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Genetic Tests For Chronic Heart Failure And Heart And Kidney Transplant Rejection

Policy Number: MP-212

ARCHIVED – Refer to AIM Genetic Testing Guidelines Effective 3/1/20

Latest Review Date: March 2020

Category: Genetic

Policy Grade: B

POLICY:

The use of peripheral blood gene expression profile tests in the management of patients post-heart transplantation, including, but not limited to the detection of acute heart transplant rejection or heart transplant graft dysfunction is considered not medically necessary and investigational.

The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction is considered not medically necessary and investigational.

DESCRIPTION OF PROCEDURE OR SERVICE:

Heart and Renal Transplant Rejection

Commercially available test, AlloMap®, uses gene expression profiling to assess heart transplant rejection. This test creates a score based on the expression of a variety of immunomodulatory genes and is proposed as an alternative or as an adjunct to invasive endomyocardial biopsy. Renal transplant rejection may be assessed by the AlloSure® test, which measures the donor-derived cell-free DNA in peripheral blood and is proposed as an alternative or adjunct treatment to invasive renal biopsy to assess kidney transplant rejection.

Noninvasive Heart Transplant Rejection Tests

One approach to assist in the detection of heart transplant rejection has focused on patterns of gene expression of immunomodulatory cells, as detected in the peripheral blood. For example, microarray technology permits the analysis of the gene expression of thousands of genes, including those with functions that are known or unknown. Patterns of gene expression can then be correlated with known clinical conditions, permitting a selection of a finite number of genes to compose a custom multigene test panel, which then can be evaluated using polymerase chain reaction (PCR) techniques. AlloMap® is a commercially available molecular expression test that has been developed to detect acute heart transplant rejection or the development of graft dysfunction. The test involves PCR-expression measurement of a panel of genes derived from peripheral blood cells and applies an algorithm to the results. The proprietary algorithm produces a single score that considers the contribution of each gene in the panel. The score ranges from zero to 40. The Allomap® website states that a lower score indicates a lower risk of graft rejection; the website does not cite a specific cutoff for a positive test. All AlloMap® testing is performed at the CareDx reference laboratory in Brisbane, CA.

Renal Transplant Rejection: Donor-Derived Cell-Free DNA

Cell-free DNA (cfDNA), released by damaged cells, and is normally present in healthy individuals. In patients who have received transplants, donor-derived cfDNA (dd-cfDNA) may be also present. It is 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 assay that quantifies the fraction of dd-cfDNA in renal transplant recipients, relative to total cfDNA, by measuring 266 single nucleotide variants. Separate genotyping of the donor or recipient is not required, but patients who receive a kidney transplant from a monozygotic (identical) twin are not eligible for this test. The fraction of dd-cfDNA relative to total cfDNA present in the peripheral blood sample is cited in the report. All AlloSure® testing is performed at the CareDx reference laboratory.

KEY POINTS:

The most recent literature update was performed through August 5, 2019.

Summary of Evidence

The evidence includes two diagnostic accuracy studies and several randomized controlled trials evaluating clinical utility for individuals who have a heart transplant who receive gene expression profiling (GEP) to assess cardiac allograft rejection. The evidence includes two diagnostic accuracy studies and several randomized controlled trials evaluating clinical utility. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The two studies (CARGO, CARGO II) examining the diagnostic performance of GEP for detecting moderate-to-severe rejection lacked a consistent threshold for defining a positive GEP test (i.e., 20, 30, or 34) and reported a low number of positive cases. In the available studies, although the negative predictive values were relatively high (i.e., at least 88%), the performance characteristics were only calculated based on ten or fewer cases of rejection; therefore, performance data may be imprecise. Moreover, the positive predictive value in CARGO II was only 4.0% for patients who were at least two to six months post-transplant and 4.3% for patients more than six months post-transplant. The clinical utility of GEP compared with routine endomyocardial biopsies has been evaluated in two RCTs, the IMAGE study assessing patients more than six months post-transplant and a small pilot randomized control trial assessing patients starting at 55 days post-transplant. The threshold indicating a positive test that seems to be currently accepted (a score of 34) was not prespecified; rather it evolved partway through the data collection period in the IMAGE study. In addition, the IMAGE study had several methodologic limitations (e.g., lack of blinding); further, the IMAGE study failed to provide evidence that GEP offers incremental benefit over biopsy performed on the basis of clinical exam or echocardiography. Patients at the highest risk of transplant rejection are patients within one year of the transplant, and for that subset there remains insufficient data on which to evaluate the clinical utility of GEP. The evidence is insufficient to determine the effects of the technology on health outcomes.

