This policy describes and clarifies coverage for Lab-Developed Tests (LDTs)
and Food and Drug Administration (FDA)-approved or cleared clinical laboratory
tests utilizing Next-Generation Sequencing (NGS) in cancer as allowable under
the National Coverage Determination (NCD) 90.2, under Section D describing
Medicare Administrative Contractor (MAC) discretion for coverage, as well as
for use of NGS in suspected myeloid neoplasms. This policy's scope is specific
for myeloid malignancies and suspected malignancies, and is exclusive of solid
tumor testing, circulating tumor DNA (ctDNA) testing, and other cancer-related
uses of NGS, such as in germline testing.

NGS testing in solid tumors is becoming a routine component of the diagnostic
process;1 the results can uncover the genomic mechanisms of cancer that have
predictive, diagnostic, and prognostic utility to the patient and are used to
better their management.2 Understanding the mechanisms of disease and
targeting treatment based on those aberrant processes (i.e., targeted
therapies) has improved patient outcomes in many tumor types and is the basis
of Precision Medicine.3 NGS adds the ability to capture abundant genomic data
both efficiently, relatively cheaply, and its use is showing to improve
patient outcomes although studies in this regard are ongoing.4 The established
NCD 90.2 confirms tests based on this methodology to be both reasonable and
necessary in Medicare beneficiaries.

**Professional Society Clinical Practice Guidelines**

Guidelines for validating clinical NGS tests for use in cancer have been
published in a joint effort by the Association for Molecular Pathology and the
College of American Pathologists.5 Guidelines for employing bioinformatics
pipelines for NGS testing have also been published by these groups,6 as well
as guidelines for interpreting somatic variants in these panels, by these
entities in collaboration with the American Society of Clinical Oncology.7

Guidelines for care of Acute myeloid Leukemia (AML) suggests or recommends to
the use of NGS testing for comprehensive prognosis and risk stratification.8

**NGS Test Description**  
NGS is not a specific test, but a sequencing methodology utilized to capture
genomic information. Unlike Sanger sequencing (the prior standard technology)
that typically provides sequence information for a single DNA strand/molecule,
NGS allows for massively parallel sequencing of millions of DNA molecules
concurrently.9,10 This allows for capturing many relevant genomic targets
simultaneously, usually by utilizing capture technologies such as by PCR
amplification or hybrid capture. As such, NGS tests for use in cancer are
often comprised of gene panels whose content is either relevant to a specific
tumor type or condition, or a larger panel of genes that can be used for
multiple tumor types, including in hematopoietic malignancies.

NGS tests can vary significantly for many reasons. While NGS defines a broad
methodology for massively parallel sequencing, different technologies that
have different strengths, weaknesses, and technical limitations or liabilities
are available.11 The most common sequencing platforms in clinical use today
are from Illumina and Thermo Fisher. While both sequence by synthesis similar
to Sanger sequencing, these platforms utilize different chemistries, signal
amplification, and detection methods. Gene panels can include only the
portions of genes that contain the most critical clinically-relevant
information, or be comprehensive, containing entire exonic gene regions
(coding regions), introns (non-coding regions), and even sequence RNA for
detecting gene fusions. Downstream from the pre-analytic processes mentioned
above, the bioinformatics used to process and assess the resultant sequencing
reads and identify variants/mutations can yield different results based on the
software used and what variant types of variants the test is attempting to
detect. These software tools must take the resultant sequencing file
(generally starting with the FASTQ format), align all possible sequences with
a reference genome (BAM/SAM), and identify variants from the reference
(typically a VCF file).6 Once such variants are identified, they must be
assessed for validity and subsequently for their clinical relevance. The types
of genomic information reported can vary, as tests can uncover a myriad of
genomic alterations such as single nucleotide variants (SNVs),
Insertions/Deletions (INDELs), Copy Number Alterations (CNAs; these can be
simply amplifications at a single locus or chromosomal gains and losses), and
gene fusions/translocations. The resultant information can also be used to
calculate additional relevant information, such as Tumor Mutation Burden
(TMB), or the presence of microsatellite instability (MSI). All these variant
classes have demonstrated clinical utility. As such, NGS testing in cancer
comprises a large heterogeneous group of assays that are substantially
different from each other. Additionally, NGS testing is highly complex and
requires expertise from handling the specimen, to running complex equipment,
to understanding the required bioinformatics, to interpreting the findings,
and creating an actionable medical report.

