Commercial

Medical Policy

Title:

AlloMap™ Molecular Expression Testing for Heart Transplant Rejection (Independence Administrators)

Policy #:

06.02.29d

Policy

This policy only applies to members for whom Independence Administrators serves as the claims administrator and whose group has not enrolled in the UM vendor program. For those groups who have been given the option to enroll in the UM vendor program, this policy is no longer applicable upon their renewal effective date. Individual member benefits must be verified before/prior to providing services.

The intent of this policy is to communicate the medical necessity criteria for the AlloMap™ molecular expression testing for heart transplant rejection.

MEDICALLY NECESSARY

The AlloMap™ Molecular Expression Test for Heart Transplantation Rejection is medically necessary and, therefore, covered when the individual is at least 6 months post--heart transplant and:

Is at least 15 years of age
Is considered to be stable (i.e., if within the first 6-month transplant window there has been no evidence of Grade 2R or Grade 3R graft rejection detected by EMB and the individual has not deteriorated since the prior clinical assessment).
Is considered to be a "low risk" for cardiac events (i.e., absence of a history of severe allograft vasculopathy, absence of antibody-mediated rejection, and absence of any signs or symptoms of heart failure).

Once the requisite clinical criteria noted above are satisfied, and the provider elects to use the AlloMap™ Molecular Expression Test, the Company will consider EITHER the use of AlloMap™ Molecular Expression Test OR the use of regularly performed EMB to monitor for post-transplantation graft rejection to be medically necessary: the Company does not consider the regular or routine use of both methods, or the routine use of one method to validate the other, to be medically necessary. However, if the member has an AlloMap™ "threshold" score of >34 (on a 40 scale), or if a compelling clinical reason exists, the provider may elect to use EMB, which is the acknowledged gold standard, for ACR monitoring.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for the AlloMap™ Molecular Expression Test for Heart Transplantation Rejection are considered experimental/investigational and, therefore, not covered because their safety and/or effectiveness cannot be established by review of the available published peer-reviewed literature.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, the AlloMap™ Molecular Expression Test for Heart Transplant Rejection is covered under the medical benefits of the Company's products when the medical necessity criteria listed in the medical policy are met.

US FOOD AND DRUG ADMINISTRATION STATUS

The AlloMap™ Molecular Expression Test for Heart Transplantation Rejection received FDA approval on August 27, 2008 as an In Vitro Diagnostic Multivariate Index Assay test.

Description

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 (ACR) is most likely to occur; there is a significant decline in the incidence of rejection after that time.

Post-transplant recipients require lifelong use of immunosuppressant drugs, with dosing adjusted based on graft function and ACR grade, which is determined by histopathology. Endomyocardial biopsies (EMB) 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. EMB, considered the standard of care, is performed periodically during the first six to 12 months post-transplant to check for heart transplant rejection in adult and adolescent heart transplant recipients.

In August 2008, the US Food and Drug Administration (FDA) cleared 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 AlloMap™ test is a panel of 20 gene assays, of which 11 are informative and 9 are used for normalization and/or quality control. Gene expression data is thereby created and used in the calculation of an AlloMap™ test score, which is a number ranging from 0 to 40. The lower the score, the lower the probability of ACR at the time of testing.

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 and 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 and Lung Transplantation (ISHLT) 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 were not addressed.

In 1990, the first uniform histological classification for heart allograft rejection was developed by the ISHLT. Originally, there were 7 grades: Grade 0 (no rejection, Grades 1A and 1B (mild rejection), Grade 2 (focal moderate rejection), Grades 3A and 3B (moderate rejection), and Grade 4 (severe rejection).

Post-CARGO study 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 study showed that, at one year or more post-transplantation, an AlloMap™ threshold of 34 had a positive predictive value 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.

Recently, results from the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, which was a non-inferiority trial, were published. This was a multicenter clinical trial of stable heart transplant patients conducted at 12 heart transplant centers in the United States. Participants were randomized to receive either the AlloMap™ test or the conventional endomyocardial biopsy method of surveillance monitoring. The patients were enrolled in the study when they were 12 months to five years post-transplant (later modified to include six to 12 months after transplant, as well) and then followed by the assigned surveillance method for up to two years. These patients were at low risk of cardiac events. The primary endpoint was an event of rejection with hemodynamic compromise, graft dysfunction due to other causes, death, or retransplantation. Secondary outcomes included the number of biopsies performed. Patient satisfaction and quality of life were also assessed.

