Genetic Testing for FLT3, NPM1, CEBPA, IDH1, and IDH2 Variants in Cytogenetically Normal Acute Myeloid Leukemia

POLICY NUMBER

A.2.04.124

DESCRIPTION

Treatment of acute myeloid leukemia (AML) is based on risk stratification, primarily related to age and tumor cytogenetics. In individuals with cytogenetically normal AML, the identification of variants in several genes, including FLT3,NPM1, and CEBPA, has been proposed to allow for further segregation in the management of this heterogeneous disease.

Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a group of diverse hematologic malignancies characterized by the clonal expansion of myeloid blasts in the bone marrow, blood, and/or other tissues. It is the most common type of leukemia in adults and is generally associated with a poor prognosis. The American Cancer Society has estimated there will be 20,800 new cases of AML and 11,220 deaths from AML in the United States in 2024.

Diagnosis and Prognosis of Acute Myeloid Leukemia

The most recent World Health Organization classification (2022) reflects the increasing number of acute leukemias that can be categorized based on underlying cytogenetic abnormalities (ie, at the level of the chromosome including chromosomal translocations or deletions) or molecular genetic abnormalities (ie, at the level of the function of individual genes, including gene variants) and those distinguished by differentiation without defining genetic abnormalities. These cytogenetic and molecular changes form distinct clinicopathologic-genetic entities with diagnostic, prognostic, and therapeutic implications. Conventional cytogenetic analysis (karyotyping) is considered to be a mandatory component in the diagnostic evaluation of a patient with suspected acute leukemia because the cytogenetic profile of the tumor is considered to be the most powerful predictor of prognosis in AML and is used to guide the current risk-adapted treatment strategies.

Molecular variants have been analyzed to subdivide AML with normal cytogenetics into prognostic subsets. In AML, three of the most frequent molecular changes with prognostic impact are variants of CEBPA, encoding a transcription factor, variants of the FLT3 gene, encoding a receptor of tyrosine kinase involved in hematopoiesis, and a variant of the NPM1 gene, encoding a shuttle protein within the nucleolus. “AML with NPM1 mutation" and "AML with CEBPA mutation” were included as categories in the 2022 World Health Organization classification of acute leukemias. AML with FLT3 variants is not considered a distinct entity in the 2022 or prior 2016 classifications. The 2008 World Health Organization classification recommended determining the presence of FLT3 variants because of the prognostic significance.

Treatment

AML has a highly heterogeneous clinical course, and treatment generally depends on the different risk stratification categories. Depending on the risk-stratification category, treatment modalities may include intensive remission induction chemotherapy, hypomethylating agents, enrollment in clinical trials with innovative compounds, palliative cytotoxic treatment, or supportive care only. For patients who achieve complete remission after induction treatment, possible postremission treatment options include intensive consolidation therapy, maintenance therapy, or autologous or allogeneic hematopoietic cell transplant.

Measurable (Minimal) Residual Disease Monitoring

Relapse in AML is believed to be due to residual clonal cells that remain following "complete response” after induction therapy but are below the limits of detection using conventional morphologic assessment. Residual clonal cells that can be detected in the bone marrow or blood are referred to as measurable residual disease (MRD), also known as minimal residual disease. Measurable residual disease assessment is typically performed by multiparameter flow cytometry or polymerase chain reaction with primers for common variants. It is proposed that finding MRD at different time points in the course of the disease (eg, after initial induction, prior to allogenic transplantation) may be able to identify patients at a higher risk for relapse. In those with a high risk of relapse during the first remission, stem cell transplantation may be a more appropriate treatment approach. Studies in both children and adults with AML have demonstrated the correlation between MRD and risk for relapse. The role of MRD monitoring in AML is evolving, and important limitations remain. Some patients may have relapse despite having no MRD, while others do not relapse despite being MRD positive. Standards have recently been introduced for identifying certain individual markers for MRD assessment, and threshold values delineating MRD positivity and negativity have recently been defined for multiparameter flow cytometry and some variants detected by polymerase chain reaction or other methods.

FLT3 Variants

FMS-like tyrosine kinase (FLT3) plays a critical role in normal hematopoiesis and cellular growth in hematopoietic stem and progenitor cells. Variants in FLT3 are among the most frequently encountered in AML. FLT3 variants are divided into 2 categories: (1) internal tandem duplications (FLT3-ITD) variants, which occur in or near the juxtamembrane domain of the receptor, and (2) point mutations resulting in single amino acid substitutions within the activation loop of the tyrosine kinase domain (FLT3-TKD).