Two types of tests are considered for coverage, "Hot-spot" tests and
comprehensive genomic profile tests (CGP). The definition of these terms, in
addition to appropriate coding information, is located in Billing and Coding
Articles associated with this LCD. These tests can detect any combination of
the previously described variant types, but in general, Hot-spot tests are
limited to SNVs and small INDELs, whereas CGPs can detect those variants in
addition to CNAs, larger INDELs, gene fusions/translocations, and be used to
calculate MSI status and TMB when relevant.

**Analytical Validity**  
Because of the number of variables described above, additional work must be
performed to assess if any given test is both reasonable and necessary for
Medicare beneficiaries and to ensure that Medicare claims are properly
understood and executed. MolDX has instituted a process for completing a
Technical Assessment (TA) that ensures that tests are appropriate for their
indications and are properly validated according to published guidelines
described above (when applicable). Specifically, in order to understand if a
test is both reasonable and necessary, it must be delineated if a test has the
properly-validated technology, variant types, gene and variant coverage, and
bioinformatics capability to deliver a clinically useful result for the
Medicare beneficiary, given their diagnosis.

Labs seeking coverage for LDTs or FDA-approved tests that are not nationally
covered utilizing NGS in cancer must submit documentation to the MolDX
contractor to allow MolDX to complete a TA. Forms to complete the process are
available on the MolDX website. Tests that are currently covered by this
contractor are not exempt from this process. Tests that are currently covered
and have not undergone a TA by MolDX will be non-covered unless complete
documents to perform a TA are submitted in a timely manner described below in
the coverage section.

**Clinical Utility in Myeloid Malignancies**  
Myeloid stem cell disorders are a heterogenous group of malignancies with
clinical and genomic overlap. According to the WHO classification, myeloid
disorders can be classified as myelodysplastic syndrome (MDS),
myeloproliferative neoplasms (MPN), overlap myelodysplastic/myeloproliferative
neoplasms (MDS/MPN), and AML.

These disorders can comprise a continuum of tumor evolution that ultimately
results in AML in many instances.12 Clonal hematopoiesis may also be detected
in elderly patients without overt evidence of myeloid neoplasia. Due to
increased risk of developing myeloid neoplasia, such patients need to be
closely monitored over time, and genomic profiling plays a role in this
process.

Currently, laboratories utilize NGS panels and DNA-based cytogenomic
microarray in laboratory work-up of myeloid disorders and AML.13 NGS, with its
ability to identify numerous relevant biomarkers concurrently, is
demonstrating a unique clinical utility in the diagnosis, prognosis/risk
stratification, and identification of targeted therapies in myeloid
malignancies.14-16

Laboratories typically use a multiplex NGS panel in the evaluation of
peripheral blood or bone marrow aspirate samples in patients suspected of
having an acute or chronic myeloid stem cell disorder.17 With the recent and
ongoing explosion of literature spanning chronic and acute myeloid disorders,
laboratories have designed NGS panels encompassing anywhere from a handful of
genes to greater than 90 genes. In a recently published paper,13 more than 70
genes that are clinically informative in acute and chronic myeloid disorders
were identified.

The utility of genomic testing in myeloid malignancies includes:

_To assist with diagnosis:_

In the setting of MDS, MDS/MPN, and MPN, establishing a diagnosis of a clonal
myeloid disorder needs to occur prior to initiation of any therapy. In all of
these disorders, the diagnostic classification relies on a multi-parameter
testing approach in addition to clinical and morphologic findings.18 In other
contexts, having mutations can support a diagnosis of a clonal myeloid disease
(versus a benign/reactive condition) when there is a high clinical index of
suspicion and/or morphologic findings are low-grade or subtle.19 NGS detection
of clonal hematopoiesis with mutation detection in patients with unexplained
cytopenias (> 4 months) is a strong predictor of who has or will have myeloid
disorder.20 When patients have a mutation with >10% variant allele frequency,
or they have 2 or more mutations identified (in a 40 gene NGS panel), the
positive predictive value is 0.86 and 0.88 respectively.21 Additionally,
molecular profiling can help differentiate myeloid neoplasms from benign
conditions with overlapping histologic findings, like aplastic anemia, as well
as to assess the latter in its likelihood of transformation into MDS.22

In AML, certain aberrations such as a RUNX1 or NPM1 mutation similarly define
a specific molecular classification of diseases in the 2017 WHO
Classification. In the setting of AML, there are well defined mutations in
genes such as JAK2, SRSF2, CSF3R, U2AF1, SF3B1, ZRSR2, ASXL1, EZH2, STAG2, and
BCOR that strongly indicate an underlying myeloid stem cell disorder.23
Genomic profiling, thus, provides a molecular-based diagnostic classification
of AML.

