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 21380 new cases of AML and 10590 deaths from AML in the United States in 2017.^1,

Diagnosis and Prognosis of AML

The most recent World Health Organization classification (2016) 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). These cytogenetic and molecular changes form distinct clinicopathologic-genetic entities with diagnostic, prognostic, and therapeutic implications.^2, 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, 3 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 mutated NPM1 or CEBPA” were included as categories in the 2016 World Health Organization classification of acute leukemias. AML with FLT3 variants is not considered a distinct entity in the 2016 classification. The 2008 World Health Organization classification recommended determining the presence of FLT3 variants because of the prognostic significance.^3,

Recent reviews (2012-2014) have highlighted the evolving classification of AML into distinct molecular subtypes.^4,5,6,7,

Treatment

AML has a highly heterogeneous clinical course, and treatment generally depends on the different risk stratification categories.^4, 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.^4,

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, and approximately 30% of AML patients harbor some form of FLT3 variant.^8,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 25% of newly diagnosed adult cases of AML, versus FLT3-TKD variants, occurring in about 7% of patients. FLT3-ITD variants are a well-documented adverse prognostic marker, particularly in patients younger than 60 years of age and with normal- or intermediate-risk cytogenetics, and are associated with an increased risk of relapse and inferior overall survival.^8,9,10, 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.^8, Once FLT3-ITD AML relapses, the disease is rapidly fatal.

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.^8,

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 reduced remission rates and/or worse survival in some studies.^8,

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.^8, For this reason, and the overall lack of sensitivity of the assay (see the Clinically Valid section), the assay is considered to be unsuitable for use as a marker of minimal residual disease.^8, Higher mutant-to-WT allelic ratios have been associated with worse outcomes.^8,

The prognostic impact of FLT3-TKD variants is less certain and has only been studied in small numbers of patients.^8,11, FLT3 tyrosine kinase inhibitors{Arcovito, 2014 #208} are under active clinical investigation.

NPM1 Variants

The most common molecular aberration in AML is a variant of NPM1, which is found in 46% to 64% of patients with cytogenetically normal AML and in 9% to 18% of patients with cytogenetically abnormal AML.^4, 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.^8, The prognostic impact in patients with an abnormal karyotype is unclear.^4,

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 15% of AML patients with a normal karyotype.^12,13,14,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; double variants of CEBPA have shown a better prognosis with higher rates of complete remission and overall survival after standard induction chemotherapy.^15,16,

Regulatory Status

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

In May 2017, the FDA granted approval for midostaurin (Rydapt®, Novartis Pharmaceuticals). Rydapt® is a targeted therapy to be used in combination with chemotherapy when an FLT3 variant is detected by the LeukoStrat® CDx FLT3 Mutation Assay (Invivoscribe).

Related Policies

• Hematopoietic Cell Transplantation for Acute Myeloid Leukemia (Policy #037 in the Treatment Section)

I. Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA variants is considered medically necessary in cytogenetically normal acute myeloid leukemia (see Policy Guidelines section).

(NOTE: Patients with cytogenetically normal AML are categorized in the intermediate-risk cytogenetic group in terms of remission rates, relapse risks, and overall survival outcomes. According to NCCN, this is the most heterogenous group in AML with varied outcomes. Genetic testing in this particular group is utilized to further subdivide these patients into prognostic subsets by identifying mutations that carry prognostic impact. This testing is intended to guide management decisions in patients who would receive treatment other than low-dose chemotherapy or best supportive care.)

(NOTE: AML patients with cytogenetic abnormalities are generally categorized in either favorable- or poor-risk status. Results of molecular profiling to identify mutations do not alter risk status based on cytogenetics or karyotyping in these specific subset of patients.)

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

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


Medicare Coverage:
There is no National Coverage Determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that this service is covered when LCD L35396 criteria is met. Please refer to Novitas Solutions Inc, LCD Biomarkers Overview (L35062) for eligibility and coverage. Available at: https://www.cms.gov/medicare-coverage-database/details/lcd-details.aspx?LCDId=35396&ver=127&name=314*1&UpdatePeriod=765&bc=AAAAEAAAAAAA&.

PROPRIETARY LABS (Labs that are the sole source for the diagnostic lab test)
For labs which are proprietary (that is, the sole source for the diagnostic lab test involved), Medicare Advantage Products will follow the Medicare Local Coverage Determination of the State where the proprietary lab is located.