The evidence includes a diagnostic accuracy study for individuals with a renal transplant and clinical suspicion of allograft rejection who receive testing of dd-cfDNA to assess renal allograft rejection. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The study examined the diagnostic performance of dd-cfDNA for detecting moderate-to-severe rejection; the negative predictive value was moderately high (84%), and performance characteristics were calculated on 27 cases of active transplant rejection. The threshold indicating a positive test was not prespecified. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Positions Statements

International Society of Heart and Lung Transplantation

In 2010, the International Society of Heart and Lung Transplantation issued guidelines for the care of heart transplant recipients. The guidelines included the following recommendations (see table below). 

Table. Guidelines for Postoperative Care of Heart Transplant Recipients

Recommendation

COR

LOE

“The standard of care for adult HT recipients is to perform periodic EMB during the first 6 to 12 post-operative months for surveillance of HT rejection.”

IIa

C

After the first post-operative year, EMB surveillance for an extended period of time (e.g., every 4–6 months) is recommended in HT patients at higher risk for late acute rejection….”

IIa

C

“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 6 months and 5 years after HT.”

IIa

B

ACR: acute heart rejection; COR: class of recommendation; EMB: endomyocardial biopsy; HT: heart transplant; LOE: level of evidence.

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 (see table below).

Table. Guidelines for Biopsy in Renal Transplant Recipients

Recommendation

SOR

LOE

“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

“We suggest kidney allograft biopsy every 7–10 days during delayed function.”

Level 2

C

“We suggest kidney allograft biopsy if expected kidney function is not achieved within the first 1–2 months after transplantation.”

Level 2

D

“We suggest kidney allograft biopsy when there is new onset of proteinuria.”

Level 2

C

“We suggest kidney allograft biopsy when there is unexplained proteinuria ≥3.0 g/g creatinine or ≥3.0 g per 24 hours.”

Level 2

C

LOE: level of evidence; SOR: strength of recommendation.

U.S. Preventive Services Task Force Recommendations

Not applicable.

KEY WORDS:

endomyocardial biopsy, heart transplant rejection, AlloMap® Test, gene expression profiling, Cardiac Allograft Rejection Gene Expression Observation (CARGO) Study, Invasive Monitoring Attenuation through Gene Expression (IMAGE) Study, MyTAIHEART, TAI, AlloSure® Test, renal allograft rejection, kidney transplant rejection, GEP, Next Generation Sequencing (NGS), dd-cfDNA, donor-derived cell-free DNA, DART Study, Viracor, TRACTM, dd-cfDNA

APPROVED BY GOVERNING BODIES:

In August 2008, AlloMap® Molecular Expression Testing (CareDx, Brisbane, CA; formerly XDx) was cleared for marketing by FDA through the 510(k) process. FDA determined that this device was substantially equivalent to existing devices, in conjunction with clinical assessment, for aiding in the identification of heart transplant recipients with stable allograft function who have a low probability of moderate/severe transplant rejection. It is intended for patients at least 15 years old who are at least two months post-transplant.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP contracts: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT codes:

0055U

Cardiology (heart transplant), cell-free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma (Effective 07/01/18)

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 (Effective 10/01/19)

81595

Cardiology (heart transplant), mRNA, gene expression profiling by real-time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score (i.e., Allomap®)

REFERENCES:

  1. Ahmad I. Biopsy of the transplanted kidney. Semin Intervent Radiol. Dec 2004; 21(4):275-281.
  2. AlloMap®: A Non-Invasive, Test Service for Heart Transplant Patients. www.allomap.com. Accessed April, 2016.
  3. Bernstein D, et al.  Gene expression profiling distinguishes moderate to severe from mild acute cellular rejection in cardiac allograft recipient. J Heart Lung Transplant. 2007 Dec; 26(12):1270-80.
  4. Bernstein D, Mital S, Addonizio L, et al. Gene expression profiling of cardiac allograft recipients with mild acute cellular rejection. Journal Heart Lung Transplant 2005; 24(2): S65.
  5. Bloom RD, Bromberg JS, Poggio ED, et al. Cell-free DNA and active rejection in kidney allografts. J Am Soc Nephrol. Jul 2017; 28(7):2221-2232.
  6. Blue Cross and 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.
  7. Cadeiras M, Shahzad K, John MM, et al. Relationship between a validated molecular cardiac transplant rejection classifier and routine organ function parameters. Clinical Transplant. May-June 2010; 24(3):321-327.
  8. CareDx. Overview: AlloMap® Testing: Answering Unmet Needs in Heart Transplant Surveillance. n.d.; www.allomap.com/providers/overview/. Accessed October 1, 2018.
  9. Celec P, Vlkova B, Laukova L, et al. Cell-free DNA: the role in pathophysiology and as a biomarker in kidney diseases. Expert Rev Mol Med. Jan 18 2018; 20:e1.
  10. Costanzo MR, Costanzo MR, Dipchand A et al. The International Society of Heart and Lung Transplantation guidelines for heart transplant recipients. J Heart Lung Transplant 2010; 29(8):914-56.
  11. Crespo-Leiro MG, Stypmann J, Schulz U, et al. Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II. Eur Heart J. Jan 7 2016.
  12. Deng MC, Eisen HJ, et al. Noninvasive discrimination of rejection in cardiac allograft recipients using gene expression profiling. American Journal Transplant 2006; 6(1): 150-160.
  13. Deng MC, Elashoff B, Pham MX et al. Utility of Gene Expression Profiling Score Variability to Predict Clinical Events in Heart Transplant Recipients. Transplantation 2014.
  14. Deng MC, et al. Early detection of cardiac allograft vasculopathy through gene expression profiling-Insights of the CARGO study. J Heart Lung Transplant 2006; 25(2), Supplement, S98.
  15. Duong Van Huyen JP, Tible M, Gay A, et al. MicroRNAs as non-invasive biomarkers of heart transplant rejection. Eur Heart J. Dec 1 2014; 35(45):3194-3202.
  16. 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. Journal Heart Lung Transplant 2005; 24(2): S162.
  17. Evans RW, Williams GE, Baron HM. The economic implications of non-invasive molecular testing for cardiac allograft rejection. American Journal Transplantation 2005; 5(6): 1553-1558.
  18. Goldberg RJ, Weng FL, Kandula P. Acute and chronic allograft dysfunction in kidney transplant recipients. Med Clin North Am. May 2016; 100(3):487-503.
  19. Haas M. The Revised (2013) Banff Classification for antibody-mediated rejection of renal allografts: update, difficulties, and future considerations. Am J Transplant. May 2016; 16(5):1352-1357.
  20. Jarcho JA. Fear of rejection- monitoring the heart-transplant recipient. New England Journal of Medicine 2010; 362(20): 1932-1933.
  21. Kasiske BL, Zeier MG, Chapman JR, et al. KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int. Feb 2010; 77(4):299-311.
  22. Kobashigawa J, Patel J, Azarbal B, et al. Randomized Pilot Trial of Gene Expression Profiling Versus Heart Biopsy in the First Year After Heart Transplant: Early Invasive Monitoring Attenuation Through Gene Expression Trial (EIMAGE). Circ Heart Fail. Feb 19 2015.
  23. Kobashigawa J, Patel J, Azarbal B, et al. Randomized pilot trial of gene expression profiling versus heart biopsy in the first year after heart transplant: early invasive monitoring attenuation through gene expression trial. Circ Heart Fail. May 2015; 8(3):557-564.
  24. Marboe CC, et al. Increased molecular testing scores associated with agreement among cardiac pathologists for the diagnosis of ISHLT 3A and higher rejection. J Heart Lung Transplant 2006; 25(2), Supplement, S105-S106.
  25. 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. Journal Heart Lung Transplant 2005; 24(2): S97.
  26. Mehra M, et al. Does induction therapy influence the utility of gene expression testing for cardiac allograft rejection? J Heart Lung Transplant 2007; 26(2), Supplement, S121.
  27. Mehra M, et al. The clinical role of gene expression testing in anticipating the future development of acute cardiac allograft rejection. J Heart Lung Transplant 2006; 25(2), Supplement, S110.
  28. Organ Procurement and Transplantation Network. National Data. 2018; optn.transplant.hrsa.gov/data/view-data-reports/national-data/#. Accessed October 1, 2018.
  29. Patel PC, Hill DA, Ayers CR, et al. High-sensitivity cardiac troponin I assay to screen for acute rejection in patients with heart transplant. Circ Heart Fail. May 2014; 7(3):463-469.
  30. Pham MX, Deng MC, et al. Molecular testing for long-term rejection surveillance in heart transplant recipients: Design of the invasive monitoring attenuation through gene expression (IMAGE) trial. Journal of Heart and Lung Transplant 2007; 26(8): 808-814.
  31. Pham MX, Teuteberg JJ, et al. Gene-Expression profiling for rejection surveillance after cardiac transplantation. New England Journal of Medicine 2010; 362:1890-1900.
  32. Solez K, Colvin RB, Racusen LC, et al. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. Apr 2008; 8(4):753-760.
  33. Starling RC, Deng MC, Kobashigawa JA, et al. The influence of corticosteroids on the alloimmune molecular signature or cardiac allograft rejection. Journal Heart and Lung Transplant 2005; 24(2): S65-S66.
  34. Starling RC, Pham M, et al.  Molecular testing in the management of cardiac transplant recipients: initial clinical experience. Journal of Heart Lung Transplant. December 2006; 25(12):1389-1395.
  35. Stewart S, Winters GL, Fishbein MC, et al. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. Nov 2005; 24(11):1710-1720.
  36. Tice JA. Gene expression profiling for the diagnosis of heart transplant rejection. California Technology Assessment Forum. 2010. Available online at: www.ctaf.org/sites/default/files/assessments/1208_file_AlloMap_2010_W.pdf.  Last accessed December 2010.
  37. XDX Expression Diagnostics, Brisbane, CA. 2010. Available online at: www.allomap.com. Last accessed March 2013.
  38. Yamani MH, Taylor DO, et al. Transplant vasculopathy is associated with increased AlloMap® gene expression score. Journal of Heart Lung Transplant.  April 2007; 26(4):403-406.