Results showed that, during a median follow-up of 19 months, cardiac transplant recipients monitored with AlloMap™ had similar two-year cumulative rates of rejection with hemodynamic compromise, graft dysfunction from other causes, death, or retransplantation as recipients who were monitored with routine biopsies (14.5 percent vs. 15.3 percent). The two-year rates of death or retransplantation were also similar in the AlloMap™ and biopsy arms (6.3 percent and 5.5 percent). The trial also showed that patients randomized to AlloMap™ underwent significantly fewer biopsies per person year of follow-up compared with patients in the biopsy group (0.5 biopsies/year vs. 3.0 biopsies/year). Patient satisfaction with AlloMap™ was higher compared with the biopsy method.

A revised heart allograft rejection grading system was developed by ISHLT and published in 2005.* There was concern that the previous system had inconsistencies of application due to inter/intraobserver variability in grading. The previous grading system was reduced from 7 categories to 4, and an "R" was added to reflect the "revised" status and avoid confusion with the previous classification system.

2005 Revised Categories for Heart Allograft Rejection from the ISHLT*

Grade 0R	No rejection
Grade 1R	Mild acute cellular rejection (interstitial and/or perivascular infiltrate with up to 1 focus of myocyte damage)
Grade 2R	Moderate acute cellular rejection (two or more foci of infiltrate with associated myocyte damage)
Grade 3R	Severe acute cellular rejection (diffuse infiltrate with multifocal myocyte damage +/- edema, +/- hemorrhage, +/- vasculitis

*Stewart S, Winters GL, Fishbeni MC, et al. Revision of the 1990 Working Formulation for the Standardization of Nomenclature in the Diagnosis of Heart Rejection. J Heart Transplant.2005;24(11):1710-1720.

In August 2010, ISHLT published Guidelines for the Care of Heart Transplant Patients in the Journal of Heart and Lung Transplantation. When discussing the noninvasive monitoring of acute heart transplant rejection, ISHLT recommends that gene expression profiling (AlloMap™) can be used to rule out the presence of ACR of grade 2R or greater in appropriate low-risk patients, between six months and five years after heart transplant. However, these same guidelines consider EMB the standard of care in these patients for surveillance of rejection.

References

Bernstein D, Mital S, Addonizio L, et al. Gene expression profiling of cardiac allograft recipients with mild acute cellular rejection. J Heart Lung Transplant. 2005;24(2 suppl):S65.

Billingham ME, Cary NR, Hammond ME, et al. A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. 1990;9(6): 587-593.

California Technology Assessment Forum (CTAF). Gene expression profiling for the diagnosis of heart transplant rejection. [CTAF Web site]. 2006. Available at: http://www.ctaf.org/content/general/detail/624. Accessed August 1, 2013.

California Technology Assessment Forum (CTAF). Gene expression profiling for the diagnosis of heart transplant rejection. [CTAF Web site]. 2010. Available at:http://www.ctaf.org/content/assessment/detail/1208. Accessed August 1, 2013.

Deng MC, Eisen HJ, Mehra MR, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. Am J Transplant. 2006;6(1):150-160.

Eisen HJ, Deng MC, Klinger TM, et al. Longitudinal monitoring of cardiac allograft recipients using peripheral blood gene expression profiling: a retrospective observational analysis of molecular testing in 19 case studies. J Heart Lung Transplant. 2005;24(2 suppl):S162.

Evans RW, Williams GE, Baron HM. The economic implications of noninvasive molecular testing for cardiac allograft rejection. Am J Transplant. 2006;5(6):1553-1558.

Fang KC. Clinical Utilities of Peripheral Blood Gene Expression Profiling in the Managment of Cardiac Transplant Patients. 2007; Journal of Immunotoxicity;4:209-217. Available at: http://informahealthcare.com/doi/pdf/10.1080/15476910701385570.
Accessed August 1, 2013.