Medicaid Coverage:

For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.

FIDE SNP:

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

Policy Guidelines: (Information to guide medical necessity determination based on the criteria contained within the policy statements above.)

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.


[RATIONALE: This policy was created in 2014 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through November 11, 2019.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing for FLT3, NPM1, and CEBPA Variants to Risk-Stratify Acute Myeloid Leukemia

Clinical Context and Test Purpose

Optimal decisions regarding treatment intensity and chemotherapy-based consolidation therapy versus allogeneic transplantation remain unclear in cytogenetically normal (CN-AML). The purpose of genetic testing in patients who have CN-AML is to provide prognostic risk stratification information that may inform decisions regarding:

• whether to use standard or increased treatment intensity in induction therapy, consolidation therapy, or in relapsed/refractory AML;
• whether to do allogeneic or autologous transplantation versus chemotherapy as consolidation therapy for an AML patient in the first remission;
• whether to use investigational therapies such as FLT3 inhibitors.

Transplantation reduces the risk of recurrence but is typically associated with at least a 20% treatment-related mortality risk.

Side effects of FLT3 inhibitors (eg, sorafenib, sunitinib, midostaurin, lestaurtinib, quizartinib) include QT prolongation, nausea, vomiting, diarrhea, anemia, abnormal liver function tests, increased bilirubin, fever, and fatigue. Currently, the FLT3 inhibitor midostaurin has been approved by the FDA to be used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Sorafenib and sunitinib are approved for treatment of other malignancies.

The question addressed in this policy is: Does FLT3, NMP1, or CEBPA genetic testing in patients with AML improve outcomes?

The following PICO was used to select literature to inform this review.

Patients

The populations of interest is patients with newly diagnosed CN-AML, those in the first remission, and those who have relapsed.

Interventions

The intervention of interest is testing for FLT3, NMP1, or CEBPA variants.

Decisions about management of AML are generally made by patients and hematologists or oncologists in the secondary or tertiary care setting.

Comparators

The comparator of interest is risk stratification without FLT3, NMP1, or CEBPA genetic testing.

Outcomes

Outcomes are focused on overall- and cancer-specific mortality, although treatment-related morbidity in the short- and long-term is also a focus.

The assays can be conducted during diagnostic evaluation, to aid in the treatment decision process.

Simplifying Test Terms

There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

• Technically reliable
• Clinically valid
• Clinically useful.

Diagnostic tests detect the presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or to predict response to therapy.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Prognosis of patients with FLT3 internal tandem duplication (ITD), NMP1, or CEBPA variants compared with patients without FLT3-ITD, NMP1, or CEBPA variants are described in Table 1. Results from systematic reviews are presented when available and individual studies are included if they described a population not represented in the systematic reviews.