_To assist with Risk Stratification_  
NGS testing is used to identify a category of AML patients who typically do
not respond to standard induction and consolidation chemotherapy. Rather,
these patients are at a high risk for relapse, disease progression, and poor
outcome, and will benefit from strategies other than traditional induction and
consolidation regimens, in particular hematopoietic stem cell transplant
(HSCT).24 There are now more than 50 genes that can render diagnostic and risk
stratification information across the spectrum of myeloid stem cell
disorders.8,25,26 The appropriate therapy can be administered in patients only
after an accurate diagnosis is rendered.

According to evidence-based guidelines from the American Society of Blood and
Bone Marrow, HSCT is considered a valuable therapeutic option in high risk
myeloid disorders and acute leukemia, provided that patients don't have
certain mutations that are associated with poor outcome in the transplant
setting [27]. Certain mutations are associated with a poor prognosis in
patients undergoing HSCT.28-30 In these situations, NGS testing can help
refine who is unlikely to benefit from HSCT.

Minimum residual disease (MRD) analysis is a useful risk stratification tool
to guide the choice of treatment intensity by providing information on: 1)
early response to treatment; 2) early detection of relapse after treatment; 3)
surveillance before and after stem cell transplantation. Recently, multiple
studies have demonstrated the utility of NGS-based analysis for this
purpose.31-35 Additionally, NGS provides advantages to other methods in its
sensitivity and in its ability to overcome clonal evolution and detect new
mutations.34,36

_To Assist with Targeted Therapies_  
FDA approved targeted therapies are now available that are directed against
specific molecular aberrations in acute leukemia, such as Midostaurin and
Enasidenib, among others.37-39 Clinical trials are currently evaluating
additional therapies in patients with high risk myeloid disorders for patients
with these and other AML-associated mutations.

Additionally, NGS can be used to monitor patients for response to their
selected therapies, by measuring changes in allelic ratios of tumor-specific
mutations, in addition to identifying when a different therapy may be
necessary.32

**Criteria for Coverage**  
The following must be present for coverage eligibility:

  * For tests that are specifically indicated in patients whom are known to have a myeloid malignancy at the time of testing, NCD 90.2 applies
  * The patient has a diagnosis of AML, MDS, or MPN. AML, MDS, and MPN are herein classified as refractory and/or metastatic cancers and fulfill the NCD 90.2 criteria.
  * The test has satisfactorily completed a TA by MolDX for the stated indications of the test.
  * The assay performed includes _at least_ the minimum genes and positions indicated for its intended use, as described in an associated coverage Article, and found in the TA forms.
  * For patients that do not have a diagnosis of a myeloid malignancy, where one is suspected, the patient must have an undefined cytopenia for greater than 4 months, other possible causes have been reasonably excluded.
  * Testing is performed on bone marrow biopsies, bone marrow aspirates, bone marrow clots, peripheral blood samples, or extramedullary sites suspected of harboring a myeloid malignancy.

**Situations in which Test should not be used or coverage is denied:**  
The test in question will be non-covered if:

  * A TA has not been satisfactorily completed by MolDX. For tests that are currently covered but a TA submission has not been made, providers must submit complete   
TA materials by February 10th, 2020, or coverage will be denied.

  * Another NGS test was performed on the same surgical specimen/ blood draw (specimen obtained on the same date of service).
  * Testing falls within scope of NCD 90.2 and has been tested with the same test for the same genetic content.

Quality: Strong/variable depending on biomarker and specific test  
Strength: Strong/variable depending on biomarker and specific test  
Weight: Strong/variable depending on biomarker and specific test

Given the abundant literature on genetic and genomic testing in cancer
diagnosis and care, this contractor feels strongly that NGS methodology for
testing is appropriate for use in Medicare Beneficiaries. However, given the
variability for what information tests can provide, additional information
must be submitted by providers to ensure the contractor A) understands what
test is being performed; B) Why it is being performed; C) If the test is both
necessary and reasonable for cancer care for its intended use.