FLT3-ITD variants are much more common than FLT3-TKD variants, occurring in 30% of newly diagnosed adult cases of AML, versus FLT3-TKD variants, occurring in about 10% of patients. FLT3-ITD variants are a well-documented adverse prognostic marker, particularly in patients younger than 60 years of age with normal- or intermediate-risk cytogenetics, and are associated with an increased risk of relapse and inferior overall survival. Patients with FLT3-ITD variants have a worse prognosis when treated with conventional chemotherapy, compared with patients with wild-type (WT; ie, nonmutated) FLT3. Although remission can be achieved in patients with FLT3-ITD variants using conventional induction chemotherapy at a frequency similar to other AML patients, the remission durations are shorter, and relapse rates are higher. The median time to relapse in patients with an FLT3-ITD variant is 6 to 7 months compared with 9 to 11 months in patients with other AML subtypes.

Because of the high-risk of relapse, hematopoietic cell transplantations as consolidation therapy of the first remission for an FLT3-ITD AML patient is often considered. However, this treatment must be weighed against the treatment-related mortality associated with a transplant.

The clinical significance of an FLT3 variant varies by the nature of the variant and the context in which it occurs. Longer FLT3-ITD variants have been associated with worse overall survival.

For FLT3-ITD variants, the allelic ratio refers to the number of ITD-mutated alleles compared with the number of WT (nonmutated) alleles. This ratio is influenced by the number of malignant versus benign cells in the sample tested and by the percentage of cells with 0, 1, or 2 mutated alleles. In most cases, the variant detected at diagnosis is also present at relapse. However, in some cases, as FLT3-ITD-positive AML evolves from diagnosis to relapse, the variant present at diagnosis may be absent (or undetectable) at relapse. This is most commonly seen where the mutant allele burden is low (5%-15%) at diagnosis. The assays for detecting FLT3-ITD, was previously considered to be unsuitable for use as a marker of minimal residual disease. Higher mutant-to-WT allelic ratios have been associated with worse outcomes.

The prognostic impact of FLT3-TKD variants is less certain and conflicting. Some studies have suggested a negative impact of tyrosine kinase domain variants on event-free survival and overall survival, while other studies have found no prognostic value, or potentially a benefit if a NPM1 mutation is also present.

NPM1 Variants

A common molecular aberration in AML is a variant of NPM1, which is found in 28% to 35% of AML cases and is more common in cytogenetically normal AML. Up to 50% of AML with mutated NPM1 also carry an FLT3-ITD. Mutated NPM1 confers an independent favorable prognosis for patients with cytogenetically normal AML and either the presence or absence of an FLT3-ITD variant. Retrospective studies of banked clinical samples have suggested that an NPM1 variant may mitigate the negative prognostic effect of an FLT3-ITD variant, but possibly only if the FLT3-ITD-to-WT allelic ratio is low. The prognostic impact in patients with an abnormal karyotype is unclear.

CEBPA Variants

CEBPA (CCAAT/enhancer-binding protein) is a transcription factor gene that plays a role in cell cycle regulation and cell differentiation. Variants to CEBPA are found in approximately 7% to 11% of AML patients. CEBPA variants can be either biallelic (double variants) or monoallelic. Monoallelic variants are prognostically similar to CEBPA WT variant and do not confer a favorable prognosis in cytogenetically normal AML, with the exception of mutations in the basic leucine zipper region; double variants of CEBPA and variants with single mutations in the basic leucine zipper region have shown a better prognosis with higher rates of complete remission and overall survival after standard induction chemotherapy.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Several laboratories offer these tests, including Quest Diagnostics, Medical Genetic Laboratories of Baylor College, Geneva Labs of Wisconsin, LabPMM, and ARUP Laboratories, and they are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed under the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

The Food and Drug Administration has granted approval for midostaurin (Rydapt®, Novartis Pharmaceuticals), gilteritinib (Xospata®, Astellas Pharma US), and quizartinib (Vanflyta®, Daiichi Sakyo) for the treatment of acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test. A list of cleared or approved companion diagnostic devices can be found at: https://www.fda.gov/medical-devices/in-vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-in-vitro-and-imaging-tools .

