Medical Policy: 02.04.75 

Original Effective Date: May 2019 

Reviewed: May 2020 

Revised: May 2020 

 

Notice:

This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Most cardiac transplant recipients experience at least one episode of rejection in the first year after transplantation. In 2005, the International Society for Heart and Lung Transplantation modified its grading scheme for categorizing cardiac allograft rejection. Revised (R) categories are as follows:

  • Grade 0R: No rejection
  • Grade 1R: Mild rejection (previously Grades 1A, 1B and 2)
  • Grade 2R: Moderate rejection (previously Grade 3A)
  • Grade 3R: Severe rejection (previously Grades 3B and 4) 

 

Acute cellular rejection is most likely to occur in the first 6 months, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a lifelong basis, dosing is adjusted based on graft function and the grade of acute cellular rejection determined by histopathology. Endomyocardial biopsies are typically taken from the right ventricle via the jugular vein periodically during the first 6-12 months post-transplant. The interval between biopsies varies among clinical centers. A typical schedule is weekly for the first month, once or twice monthly for the following 6 months, and several times (monthly to quarterly) between 6 months and a year post-transplant. Surveillance biopsies may also be performed after the first postoperative year e.g., on a quarterly or semi-annual basis. This practice, although common, has not been demonstrated to improve transplant outcomes.

 

Endomyocardial biopsy is invasive and carries a risk of adverse effects; therefore, non-invasive methods of detecting cellular rejection are being explored. Individualized adjustment of the level of immunosuppression based on the risk of rejection and risk of immunosuppression-related adverse events is challenging to implement. It has been proposed that this level of personalization may be possible with molecular diagnostic techniques. Further evidence will be needed to determine the utility of this molecular diagnostic assay as a replacement for routine biopsies and its potential role in weaning immunosuppression and other aspects of long-term management of cardiac transplant recipients.

 

Noninvasive Transplant Rejection Tests

The Heartsbreath test

The Heartsbreath test, is a noninvasive test that measures breath markers of oxidative stress, has been developed to assist in the detection of heart transplant rejection. In heart transplant recipients, oxidative stress appears to accompany allograft rejection that degrades membrane polyunsaturated fatty acids, and evolving alkanes and methylalkanes that are in turn excreted as volatile organic compounds in breath. The Heartsbreath test analyzes the breath methylated alkane contour , which is derived from the abundance of C4-C20 alkanes and monomethylalkanes and has been identified as a marker to detect grade 3 (clinically significant) heart transplant rejection.

 

Allomap®

A non-invasive testing approach has focused on patterns of gene expression as detected in the peripheral blood. Allomap® analyzes the expression of 20 genes in a transplant recipient’s blood sample to determine whether the patient’s immune system is launching an attack. It is intended for patients at least 15 years-old who are at least 2 months post-transplant. AlloMap® for heart transplant recipients involves measurement of a panel of genes derived from peripheral blood cells, and application of an algorithm to the results. The algorithm produces a single score with the lower scores indicating a lower risk of graft rejection.

 

Microarray Gene Expression ProfileTesting (MMDx-Heart, MMDx-Kidney, MMDx-Lung)

The MMDx system uses predefined algorithms to assess the probability of rejection or injury by assessing microarrays to measure mRNA levels. The additional accuracy of biopsy testing and treatment decisions are not changed by information obtained from this testing. Current clinical trials are ongoing. 

 

The Viracor TRAC™ dd-cfDNA assay determines the percentage of circulating cell-free DNA (cfDNA) in transplant recipients derived from donor grafts. cfDNA is extracted from plasma isolated from whole blood collected. NGS and genome-wide recipient genotype data are then analyzed by a bioinformatics pipeline that calculates the percentage of dd-cfDNA present. This test was developed and its performance characteristics determined by Viracor Eurofins.

 

Cell-free DNA (dd-cfDNA) Testing (e.g. Allosure, myTAIHEART)

Cell-free DNA (cfDNA), released by damaged cells, is normally present in healthy individuals. In patients who have received transplants, donor-derived cfDNA (dd-cfDNA) may also be present. It has been proposed that allograft rejection, which is associated with damage to transplanted cells, may result in an increase in dd-cfDNA. AlloSure is a commercially available, next-generation sequencing (NGS) assay which quantifies the fraction of dd-cfDNA in renal transplant recipients, relative to total cfDNA, by measuring 266 single nucleotide variants (SNVs). The myTAIHEART reports the ratio of donor specific cfDNA to total cfDNA as the donor fraction (%) and categorizes the patient as at low or increased risk of moderate/severe acute cellular rejection.

