LCD L40058: MolDX: Molecular Testing for Solid Organ Allograft Rejection

DEFINITIONS

For purposes of this policy the following definitions are used:

• ACR – Acute Cellular Rejection (also referred to as TCMR: T-cell mediated rejection)

• AMR – Antibody-Mediated Rejection

• AR – Acute Rejection/Active Rejection

• AV – Analytical Validity

• CV – Clinical Validity

• dd-cfDNA – Donor-Derived Cell-Free DNA

• GEP – Gene Expression Profiling

• MOT – Multiorgan Transplantation

• Clinical suspicion of rejection – patient has specific clinical (physical and/or biological) signs or symptoms of organ injury/rejection, as defined in existing guidelines and demonstrated in the medical record.

• For-cause testing – the evaluation of a patient with clinical suspicion of rejection.

• SubAR – Subclinical acute rejection; the patient does not have clinical suspicion of rejection but may have allograft inquiry warranting evaluation by surveillance (protocol) testing.

• Surveillance (Protocol) testing – the evaluation of an asymptomatic (no clinical signs or symptoms of organ injury/rejection) patient for subAR.

This Medicare contractor will provide limited coverage for molecular and proteomic diagnostic tests used in the evaluation and management of patients who have undergone solid organ transplantation. These tests can inform decision making along with standard clinical assessments in their evaluation of organ injury for active rejection (AR). These tests may be ordered by qualified physicians or providers operating within their scope of practice considering the diagnosis of AR, helping to rule in or out this condition and when assessing the need for or results of a diagnostic biopsy. They should be considered along with other clinical evaluations and results and may be particularly useful in patients with significant contraindications to invasive procedures.

Molecular and proteomic diagnostic tests that assess a transplanted allograft for rejection status are covered when ALL of the following criteria are met:

• The test must provide information about at least one of the two following clinical status determinations:

• AR status

• Acute Cellular or Antibody-mediated rejection (ACR or AMR) status

• The intended use of the test must be to inform clinical decision-making.

• One of the following is true:

• There is clinical suspicion of rejection AND the test performs one of the following functions:

• Assists in the evaluation of adequacy of immunosuppression or response to treatment, wherein a non-invasive or minimally invasive test can be used in lieu of a tissue biopsy, OR

• Serves as a rule-out test for AR in validated populations of patients with clinical suspicion of rejection with a non-invasive or minimally invasive test to make a clinical decision regarding obtaining a biopsy, OR

• Further evaluates allograft status for the probability of allograft rejection after a physician-assessed pretest review of clinical and biological factors concerning for risk of rejection, OR

• Assesses rejection status in patients who have received a biopsy, but the biopsy results are inconclusive, unexpected given the patient’s clinico-laboratory presentation, or limited by insufficient material, OR

• The patient does not have clinical suspicion of rejection AND is being evaluated for subclinical rejection AND both of the following are true:

• The patient is not being actively evaluated for rejection (i.e. has not been tested for clinical suspicion of rejection within the prior month) AND

• The surveillance testing service is performed according to a clinically validated cadence (in peer-reviewed published evidence or established national consensus guidelines) utilizing the number of test timepoints that have demonstrated clinical validity and utility appropriate for the specific transplant type. NOTE:

• At this time, evidence demonstrating the optimal surveillance testing cadence is in development.

• The service may include the following number of timepoints in the first year post-transplantation: Kidney (6), Heart (12), and Lung (12). Similarly, after the first year, surveillance timepoints may continue at a frequency of 4 per year in years 2 and 3 post-transplantation and with a frequency per year thereafter according to the clinical validity and utility of the analyte in later years, as demonstrated in the peer-reviewed published literature and/or national/society guidelines.

• The test demonstrates analytical validity (AV), including an analytical and clinical validation for any given measured analytes, and has demonstrated equivalence or superiority for sensitivity or specificity (depending on intended use) of detecting allograft rejection to other already-accepted tests for the same intended use measuring the same or directly comparable analytes under this policy.

• Clinical validity (CV) of any analytes (or expression profiles) measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population. The degree of validity must be similar or superior to established and covered tests under this policy (see associated coverage Articles). If conducted with concordance to tissue histologic evaluation, the appropriate Banff Classification for renal allografts or other accepted criteria (if existing) must be used.

• The test is being used in a patient who is part of the population (disease and intended use) in which the test was analytically validated and has demonstrated CV.

• For a given patient encounter, only one molecular test for assessing allograft status may be performed. A test may include more than one assay; however, multianalyte and combination tests must demonstrate superiority and additive benefit when compared to respective single analytes or components.

• For minimally or non-invasive tests, the benefit to risk profile of the molecular test is considered by the ordering clinician to be more favorable than the benefit to risk profile of a tissue biopsy, or a tissue biopsy cannot be obtained, when the test and biopsy provide similar information. For example, this may be the case if a biopsy is considered medically contraindicated in a patient.