IDH 1 and 2 Variants

Isocitrate dehydrogenase 1 and 2 (IDH 1 and 2) are the most frequently mutated metabolic genes in human cancer. The presence of and IDH1 or IDH2 variation has both diagnostic and prognostic significance in central nervous system tumors and prognostic value in hematologic disorders, such as myelodysplastic syndrome or acute myeloid leukemia.

POLICY

Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, CEBPA, IDH1 and IDH2 variantsmay be considered medically necessary in cytogenetically normal AML (see Policy Guidelines section).

Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, CEBPA, IDH1 and IDH2 variantsis considered investigational in all other situations.

Genetic testing for FLT3 tyrosine kinase domain (FLT3-TKD) variants is considered investigational.

Genetic testing for FLT3,NPM1, and CEBPA variants to detect minimal residual disease is considered investigational.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetic testing for cytogenetically normal acute myeloid leukemia is intended to guide management decisions in individuals who would receive treatment other than low-dose chemotherapy or best supportive care.

Genetic testing for IDH1 and IDH2 variants is intended for use as diagnostic and prognostic value in hematologic disorders, such as acute myeloid leukemia.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting. 

POLICY HISTORY

11/20/2014: New policy added. Approved by Medical Policy Advisory Committee.

12/31/2014: Added the following new 2015 CPT code to the Code Reference section: 81246.

08/18/2015: Medical policy revised to add ICD-10 codes.

12/31/2015: Policy title updated to include CEBPA mutations. Policy description updated regarding CEBPA mutations. Policy statement updated to add CEBPA mutations as medically necessary. Policy statement updated to state that genetic testing for FLT3, NPM1, and CEBPA mutations to detect minimal residual disease is considered investigational. Policy guidelines updated to clarify that genetic testing for cytogenetically normal acute myeloid leukemia is intended to guide management decisions in patients who would receive treatment other than low-dose chemotherapy or best supportive care. Added medically necessary and investigative definitions. Code Reference section updated to add new 2016 CPT code 81218.

06/07/2016: Policy number A.2.04.124 added.

01/30/2017: Policy title updated to add "Cytogenetically Normal." Policy description updated regarding laboratory-developed tests. Policy statements updated to change "mutations" to "variants."

09/29/2017: Code Reference section updated to add new CPT code 0023U, effective 10/01/2017.

02/07/2018: Policy title updated to change "Mutations" to "Variants." Policy description updated regarding 2017 data from the American Cancer Society and laboratory testing. Policy statements unchanged.

06/15/2018: Code Reference section updated to add new CPT codes 0046U and 0049U, effective 07/01/2018.

02/15/2019: Policy reviewed; no changes.

02/12/2020: Policy reviewed; no changes.

03/02/2021: Policy description updated regarding 2020 data for acute myeloid leukemia and information regarding measurable (minimal) residual disease monitoring and FDA approvals. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

02/08/2022: Policy description updated regarding acute myeloid leukemia and the FLT3, NPM1, and CEBPA variants. Policy statements unchanged.

03/23/2023: Policy description updated regarding acute myeloid leukemia, measurable (minimal) residual disease monitoring, and CEBPA variants. Policy statements unchanged. Policy Guidelines updated to change "patients" to "individuals."

07/01/2023: Policy title changed from "Genetic Testing for FLT3, NPM1, and CEBPA Variants in Cytogenetically Normal Acute Myeloid Leukemia" to "Genetic Testing for FLT3, NPM1, CEBPA, IDH1 and IDH2 Variants in Cytogenetically Normal Acute Myeloid Leukemia." Policy description updated regarding IDH1 and IDH2 variants. Policy statement updated to add that genetic testing for IDH1 and IDH2 variants may be considered medically necessary in cytogenetically normal AML. It is considered investigational in all other situations. Policy Guidelines updated to state that genetic testing for IDH1 and IDH2 variants is intended for use as diagnostic and prognostic value in hematologic disorders, such as acute myeloid leukemia. Code Reference section updated to add CPT codes 81120 and 81121.

02/20/2024: Policy description updated regarding new data for acute myeloid leukemia and devices. Policy statements unchanged.

06/25/2024: Policy reviewed; no changes.

03/06/2025: Policy description updated regarding new data for acute myeloid leukemia. Policy statements unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.124

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

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