POLICY HISTORY:

Medical Policy Group, December 2004 (4)

Medical Policy Administration Committee, January 2005

Available for comment January 21-March 7, 2005

Medical Policy Group, December 2006 (1)

Medical Policy Administration Committee, January 2007

Available for comment January 30-March 8, 2007

Medical Policy Group, September 2007 (3)

Medical Policy Administration Committee October 2007

Medical Policy Group, September 2009 (1)

Medical Policy Group, November 2010 (1): No change in policy statement

Medical Policy Group, April 2012 (1): Update to Key Points and References related to MPP update; no change to policy statement

Medical Policy Panel, April 2013

Medical Policy Group, April 2013 (1): Literature search updated; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, April 2014 (1): Policy statements edited for clarity, no change in coverage or intent; update to Description, Key Points and References; addition of CPT code 86849 related to usage for AlloMap®

Medical Policy Panel, April 2015

Medical Policy Group, May 2015 (3):  2015 Updates to Title, Description, Key Points, Governing Bodies, Coding, & References; no change in policy statement; title updated to clarify as Heart Transplant Rejection Laboratory Testing

Medical Policy Group, November 2015: 2016 Annual Coding Update.  Updated CPT code 81495 to 81595 per coding update.

Medical Policy Group, June 2016 (3):  2016 Updates to Description, Key Points, Policy and References: No change in intent of policy statement-clarifying information only added.

Medical Policy Panel, October 2017

Medical Policy Group, October 2017 (3): 2017 Updates to Title, Description, Key Points & References; edits made to policy statement with no change in policy intent.

Medical Policy Group, June 2018: Quarterly coding update, July 2018. Added new CPT code 0055U to Current Coding. Added Key Words myTAIHEART, TAI.

Medical Policy Panel, October 2018

Medical Policy Group, November 2018 (3): Updates to Description, Key Points, Practice Guidelines, References, and Key Words: added AlloSure® Test, renal allograft rejection, kidney transplant rejection, GEP, Next Generation Sequencing (NGS), dd-cfDNA, donor-derived cell-free DNA, and DART Study. Added policy statement: “The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction, is considered investigational.” Title expanded to include kidney transplant rejection laboratory testing.

Medical Policy Group, September 2019: October 2019 quarterly coding update. Added CPT code 0018U.  Added Key Words Viracor and TRACTM dd-cfDNA.

Medical Policy Panel, October 2019

Medical Policy Group, November 2019 (3): 2019 Updates to Key Points. No changes to policy statement or intent.

Medical Policy Group, March 2020 (9): Removed all non-genetic information from this policy and placed into MP 532, including topics: measurement of volatile organic compounds, HeartsBreath test, and CPT codes: 0085T and 86849. No change to policy statement or coverage intent, testing remains investigational. Changed name of this policy to: Genetic Tests for Heart Failure and Heart & Kidney Transplant Rejection. This policy is included in the genetic testing management program.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.