• The test successfully completes a MolDX Technical Assessment that will ensure that AV, CV, and clinical utility criteria set in this policy are met to establish the test as reasonable and necessary.

• A test and biopsy should not be performed simultaneously. However, in very high-risk patients with overt signs and symptoms of rejection, a molecular test and biopsy may be performed together in urgent situations ONLY when the information derived from the test is complementary to the biopsy, established to meet CV requirements outlined above for that information, and demonstrated to improve outcomes in patients when performed along with biopsies. We expect these situations to be extremely rare.

Other transplant types will also be considered for coverage according to the criteria established in this LCD.

Covered tests with AV significantly below similar services may have coverage rescinded.

Allograft solid-organ transplantation has become a standard of care in patients with end-stage organ disease. In some patients, these treatments, along with other advances in care, have transformed fatal disease into treatable and preventable disease. 1-3 Transplant patients are placed on immunosuppressant drug therapy and are routinely monitored for indicators of rejection to prolong the survival of the donor allograft. Serologic and laboratory markers aid in monitoring graft function and in the early detection of AR which may occur as ACR or AMR. 4 Transplant recipients may also undergo (a) surveillance biopsies to detect subclinical acute rejection (subAR) and other histologic changes that precede functional allograft decline and/or (b) for-cause biopsies when clinically indicated. With early intervention, these changes may still be amenable to treatment. Early detection of AR has led to significant improvement in allograft survival in the first 12 months post-transplantation. 5,6

The importance of graft rejection and immunosuppression was discovered early on following the development of transplantation, a challenge that started to be overcome with the availability of immunosuppressants, though with the current standard-of-care for managing solid organ transplant patients, the risk of rejection remains a problem for years after transplantation. 6-9 Though organ transplant recipients remain at risk for rejection indefinitely, the risk is highest in the first year post-transplant. 10-12 Graft assessment is also used clinically to assist in the management of immunosuppression; the clinical value it brings is that it allows modification of immunosuppressive therapy to maximize graft longevity, which is a focus of post-transplant care. Histology has traditionally been used, often in conjunction with clinical and laboratory markers, as a common graft assessment tool. 9,13-19 While histology is considered the gold standard of diagnosis at this point in time, it requires a biopsy, which is invasive and may be associated with significant risks, complications and access to care barriers.

The interpretation of relevant histopathologic findings for the purpose of guiding management also poses a challenge. For example, in kidney transplantation, there has been heterogeneity in the literature regarding the definition and treatment of borderline and subAR, making it challenging to compare results between studies. 20-25 Borderline rejection is a heterogeneous diagnosis and includes the broad range of mild “inconsequential” inflammation to clinically significant ACR that can lead to inferior graft function. 24 Further, subAR can be detected in up to 25% of surveillance biopsies performed in the first year following kidney transplantation (a number that may be decreasing as immunosuppressive regimens improve); however, the clinical relevance of finding borderline and subAR has been uncertain for many years. 26-28 Nevertheless, it is now generally accepted that subAR is associated with worse graft outcomes 20,23,26,29-31 that may be improved with early diagnosis and treatment. 32,33 In a study from the University of Wisconsin, where donor specific antibody (DSA)-based protocol biopsies were performed at months 3 and 12 for kidney transplant recipients, patients with treated subclinical acute AMR were found to have similar good outcomes as those who underwent protocol biopsy but who were without rejection. 32 The treated subAR patients also fared significantly better than those who underwent a clinically indicated biopsy with or without AMR. 32 Another study from Johns Hopkins University evaluated kidney transplant recipients though year 5 post-transplantation and found no statistically significant difference in graft loss for patients with treated subclinical AMR compared to their matched controls; however patients with subclinical AMR who did not receive treatment had a 3.34-fold (95% CI: 1.37–8.11; p = 0.008) higher risk of graft loss. 33 Protocol biopsies in this study, which demonstrate value for renal surveillance testing, were performed at 1, 3, 6 and 12 months following ABO- and HLA-incompatible live donor transplants. 33

Despite evidence supporting its value, up to 80% of transplant centers do not routinely perform surveillance biopsies after kidney transplantation because of the relatively low incidence of subAR, the risk–benefit ratio of protocol biopsies and the fact that protocol biopsies have not definitively been shown to improve outcomes. 23,27,28,34 Further, the most current KDIGO guidelines on the management of kidney transplant recipients (published in 2009) also do not recommend surveillance biopsies. 12 For those centers that do perform surveillance biopsies, the surveillance biopsy testing schedules are not standardized. 23,27 The current care model for monitoring patients after kidney transplantation ranges from not using surveillance biopsies at all, to using them selectively in “high-immunologic risk” patients, to routine use in all patients. 27,30,32,35 Though there is no one standard of practice regarding the performance of surveillance biopsies in kidney transplantation, some center protocols have been published. 27,36