloMap™ threshold of 34 had a positive predictive value (PPV) of 7.8 percent for scores greater than or equal to 3A/2R on biopsy and a negative predictive value of 100 percent for AlloMap™ scores below 34. These findings are limited due to a very low number of events; only five biopsy samples (2.4 percent) were found to have a grade of 2R or greater. At one year, 28 percent of the sample showed an elevated AlloMap™ score (greater than 34) even though there was absence of evidence of rejection on biopsy. The significance of chronically elevated AlloMap™ scores in the absence of clinical manifestation of graft dysfunction and the actual impact on the number of biopsies performed is currently unknown.
Evans and colleagues discussed the economic implications of noninvasive testing for cardiac allograft rejection, based on the assumption that a positive AlloMap™ test would result in a confirmatory biopsy, while a negative test would permit deferral of a biopsy. Based on the results of the CARGO study, the authors estimate that during the first post-transplant year, the numbers of endomyocardial biopsies would be halved, resulting in an aggregate cost savings for all heart transplant patients of 12 million dollars per year.
A review from the California Technology Assessment Forum concluded that given the post-hoc change in the threshold and the small size of the CARGO primary validation study, “it would be prudent to require independent confirmation of the CARGO study results” before widespread adoption of AlloMap™ gene expression profiling to monitor heart transplant patients. This 2006 technology assessment also noted that there were no studies that compared clinical outcomes of individuals monitored with gene expression profiling to those of individuals monitored with endomyocardial biopsies. Some of these issues will be addressed by an ongoing randomized clinical trial (IMAGE) comparing AlloMap™ molecular testing with traditional biopsy-based surveillance for heart transplantation rejection. The IMAGE trial began recruiting subjects in January 2005. The design and objectives of the IMAGE trial have been reported, but no results are available at this time.
If you have any questions, contact your Network Coordinator.
| |