 

Gene Expression Panel Testing

NanoString Technologies has announced the launch of nCounter Human Organ Transplant, a gene expression panel for researchers to evaluate the human immune response following organ transplantation. Created through a collaboration between NanoString and the Banff Foundation for Allograft Pathology, a global consortium of 6 transplant institutes. The customizable, 770-gene expression panel was developed specifically for use with the predominant transplant organs including kidney, heart, lung, and liver and includes genes across 37 different pathways, critical components of the immune response, tissue injury, and mechanisms of action for immunosuppressive drugs. The panel also includes probes for detection of common viral infections known to be problematic with transplants including BK polyomavirus, cytomegalovirus and Epstein-Barr virus. The Human Organ Transplant Panel is for research use only; not for use in diagnostic procedures. Veracyte system. HistoMap is being developed using the Human Organ Transplant (HOT) panel from the Banff Foundation for Allograft Pathology.

 

Guidelines and Position Statements

International Society of Heart and Lung Transplantation

In 2010, the International Society of Heart and Lung Transplantation (ISHLT) issued guidelines for the care of heart transplant recipients which included the following:

  • The standard of care for adult heart transplant recipients is to perform periodic endomyocardial biopsy (EMB) during the first 6-12 months after transplant for rejection surveillance;
  • After the first year post-transplant, EMB surveillance every 4-6 months is recommended for patients at higher risk of late acute rejection;
  • Gene expression profiling using the AlloMap test can be used to rule out acute heart rejection (grade 2 or greater) in appropriate low risk patients between 6 months and 5 years post-transplant.

 

Kidney Disease Improving Global Outcomes

The Kidney Disease Improving Global Outcomes (2009) issued guidelines for the care of kidney transplant recipients, The guidelines included the following recommendations.

 

Guidelines for Biopsy in Renal Transplant Recipients

Recommendation: "We recommend kidney allograft biopsy when there is a persistent, unexplained increase in serum creatinine.” Level 1 C

 

"We suggest kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection.” Level 2 D

 

Prior Approval:

 

Policy:

AlloMap® molecular expression testing may be considered medically necessary as a non-invasive method of determining the risk of rejection in heart transplant recipients at least 15 years of age, between 6 months and 5 years post-transplant.

 

Breath test for measurement of volatile organic compounds to detect heart transplant rejection (e.g. Heartsbreath) is considered investigational.

 

Donor-derived cell-free DNA (dd-cfDNA) testing (e.g. Allosure, myTAIHEART, Prospera, Viracor TRAC) for transplant rejection status is considered investigational.

 

Microarray gene expression profiling panels for transplant rejection status (e.g. MMDx-Kidney, MMDx-Heart, kSORT) are considered investigational.

 

Human organ transplant panels (e.g. nCounter, HistoMAP) are considered investigational.

 

Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81595 Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing sub-fraction of peripheral blood, algorithm reported as a rejection risk score
  • 0055U Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma
  • 0087U Cardiology (heart transplant), mRNA gene expression profiling by microarray of 1283 genes, transplant biopsy tissue, allograft rejection and injury algorithm reported as a probability score
  • 0088U Transplantation medicine (kidney allograft rejection), microarray gene expression profiling of 1494 genes, utilizing transplant biopsy tissue, algorithm reported as a probability score for rejection
  • 81479 Unlisted molecular pathology procedure
  • 81599 Unlisted multianalyte assay with algorithmic analysis
  • 86849 Unlisted immunology procedure 
  • 0118U Transplantation medicine, quantification of donor-derived cell-free DNA using whole genome next-generation sequencing, plasma, reported as percentage of donor-derived cell-free DNA in the total cell-free DNA

 

Selected References:

  • American College of Cardiology (ACC). 2017 ACC/AHA/HFSA/ISHLT/ACP advanced training statement on advanced heart failure and transplant cardiology (revision of the ACCF/AHA/ACP/HFSA/ISHLT 2010 clinical competence statement on management of patients with advanced heart failure and cardiac transplant). Published June 20, 2017.
  • Bloom RD., Bromberg JS, Poggio E, et al. Cell-free DNA and active rejection in kidney allografts. J Am SocNephrol. 2017; 28:2221.
  • Blue Cross Blue Shield Association Technology Evaluation Center (TEC). Gene expression profiling as a noninvasive method to monitor for cardiac allograft rejection. TEC Assessments 2011; volume 26, tab 8.
  • Bromberg JS, Brennan DC, Poggio E, et al. Biological variation of donor-derived cell-free DNA in renal transplant recipients: clinical implications. J Appl Lab Med. 2017; 2:309.
  • Braga, J., Santos, I., McDonald, M., Shah, P., and Ross, H. (2012, March-April) Factors associated with the development of cardiac allograft vasculopathy--a systematic review of observational studies. Clinical Transplantation, 26 (2), 111-24.
  • Centers for Medicare & Medicaid Services. CMS.gov. NCD for Heartsbreath test for heart transplant rejection (260.10). 
  • ClinicalTrials.gov, Outcomes AlloMap Registry Study: the Clinical Long-term Management and Outcomes of Heart Transplant Recipients With Regular Rejection Surveillance Including Use of AlloMap Gene-expression Profiling Testing; sponsored by CareDx
  • ClinicalTrials.gov, Utility of Donor-Derived Cell-free DNA in Association With Gene-Expression Profiling (AlloMap®) in Heart Transplant Recipients (D-OAR); sponsored by CareDx.
  • ClinicalTrials.gov, Evaluation of Patient Outcomes From the Kidney Allograft Outcomes AlloSure Registry, sponsored by CareDx.
  • Costanzo MR, Dipchand A, Starling R. et al. The International Society of Heart and Lung Transplantation guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2010; 29(8):914-956.
  • Crespo-Leiro, M., Stypmann, J., Schulz, U., Zuckerman, A., Mohacsi, P, Bara, C., et al. (2015). Performance of gene-expression profiling test score variability to predict future clinical events in heart transplant recipients. BMC Cardiovascular Disorders, 15:120.
  • Crespo-Leiro, M., Stypmann, J., Schulz, U., Zuckerman, A., Mohacsi, P, Bara, C., et al. (2016). Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. European Heart Journal, 37, 2591-2601.
  • Deng, M., Elashoff, B., Pham, M., Teuteberg, J., Kfoury, A., Starling, R., et al. (2014). Utility of gene expression profiling score variability to predict clinical events in heart transplant recipients. Transplantation, 97 (6), 708-714.
  • ECRI Institute. Emerging Technology Evidence Report. Gene expression profiling to monitor heart transplant rejection.
  • Grskovic M, Hiller DJ, Eubank LA, et al. Validation of a clinical-grade assay to measure donor-derived cell-free DNA in solid organ transplant recipients. J Mol Diagn. 2016;18:890.
  • Hidestrand M, Tomita-Mitchell A, Hidestrand PM, et al. Highly Sensitive Non-Invasive Cardiac Transplant Rejection Monitoring Using Targeted Quantification of Donor Specific Cell Free DNA. Journal of the American College of Cardiology. 2014;63(12):1224-1226. doi:10.1016/j.jacc.2013.09.029.
  • Halloran PF, Famulski KS, Reeve J. Molecular assessment of disease states in kidney transplant biopsy samples. Nat Rev Nephrol. 2016 Sep;12(9):534-48.
  • International Society of Heart and Lung Transplantation. (2010) Guidelines for the care of heart transplant recipients.  The Journal of Heart and Lung Transplantation, 29 (8), 914-956.
  • Jordan SC, Bunnapradist S, et al. Donor-derived Cell-free DNA Identifies Antibody-mediated Rejection in Donor Specific Antibody Positive Kidney Transplant Recipients. Transplant Direct. 2018 Aug 20;4(9):e379.
  • Kobashigawa, J., Patel, J., Azarbal, B., Kittleson, M., Chang, D., Czer, L. et. al. (2015) Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant. Circulation: Heart Failure, 8 (3), 557-564.
  • Kieran M. Halloran, et al. Molecular assessment of rejection and injury in lung transplant biopsies. J Heart Lung Transplant. 2019 Feb;38(5):504-513.
  • Loupy A, Duong Van Huyen JP, Hidalgo L, et al. Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection. Circulation 2017; 135:917.
  • Mavrogeni, S.,  Athanasopoulos, G., Gouziouta, A., Leontiadis, E., Adamopoulos, S., and Kolovou, G. (2017, April) Cardiac transplantation: towards a new noninvasive approach of cardiac allograft rejection. Expert Reviews in Cardiovascular Therapy, 15 (4), 307-313. Abstract retrieved July 27, 2018 from PubMed database.
  • Pham, M., Teuteberg, J., Kfoury, A., Starling, R., Deng, M., Cappola, T., et al. (2010, May) Gene-expression profiling for rejection surveillance after cardiac transplantation. New England Journal of Medicine, 362 (20), 1880-1900.
  • Rodriguez Faba, O., Boissier, R., Budde, K., Figueiredo, A., Taylor, C. F., Hevia, V., . . . Breda, A. (2018). European Association of Urology Guidelines on Renal Transplantation: Update 2018. Eur Urol Focus, 4(2), 208-215. doi:10.1016/j.euf.2018.07.014
  • Stehlik J, Kobashigawa J, Hunt SA, Reichenspurner H, Kirklin JK. Honoring 50 Years of Clinical Heart Transplantation in Circulation: In-Depth State-of-the-Art Review. Circulation. 2018;137:71–87.
  • UpToDate, Inc. Investigational methods in the diagnosis of acute renal allograft rejection. Updated March 5, 2018.
  • Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. Oct 15 2013;62(16):e147-239.
  • Viracor. (2019). Viracor TRAC™ Lung dd-cfDNA.

 

Policy History:

  • May 2020 - Annual Review, Policy Revised
  • May 2019 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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