Table 1. Survival Outcomes of Patients With FLT3-ITD, NMP1, or CEBPA Variants

Study	Design	Participants	Outcomes
Port et al (2014)17,	Systematic review of 19 studies published between 2000 and 2012, with 4 studies included in the meta-analysis	1942 patients with CN-AML <60 y in meta-analysis	FLT3-ITD WT vs FLT3-ITD variant: OS HR=1.9 (95% CI, 1.6 to 22) RFS HR=1.8 (95% CI, 1.5 to 2.2) NPM1 WT vs NPM1 variant: OS HR=0.6 (95% CI, 0.5 to 0.7) RFS HR=0.6 (95% CI, 0.5 to 0.6) CEBPA WT vs CEBPA variant: OS HR=0.4 (95% CI, 0.3 to 0.5) RFS HR=0.4 (95% CI, 0.3 to 0.6)
Li et al (2015)16,	Systematic review of 10 studies published before Aug 2014	6219 patients with AML	Any AML: CEBPA monoallelic vs WT OS HR=1.1 (95% CI, 0.9 to 1.5) EFS HR=1.1 (95% CI, 0.8 to 1.5) CEBPA biallelic vs WT: OS HR=0.4 (95% CI, 0.3 to 0.5) EFS HR=0.4 (95% CI, 0.3 to 0.5) CN-AML: CEBPA monoallelic vs WT: OS HR=1.1 (95% CI, 0.9 to 1.5) EFS HR=0.9 (95% CI, 0.7 to 1.2) CEBPA biallelic vs WT: OS HR=0.3 (95% CI, 0.2 to 0.4) EFS HR=0.4 (95% CI, 0.3 to 0.5)
Dickson et al (2016)18,	Retrospective analysis of patients enrolled in an RCT between 1990 and 1998	662 AML patients >60 y	1-y OS: CEBPA, biallelic: 75% NPM1 variant, FLT3-ITD WT: 54% All others: 33% 3-y OS: CEBPA, biallelic: 17% NPM1 variant, FLT3-ITD WT: 29% All others: 12%
Wu et al (2016)19,	Systematic review of 10 cohort studies published between 1995 and 2015	1661 pediatric patients with AML	FLT3-ITD WT vs FLT3-ITD variant: OS HR=2.2 (95% CI, 1.6 to 3.0) EFS HR=1.7 (95% CI, 1.4 to 2.1)
Kuwatsuka et al (2017)20,	Retrospective analysis of patients enrolled in 2 clinical trials between 2001 and 2010	103 adolescent and young adults (age range, 15-39 y) with AML	FLT3-ITD WT vs FLT3-ITD variant: OS HR=2.1 (95% CI, 1.1 to 4.1) EFS HR=2.4 (95% CI, 1.3 to 4.2) NPM1 WT vs NPM1 variant: OS HR=0.2 (95% CI, 0.06 to 1.0) RFS HR=0.2 (95% CI, 0.09 to 0.7)

AML: acute myeloid leukemia; CI: confidence interval; CN; cytogenetically normal; EFS: event-free survival; HR: hazard ratio; ITD: internal tandem duplication; OS, overall survival; RCT: randomized controlled trial; RFS: recurrence-free survival; WT; wild-type.

Section Summary: Clinically Valid

The FLT3-ITD variant is quite common in AML, particularly in patients with normal karyotypes, and has been associated with poorer survival (overall, event-free, and recurrence-free) in children, younger adults, and older adults. The prognostic effect of FLT3 tyrosine kinase domain variants is uncertain. NPM1 variants are found in approximately half of the patients with CN-AML. NPM1 variants are associated with improved outcomes; however, the superior prognosis is limited to those with NPM1 variants who do not have an FLT3-ITD variant. CEBPA variants are found in approximately 15% of patients with CN-AML. Patients with CEBPA variants have a favorable prognosis, although the effect may be limited to patients who carry 2 copies of the mutant allele (biallelic).

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

The literature on the use of genetic markers consists mostly of retrospective analyses, with RCTs published in 2016 and 2017.

Randomized Controlled Trials

Knapper et al (2017) published results from 2 RCTs in which patients with previously untreated AML and confirmed FLT3 variants were randomized to lestaurtinib (an FLT3 inhibitor) or a placebo following each of 4 cycles of induction and consolidation chemotherapy (see Table 3).^21, Patients with ITD subtype (74%), tyrosine kinase domain subtype (23%), and both subtypes (2%) were included. There were no significant differences in remission or survival estimates between treatment groups (see Table 4).

Stone et al (2017) published results from an RCT in which patients with previously untreated AML and confirmed FLT3 variants were randomized to standard chemotherapy with or without midostaurin (see Table 2).^22, Patients with ITD (77%), and tyrosine kinase domain (23%) subtypes were included. The addition of midostaurin did not affect complete remission rates or time to complete remission; however, overall and event-free survival was significantly better in the midostaurin group than in the placebo group (see Table 3).

Table 2. Summary of RCT Characteristics

					Treatment
Study	Countries	Sites	Dates	Participants	Active	Comparator
Knapper et al (2017)21,	England, Denmark, New Zealand	>130	May 2002 to Dec 2014	Patients with previously untreated AML and confirmed FLT3 variants, mostly <60 y	n=300 4 cycles of induction and consolidation chemotherapy, followed by lestaurtinib (FLT3 inhibitor)	n=200 4 cycles of induction and consolidation chemotherapy, followed by placebo
Stone et al (2017)22,	17 in North America, Europe, Australia	225	May 2008 to Oct 2011	Patients with previously untreated AML and confirmed FLT3 variants, 18-59 y	n=360 Standard chemotherapy plus midostaurin (kinase inhibitor)	n=357 Standard chemotherapy plus placebo

AML: acute myeloid leukemia; RCT: randomized controlled trial.

Table 3. Summary of RCT Outcomes

Study	Outcomes	Active	Control	HR (95% CI)
Knapper et al (2017)21,
	CR + CRi			1.4 (0.7 to 2.8)
	5-y overall survival	NR	NR	0.9 (0.7 to 1.1)
	5-y overall survival, censored at SCT	NR	NR	0.9 (0.7 to 1.3)
	5-y cumulative incidence, relapse	NR	NR	0.9 (0.7 to 1.1)
	5-y cumulative incidence, death in remission	NR	NR	1.1 (0.6 to 2.0)
	5-y relapse-free survival	NR	NR	0.9 (0.7 to 1.1)
Stone et al (2017)22,
	CR rate (95% CI)	59 (54 to 64)	54 (48 to 59)	NS
	Time to complete remission (range), median days	35 (20-60)	35 (20-60)	NS
	Overall survival (95% CI), median months	75 (31 to NR)	26 (19 to 43)	0.8 (0.6 to 1.0)
	Event-free survival (95% CI), median months	8.2 (5 to 11)	3 (2 to 6)	p=0.002

CI: confidence interval; CR: complete remission; CRi: complete remission with incomplete peripheral blood count recovery; HR: hazard ratio; NR: not reported; NS: not significant; RCT: randomized controlled trial; SCT: stem cell transplantation.

Retrospective Studies

Literature from retrospective analyses describing outcomes by type of treatment for patients with and without FLT3-ITD, CEBPA, and NPM1 variants are shown in Table 4. Results from systematic reviews are presented when available and individual studies are shown if the populations were not included in the scope of the systematic reviews. Narrative summaries of select studies are presented following the table.

Most of the literature consists of analyses of FLT3-ITD variants and survival outcomes with the use of allogeneic hematopoietic cell transplantations (allo-HCT) in patients depending on the presence of this type of variant. In general, the data support use of HCT in patients with FLT3-ITD variants, however, not all studies have shown consistent results.^8,

Table 4. Retrospective Analyses of Results by Treatment of Patients With and Without Genetic Variants

Study	Design	Participants	Outcomes Estimate (95% CI)
Schlenk et al (2008)23,	Retrospective analysis of patients in 4 AML therapy RCTs conducted between 1993 and 2004	872 adults <60 y with CN-AML, 53% NPM1 variant, 31% FLT3-ITD variant, 11% FLT3-TKD variant, 13% CEBPA variant	Allo-HCT vs other consolidation therapy: NPM1 without FLT3-ITD Relapse rate HR=0.9 (0.5 to 1.8) Other genotypes (excluding CEBPA, NPM1 without FLT3-ITD): Relapse rate HR=0.6 (0.4 to 0.9)
Schlenk et al (2013)24,	Retrospective analysis of patients in 7 AML therapy RCTs conducted between 1987 and 2009	124 adults <60 y with CN-AML who were CEBPA biallelic and had CR after induction therapy	Allo-HCT vs chemo: RFS HR=0.2 0.1 to 0.5) OS HR=0.5 (0.2 to 1.2) Auto-HCT vs chemo: RFS HR=0.4 (0.2 to 0.8) OS HR=0.6 (0.2 to 1.4)
Willemze et al (2014)25,	Retrospective analysis of EORTC-GIMEMA AML-12 RCT conducted between 1999 and 2008	613 patients with AML, ages 15-60 y; 126 (21%) FLT3-ITD variant	Patients with FLT3-ITD variant categorized as very bad risk: OS at 6 y in patients at very bad risk 20% in standard cytarabine group vs 31% in high-dose group: HR=0.70 (0.47 to 1.04)
Chou et al (2014)26,	Retrospective analysis of patients from Taiwanese university hospital between 1995 and 2007	325 adults with AML who received conventional induction chemo; 81 (25%) FLT3-ITD, 69 (21%) NPM1, 33 (10%) NPM1 with FLT-ITD WT, 42 (13%) CEBPA biallelic	Non-allo-HCT: CEBPA biallelic vs other OS HR=0.5 (0.3 to 0.8) NPM1 variant with FLT3-ITD WT: OS HR=0.4 (0.2 to 0.7) Allo-HCT: CEBPA biallelic vs other: OS HR=0.3 (0.1 to 1.2) NPM1 variant with FLT3-ITD WT: OS HR=NR
Ma et al (2015)27,	Systematic review of 9 studies of chemo vs HCT published between 1989 and 2013	Patients with AML, FLT3-ITD variant	Allo-HCT vs chemo: OS OR=2.9 (2.0 to 4.1) DFS OR=2.8 (1.9 to 4.3) Relapse rate OR=0.1 (0.05 to 0.2)
Tarlock et al (2016)28,	Retrospective analysis of 2 AML RCTs conducted between 2003 and 2005	183 children with AML, FLT3-ITD variant who received standard chemo and HCT	Standard chemo with vs without gemtuzumab ozogamicin: Overall Relapse rate, 37% vs 59% (p=0.02) DFS=47% vs 41% (p=0.45) TRM=16% vs 0% (p=0.008) Patients with high FLT3-ITD allelic ratio Relapse rate, 15% vs 53% (p=0.007) DFS 65% vs 40% (p=0.08) TRM=19% vs 7% (p=0.08)
Ahn et al (2016)29,	Retrospective analysis of patients from 7 institutions in South Korea from 1998 to 2012	404 CN-AML patients ages ≥15 y treated with conventional induction chemo; 51 (13%) CEBPA biallelic	Overall, by CEBPA: 5-y OS biallelic, 62% (43% to 82%) 5-y OS monoallelic, 44% (19% to 69%) 5-y OS WT=26% (19% to 32%) Biallelic vs others: HR=0.4 (p=0.001) Among CEBPA biallelic: Chemo: 5-y OS=60% (40% to 81%) 5-y EFS=39% (15% to 64%) 5-y relapse incidence, 38% (17% to 59%) Allo-HCT: 5-y OS=72% (54% to 90%) 5-y EFS=73% (55% to 90%) 5-y relapse incidence, 8% (1% to 23%)
Brunner et al (2016)30,	Retrospective analysis of patients at 2 U.S. institutions between 2008 and 2014	81 consecutive AML patients who underwent FLT3-ITD testing who achieved CR with induction chemo followed by allo-HCT	Sorafenib maintenance therapy vs no sorafenib 2-y OS=81% vs 62%; HR=0.3 (0.1 to 0.8) 2-y PFS=82% vs 53%; HR=0.3 (0.1 to 0.8)
Versluis et al (2017)31,	Retrospective analysis of patients from 4 trials who achieved CR after 1 or 2 induction chemo cycles	Intermediate risk patients receiving the following postremission treatment: chemo (n=148); auto-HCT (n=168); allo-HCT with MAC (n=137); and allo-HCT with RIC (n=68)	Auto-HCT vs chemo: no difference in OS, RFS, relapse, or NRM Allo-HCT with MAC vs chemo: no difference OS RFS: HR=0.7 (0.5 to 1.0) Relapse: HR=0.2 (0.1 to 0.3) NRM: HR=9.1 (2.7 to 30.4) Allo-HCT with RIC vs chemo: no difference in NRM OS HR=0.5 (0.3 to 0.9) RFS HR=0.5 (0.3 to 0.8) Relapse HR=0.3 (0.2 to 0.6) Allo-HCT with MAC vs auto-HCT: no difference in OS or RFS Relapse HR=0.3 (0.2 to 0.5) NRM HR=5.7 (2.3 to 13.9) Allo-HCT with RIC vs auto-HCT: no difference in NRM: OS HR=0.6 (0.4 to 1.0) RFS HR=0.6 (0.4 to 1.0) Relapse HR=0.5 (0.3 to 0.9)

Allo: allogeneic; AML: acute myeloid leukemia; auto: autologous; chemo: chemotherapy; CI: confidence interval; CN; cytogenetically normal; CR: complete remission; DFS: disease-free survival; EFS: event-free survival; HCT: hematopoietic cell transplantation; HR: hazard ratio; ITD: internal tandem duplication; MAC: myeloablative conditioning; NR: not reported; NRM: nonrelapse mortality; OR: odds ratio; OS: overall survival; PFS: progression-free survival; RCT: randomized controlled trial; RFS: recurrence-free survival; RIC: reduced-intensity conditioning; TKD: tyrosine kinase domain; TRM: treatment-related mortality; WT: wild-type.

Ma et al (2015)^27, performed a systematic review including 7 studies^{32,33,34,35,36,37,38,} published up to December 2012 that described the use of HCT or chemotherapy in patients with AML in the first complete remission who had FLT3-ITD variants. All studies were retrospective or nonrandomized controlled analyses. Allo-HCT was associated with a longer OS (OR=2.9; 95% CI, 2.0 to 4.1), longer DFS (OR=2.8; 95% CI, 1.9 to 4.3), and reduction in relapse rate (OR=0.1; 95% CI, 0.05 to 0.2) compared with chemotherapy. OS and DFS rates favored allo-HCT but did not differ significantly between allo-HCT and autologous HCT (OS OR=1.4; 95% CI, 0.8 to 2.4; DFS OR=1.6; 95% CI, 0.8 to 3.3); however, relapse rates were lower for allo-HCT (OR=0.4, 95% CI, 0.2 to 0.7).

Willemze et al (2014) conducted a randomized trial in 1942 patients newly diagnosed with AML, ages 15 to 60 years, to compare remission induction treatment containing standard or high-dose cytarabine.^25, In both arms, patients who achieved complete remission received consolidation therapy with either autologous HCT or allo-HCT. Patients were subclassified as a good risk, intermediate risk, bad risk, very bad risk, or unknown risk, according to cytogenetics and FLT3-ITD variant. Testing for FLT3-ITD variants showed that, in the standard-dose cytarabine group, 50% were negative, 13% were positive, and 37% were indeterminate. In the high-dose cytarabine group, 48% were negative, 14% were positive, and 38% were indeterminate. All patients with an FLT3-ITD variant were categorized as a very bad risk. OS at 6 years in the patients categorized as very bad risk was 20% in the standard cytarabine group and 31% in the high-dose group (HR=0.70; 95% CI, 0.47 to 1.04; p=0.02). Trialists concluded that patients with very bad risk cytogenetics and/or FLT3-ITD variants benefited from high-dose cytarabine induction treatment.

Chou et al (2014) retrospectively analyzed 325 adults with AML to determine the prognostic significance of 8 variants, including CEBPA, FLT3-ITD, and NPM1, on OS between patients who received allo-HCT (n=100) and those who did not (n=255).^26, Karyotype included favorable (ie, variant CEBPA or NPM1 but without FLT3-ITD; n=51), intermediate (n=225), and unfavorable (n=40). Patients were selected from a single Taiwanese hospital between 1995 and 2007. Pediatric patients and those receiving only supportive care were excluded from the study. Patients received induction chemotherapy followed by allo-HCT or consolidation chemotherapy for those patients who did not achieve complete remission. In the non-allo-HCT patients, NPM1 variant/FLT3-ITD WT (HR=0.363; 95% CI, 0.188 to 0.702; p=0.003) and CEBPAdouble variant (HR=0.468; 95% CI, 0.265 to 0.828; p=0.009) were significant good prognostic factors of OS in a multivariate analysis. None of the other gene variants had a significant impact on OS in the HCT and non-HCT groups in the multivariate analysis. Authors presented survival curves stratified by CEBPAand FLT3-ITD variants and found that, in the non-HCT group, CEBPA and FLT3-ITD WT variants were prognostic of improved OS (p=0.008 and p=0.001, respectively), but, in the allo-HCT group, neither variant had a prognostic effect. The inability to detect variants of prognostic significance in the HCT group could have been due to the small number of patients with the studied variants (CEBPA=9, NPM1=13, FLT3-ITD=25).

Section Summary: Clinically Useful

There are RCTs providing direct evidence of clinical utility, randomizing patients with AML and confirmed FLT3 variants to different treatments. One RCT evaluated the addition of an FLT3 inhibitor, and one tested the addition of midostaurin to the chemotherapy regimen. No significant difference between treatment groups was found with the addition of the FLT3 inhibitor, while the addition of midostaurin significantly improved OS and event-free survival compared with placebo. Additionally, a chain of evidence for clinical utility can be constructed from retrospective analyses suggesting that risk stratification (favorable, intermediate, and poor) based on the presence of NPM1, FLT3-ITD, or CEBPA variants can help guide therapy decisions that are associated with improved outcomes. Patients with a favorable prognosis, including those who have NPM1 variants without FLT3-ITD variant or double-mutation CEBPA, may not derive an OS benefit with allo-HCT. Treatment of patients with intermediate or poor prognosis, including FLT3-ITD variant, depends on several risk factors but HCT may improve outcomes.

Summary of Evidence

For individuals who have cytogenetically normal AML who receive genetic testing for variants in FLT3, NPM1, and CEBPA to risk-stratify AML, the evidence includes RCTs, retrospective observational studies, and systematic reviews of these studies.Relevant outcomes are OS, disease-specific survival, test validity, and treatment-related mortality and morbidity. FLT3-ITD variants confer a poor prognosis, whereas NPM1 (without the FLT3-ITD variant) and biallelic CEBPA variants confer a favorable prognosis. The prognostic effect of FLT3 TKD variants is uncertain. Data have suggested an OS benefit with transplantation for patients with FLT3-ITD, but do not clearly demonstrate an OS benefit of transplantation for patients with NPM1 and CEBPA variants. Major professional societies and practice guidelines have recommended testing for these variants to risk-stratify and to inform treatment management decisions, including possible hematopoietic cell transplant. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (v.2.2020) provide the following recommendations^14,:

For the evaluation for acute leukemia, “bone marrow core biopsy and aspirate analysis, including immunophenotyping and cytochemistry.”

“A variety of gene mutations are associated with specific prognoses (category 2A) and may guide medical decision making (category 2B). Other mutations, such as ASXL1, BCR-ABL, and PML-RAR alpha may have therapeutic implications. The field of genomics in myeloid malignancies, and related implications in AML, are evolving rapidly. While the above mutations should be tested in all patients, multiplex gene panels and next-generation sequencing analysis are recommended for a comprehensive prognostic assessment... Peripheral blood may alternatively be used to detect molecular abnormalities in patients with morphologically detectable, circulating leukemic blasts."

The guideline defined the following risk status based on molecular abnormalities:

Table 5. Risk Factors Based on Genetic Abnormalities

Risk Category	Genetic Abnormality
Favorable	t(8;21)(q22;q22.1); RUNX!-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Bialletic mutated CEBPA Mutated NPM1 without FLT3-ITD or with FLT3-ITD
Intermediate	Mutated NPM1 and FLT3-ITD Wild-type NPM1 without FLT3-ITD or with FLT3-ITD (without adverse-risk genetic lesions) T(9;11)(p21.3;q23.3); MLLT3-KMT2A Cytogenetic abnormalities not classified as favorable or adverse
Poor/Adverse	t(6;9)(p23;q34.1); DEK-NUP214 t(v;11q23); KMT2A rearranged t(9;22)(q34.1;q11.2); BCR-ABL1 inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) -5 or del(5q); -7; -17/abn(17p) Complex karyotype, monosomal dryotype Wild-type NPM1 and FLT3-ITD Mutated RUNX1 Mutated ASXL1 Mutated TP53

Adapted from NCCN guidelines for AML (v.2.2020).
European Leukemia Net

The European Leukemia Net (2010) international expert panel recommendations for the diagnosis and management of adults with AML were updated in 2017.^39, The panel of 22 international experts on AML recommended that screening for NPM1, CEBPA, and FLT3 variants should be part of the diagnostic workup in patients with cytogenetically normal AML because they define disease categories that can inform treatment decisions. Table 5 outlines the risk stratification by genetic variants, and Table 6 summarizes recommended conventional care regimens based on risk category and age.

Table 6. Risk Stratification by Genetic Variant

Genetic Variant	Risk Category
Biallelic CEBPA	Favorable
Mutated NPM1 without FLT3-ITD	Favorable
Mutated NPM1 with FLT3-ITD (low allelic ratio)	Favorable
Mutated NPM1 with FLT3-ITD (high allelic ratio)	Intermediate
Wild-type NPM1without FLT3-ITD	Intermediate
Wild-type NPM1 with FLT3-ITD (low allelic ratio)	Intermediate
Wild-type NPM1 with FLT3-ITD (high allelic ratio)	Adverse

Adapted from Dohner et al (2017).^39,
ITD: internal tandem duplication.

Table 7. Conventional Care Regimens by Risk and Age Categories

Risk and Age Categories	Conventional Care
Patients 18 to 60/65 years
Favorable	2 to 4 cycles intermediate-dose cytarabine
Intermediate	Allogeneic HCT from matched related or unrelated donor 2 to 4 cycles intermediate-dose cytarabine High-dose therapy and autologous HCT
Adverse	Allogeneic HCT from matched related or unrelated donor
Patients >60/65 years
Favorable	2 to 3 cycles intermediate-dose cytarabine
Intermediate/adverse	Consider allogeneic HCT from matched related or unrelated donor Investigational therapy

Adapted from Dohner et al (2017).^39,
HCT: hematopoietic cell transplant.
U.S. Preventive Services Task Force Recommendations

Not applicable

Ongoing and Unpublished Clinical Trials

Select currently ongoing and unpublished trials that might influence this review are listed in Table 8.

Table 8. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02474290	Sorafenib for Prophylaxis of Leukemia Relapse in Allogeneic Hematopoietic Stem Cell Transplant Recipients With FLT3-ITD Positive Acute Myeloid Leukemia	196	Aug 2019(completed)
NCT02039726a	Phase 3 Open-label Randomized Study of Quizartinib Monotherapy Versus Salvage Chemotherapy in Subjects With FLT3-ITD Positive AML Refractory to or Relapsed After First-line Treatment With or Without HSCT Consolidation	367	Jul 2019
NCT01296178	PROTOCOL FOR First Line TREATMENT ADAPTED TO RISK of Acute Myeloblastic Leukemia in Patients LESS THAN OR EQUAL TO 65 YEARS	200	Dec 2019
NCT02156297	Sorafenib to Treat AML Patients with FLT3-ITD Mutation, a Non-interventional Cohort Study	100	Aug 2019 (Last update posted 10/08/2015)
NCT01477606a	Phase II Study Evaluating Midostaurin in Induction, Consolidation, and Maintenance Therapy also after Allogeneic Blood Stem Cell Transplantation in Patients with Newly Diagnosed Acute Myeloid Leukemia Exhibiting an FLT3 internal Tandem Duplication	440	Jun 2020
NCT00893399	Phase III Study of Chemotherapy in Combination With ATRA With or Without Gemtuzumab Ozogamicin in Patients With Acute Myeloid Leukemia and NPM1 Gene Mutation	588	Jul 2020
NCT02668653a	Phase 3, Double-Blind, Placebo-controlled Study of Quizartinib Administered in Combination With Induction and Consolidation Chemotherapy, and Administered as Maintenance Therapy in Subjects 18 to 75 Years Old With Newly Diagnosed FLT3-ITD (+) Acute Myeloid Leukemia (QuANTUM)	536	Nov 2020
NCT03031249	Efficacy and Safety of ATO Plus ATRA in Nucleophosmin-1 Mutated Acute Myeloid Leukemia	250	Dec 2022
NCT02927262a	A Phase 3 Multicenter, Randomized, Double-Blind, Placebo-controlled Trial of the FLT3 Inhibitor Gilteritinib Administered as Maintenance Therapy Following Induction/Consolidation Therapy for Subjects with FLT3/ITD AML in First Complete Remission	354	Mar 2021
Unpublished
NCT01237808	Study of Low-Dose Cytarabine and Etoposide With or Without All-Trans Retinoic Acid in Older Patients Not Eligible for Intensive Chemotherapy With Acute Myeloid Leukemia and NPM1 Mutation	144	Jul 2018
NCT00860639	Randomized Open Phase III Trial Testing Efficacy of Gemtuzumab Ozogamycin Associated to Intensive Chemotherapy for Patients Aged Between 18-60 Years and Presenting an AML With Intermediate Risk	327	Sep 2016 (completed; last update posted 01/27/2017)

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Genetic Testing for FLT3, NPM1, and CEBPA Mutations in Cytogenetically Normal Acute Myeloid Leukemia
Genetic Testing for FLT3, NPM1, and CEBPA Mutations in Acute Myeloid Leukemia
Genetic Testing for FLT3 and NPM1 Mutations in Acute Myeloid Leukemia
FLT3
FLT3/ITD
FLT3/TKD
NPM1
CEBPA

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35. Gale RE, Hills R, Kottaridis PD, et al. No evidence that FLT3 status should be considered as an indicator for transplantation in acute myeloid leukemia (AML): an analysis of 1135 patients, excluding acute promyelocytic leukemia, from the UK MRC AML10 and 12 trials. Blood. Nov 15 2005;106(10):3658-3665. PMID 16076872

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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

81218
81245
81246
81310