International Society for Heart and Lung Transplantation (ISHLT). Guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010;29:914-956. Available at:
http://download.journals.elsevierhealth.com/pdfs/journals/1053-2498/PIIS105324981000358X.pdf. Accessed August 1, 2013.

International Society for Heart and Lung Transplantation (ISHLT). Press Release, April 22, 2010: International Society for Heart & Lung Transplantation and XDx Announce Results of IMAGE Study Demonstrating Non-Inferiority of AlloMap™® to Routine Biopsy for Routine Surveillance After Heart Transplantation. Available at: http://www.xdx.com/documents/2010 Press Release/FINAL ISHLT XDx joint release IMAGE study.pdf. Accessed August 1, 2013.

Mandras SA, Crespo J, Patel HM. Innovative application of immunologic principles in heart transplantation. The Oschner Journal. 2010;10:231-235. Available at: http://www.ochsnerjournal.org/doi/pdf/10.1043/TOJ-10-0024.1. Accessed August 1, 2013.

Mehra M, Parameshwar J. Gene expression profiling and cardiac allograft rejection monitoring: is IMAGE just a mirage? J Heart Lung Transplant.2010; 29:599-601.

Marboe CC, Lal PG, Chu K, et al. Distinctive peripheral blood gene expression profiles in patients forming nodular endocardial infiltrates (Quilty lesions) following heart transplantation. J Heart Lung Transplant. 2005;24(2 suppl):S97.

National Institutes of Health. A comparison of AlloMap™ molecular testing and traditional biopsy-based surveillance for heart transplant rejection early post-transplantation (>2-6 months). [Clinical Trials.gov web site]. Available at: http://www.clinicaltrials.gov/ct2/show/NCT00962377?term=AlloMap&recr=Open&rank=2. Accessed August 1, 2013.

Pham MX, Deng MC, Kfoury AG, et al. Molecular testing for long-term rejection surveillance in heart transplant recipients: design of the Invasive Monitoring Attenuation Through Gene Expression (IMAGE) trial. J Heart Lung Transplant. 2007;26(8):808-814.

Pham MX, Teuteberg JJ, Kfoury AG, et al. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010;362(20):1890-1900.

Phillips M, Boehmer JP, Cataneo RN, et al. Heart allograft rejection: detection with breath alkanes in low levels (the HARDBALL study). J Heart Lung Transplant. 2004;23(6):701-708.

Starling RC, Deng MC, Kobashigawa JA, et al. The influence of corticosteroids on the alloimmune molecular signature or cardiac allograft rejection. J Heart Lung Transplant. 2005;24(2 suppl):S65-S66.

Starling RC, Pham M, Valantine H, et al; Working Group on Molecular Testing in Cardiac Transplantation. Molecular testing in the management of cardiac transplant recipients: initial clinical experience. J Heart Lung Transplant. 2006;25(12):1389-1395.

Stewart S, Winters GL, Fishbeni MC, et al. Revision of the 1990 Working Formuation for the Standardization of Nomenclature in the Diagnosis of Heart Rejection. J Heart Transplant.2005;24 (11):1710-1720.

US Food and Drug Administration (FDA). Center for Devices and Radiological Health. AlloMap™ Molecular Expression Testing. Premarket notification database. [FDA Web site]. 08/08/08. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/PMNSimpleSearch.cfm?db=PMN&ID=K073482. Accessed August 1, 2013.

XDx Expression Diagnostics. AlloMap™ Molecular Expression Testing. Product Web site. Available at: http://www.allomap.com/. Accessed August 1, 2013.

Yamani MH, Taylor DO, Rodriguez ER, et al. Transplant vasculopathy is associated with increased AlloMap™ gene expression score. J Heart Lung Transplant. 2007;26(4):403-406.

Coding

CPT Procedure Code Number(s)

81595

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Z48.21 Encounter for aftercare following heart transplant

Z48.280 Encounter for aftercare following heart-lung transplant

Z94.1 Heart transplant status

Z94.3 Heart and lungs transplant status

HCPCS Level II Code Number(s)

G0452 Molecular pathology procedure; physician interpretation and report

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Version Effective Date:

7/1/2016

Version Issued Date: