Medical Policy

Policy Num:      11.003.060
Policy Name:    Genetic Testing for FLT3, NPM1, and CEBPA Variants in Cytogenetically Normal Acute Myeloid Leukemia
Policy ID:           [11.003.060]  [Ac / B / M+ / P+]  [2.04.124]

Last Review:      February 20, 2025
Next Review:      February 20, 2026
 

Related Policies

11.003.111 - Next-Generation Sequencing for the Assessment of Measurable Residual Disease
08.001.050 Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

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

Summary

Description

Treatment of acute myeloid leukemia (AML) is based on risk stratification, primarily related to patient age and tumor cytogenetics. In patients 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.

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 overall survival, disease-specific survival, test validity, and treatment-related mortality and morbidity. FLT3 internal tandem duplication variants confer a poor prognosis, whereas NPM1 (without the FLT3 internal tandem duplication variant) and CEBPA variants (including biallelic mutations and single mutations in the basic leucine zipper region) confer a favorable prognosis. The prognostic effect of FLT3 tyrosine kinase domain variants is uncertain. Data have suggested an overall survival benefit with transplantation for patients with FLT3 internal tandem duplication, but do not clearly demonstrate an overall survival benefit of transplantation for patients with NPM1 and CEBPA variants. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have AML with a genetic variant in FLT3, NPM1, or CEBPA, the evidence for measurable residual disease (MRD) monitoring of these genetic variants is limited to retrospective observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, and treatment-related mortality and morbidity. Detection of MRD based on NPM1 variant presence is associated with higher risks for relapse and lower overall survival; prospective evaluations using MRD results to direct prognostic evaluation and treatment decisions are needed. For the use of genetic variants to detect MRD, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

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. Specifically, guidelines from the National Comprehensive Cancer Network (AML, version 2.2022) recommend workup of certain karyotypic and molecular abnormalities as they provide prognostic information for both treatment decisions and risk of relapse. Several gene mutations are associated with specific prognoses and may guide treatment decisions; these include FLT3 internal tandem duplication, FLT3 tyrosine kinase domain, NPM1, and CEBPA (biallelic). The guidance recommends that all patients should be tested for mutations in these genes. The role of MRD assessment for prognosis and treatment is evolving and the use of MRD is still under investigation.

OBJECTIVE

The objective of this evidence review is to examine whether genetic testing for FLT3, NPM1, and CEBPA variants improve the net health outcome in individuals with cytogenetically normal acute myeloid leukemia.

POLICY

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

Genetic testing for FLT3-ITD , NPM1, and CEBPA variants is considered investigational in all other situations.

Genetic testing for FLT3 tyrosine kinase domain variants is considered investigational.

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

POLICY GUIDELINES

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.

Coding

See the Codes table for details.

BENEFIT APPLICATION

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.  Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

BACKGROUND

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 20,050 new cases of AML and 11,540 deaths from AML in the United States in 2022.^1,

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.^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 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.^2,3, The 2008 World Health Organization classification recommended determining the presence of FLT3 variants because of the prognostic significance.^4,

Treatment

AML has a highly heterogeneous clinical course, and treatment generally depends on the different risk stratification categories.^5, 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.^6, 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.^7,

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.^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 30% of newly diagnosed adult cases of AML, versus FLT3-TKD variants, occurring in about 10% of patients.^9,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.^8,10,11, 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,

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 worse overall survival.^12,

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, The assays for detecting FLT3-ITD , was previously 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 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.^13,14,9, Next generation FLT3 tyrosine kinase inhibitors with greater specificity for FLT3 have been under clinical investigation, including gilteritinib, which was approved by the U.S. Food and Drug Administration (FDA) in 2018.^13,

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.^9, Up to 50% of AML with mutated NPM1 also carry an FLT3-ITD.^15, 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.^15,

CEBPA Variants

CEBPA (CCAAT/enhancer-binding protein) is a transcription factor gene that plays a role in cell cycle regulation and cell differentiation. Variants of CEBPA are found in approximately 7% to 11% of AML patients.^16,17,9,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.^18,19,20,21,

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, and they 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 U.S. Food and Drug Administration 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). In 2018, gilteritinib (Xospata®, Astellas Pharma US) was approved by the FDA for the treatment of relapsed or refractory acute myeloid leukemia with a FLT3 mutation as detected by an FDA-approved test.

RATIONALE

This evidence review was created in July 2014 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 27, 2024.

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.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1

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 acute myeloid leukemia (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 acute myeloid leukemia (AML);

• whether to do allogeneic or autologous transplantation versus chemotherapy as consolidation therapy for an AML patient in the first remission;

• whether to use therapies such as FLT3 inhibitors.

Genetic testing can be used during the initial evaluation of leukemia to provide prognostic information and guide treatment decisions.

Induction therapy usually consists of 7 days of continuous-infusion cytarabine at 100 to 200 mg/m² with 3 days of anthracycline. Studies have shown greater efficacy at higher doses but also increased toxicity.

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, quizartinib, gilteritinib) 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 U.S. Food and Drug Administration to be used in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Sorafenib and sunitinib are approved for treatment of other malignancies. Gilteritinib is only approved for treatment of relapsed or refractory AML.

The question addressed in this evidence review is: Does FLT3, NPM1, or CEBPA genetic testing improve the net health outcome in individuals with AML?

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

Populations

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

Interventions

The intervention of interest is testing for FLT3, NPM1, or CEBPA variants. During initial assessment of AML, genetic testing provides prognostic risk assessment and helps guide treatment decisions.

Comparators

The comparator of interest is risk stratification without FLT3, NPM1, or CEBPA genetic testing.

Outcomes

The general outcomes of interest are overall survival, disease-free survival, test validity, treatment-related mortality, and treatment-related morbidity.

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.

Study Selection Criteria

For the evaluation of clinical validity of the genetic tests for FLT3, NPM1, and CEBPA, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

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).

Review of Evidence

Prognosis of patients with FLT3 internal tandem duplication (ITD), NPM1, or CEBPA variants compared with patients without FLT3-ITD, NPM1, 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, NPM1, or CEBPA Variants

   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.

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 for initial evaluation consists mostly of retrospective analyses and RCTs evaluating FLT3 inhibitors in patients with confirmed FLT3 variants.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

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 (a FLT3 inhibitor) or placebo following each of 4 cycles of induction and consolidation chemotherapy (see Tables 2 and 3).^28, Patients with ITD subtype (74%), tyrosine kinase domain subtype (TKD, 23%), and both subtypes (2%) were included. There were no significant differences in remission or survival estimates between treatment groups (see Table 3).

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 Tables 2 and 3).^29, Patients with ITD (77%) and TKD (23%) subtypes were included. The addition of midostaurin did not affect complete remission rates or time to complete remission in the overall cohort; however, overall and event-free survival was significantly better in the midostaurin group than in the placebo group (see Table 3). Voso et al (2020) published a subgroup analysis of the trial evaluating outcomes in patients with the TKD subtype.^30, In this subgroup, 5-year event-free survival was significantly better in the midostaurin group than in the placebo group (45.2% vs. 30.1%; hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.45 to 0.99; p=.044), but 5-year overall survival was similar between the 2 treatment groups (65.9% vs. 58.0%; HR, 0.74; 95% CI, 0.44 to 1.23; p=.244).

Perl et al (2019) published results from an RCT evaluating patients with relapsed/refractory FLT3-mutated AML who were randomized to gilteritinib (a FLT3 inhibitor) or salvage chemotherapy (see Tables 2 and 3).^31, Patients with the ITD subtype (88.4%), TKD subtype (8.4%), and both subtypes (1.9%) were included. Overall, 60.6% of patients had relapsed disease, and 39.4% had primary refractory disease. Median overall survival and percent of patients achieving complete remission was significantly better with gilteritinib.

Cortes et al (2019) published results from an RCT evaluating patients with relapsed/refractory FLT3-mutated AML who were randomized to quizartinib (a FLT3 inhibitor) or salvage chemotherapy (see Tables 2 and 3).^32, Only patients with the FLT3 ITD subtype were included. One third of patients had refractory disease, while the rest had relapsed disease. Overall survival was improved with quizartinib compared to salvage chemotherapy.

Table 2. Summary of RCT Characteristics

   allo-HCT: allogenic hemopoietic stem cell transplant; AML: acute myeloid leukemia; RCT: randomized controlled trial.

Table 3. Summary of RCT Outcomes

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

Retrospective Studies

Outcomes Based on Genetic Variant Status

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

   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)^37, performed a systematic review including 7 studies^{43,44,45,46,47,48,49,} 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. Overall survival 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.^35, 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. Overall survival 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=.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).^36, 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=.003) and CEBPA double variant (HR , 0.468; 95% CI, 0.265 to 0.828; p=.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 CEBPA and FLT3-ITD variants and found that, in the non-HCT group, CEBPA and FLT3-ITD WT variants were prognostic of improved OS (p=.008 and p=.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: Testing for FLT3, NPM1, and CEBPA Variants to Risk-Stratify Acute Myeloid Leukemia

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 TKD variants is uncertain. NPM1 variants are found in approximately half of 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) and those with single mutations in the basic leucine zipper region. 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 a FLT3 inhibitor, and 1 tested the addition of midostaurin to the chemotherapy regimen in patients with previously untreated AML. 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. Another 2 RCTs evaluated comparative outcomes of treatment with a FLT3 inhibitor versus salvage chemotherapy in relapsed/refractory AML. Both gilteritinib and quizartinib prolonged survival compared to salvage chemotherapy in this population. 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 those with CEBPA biallelic or single basic leucine zipper region-mutant variants, 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 overall survival, disease-specific survival, test validity, and treatment-related mortality and morbidity. FLT3 internal tandem duplication variants confer a poor prognosis, whereas NPM1 (without the FLT3 internal tandem duplication variant) and biallelic CEBPA variants confer a favorable prognosis. The prognostic effect of FLT3 tyrosine kinase domain variants is uncertain. Data have suggested an overall survival benefit with transplantation for patients with FLT3 internal tandem duplication, but do not clearly demonstrate an overall survival benefit of transplantation for patients with NPM1 and CEBPA variants. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Testing for FLT3, NPM1, or CEBPA Variants for Measurable Residual Disease Monitoring

Clinical Context and Test Purpose

The purpose of testing for FLT3, NPM1, or CEBPA variants in patients who have AML is to monitor for measurable residual disease (MRD) that may inform treatment decisions.

The question addressed in this evidence review is: Does FLT3, NPM1, or CEBPA genetic testing improve the net health outcome in individuals with AML who may have MRD?

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

Populations

The relevant population of interest is patients with AML and a variant in FLT3, NPM1, or CEBPA.

Interventions

The intervention of interest is testing for FLT3, NPM1, or CEBPA variants. MRD evaluation is intended to assess risk for relapse and guide potential preemptive therapy.

Comparators

The comparator of interest is MRD surveillance based on morphologic relapse or other MRD methods without FLT3, NPM1, or CEBPA genetic testing.

Outcomes

The general outcomes of interest are overall survival, disease-free survival, test validity, treatment-related mortality, and treatment-related morbidity.

Study Selection Criteria

For the evaluation of clinical validity of the genetic tests for FLT3, NPM1, and CEBPA, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

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).

Review of Evidence

Monitoring for MRD can provide prognostic information on the risk of relapse in patients with NPM1- or FLT3-ITD-mutated AML; results of studies evaluating the use of MRD with these variants are summarized in Table 5.

Table 5. Prognostic Value of NPM1or FLT3-ITD MRD Assessment

   AML: acute myeloid leukemia; CI: confidence interval; CIR: cumulative incidence of relapse; CR: complete remission; CRp: complete remission with incomplete platelet recovery; HR: hazard ratio; MFC: multiparameter flow cytometry; MRD: measurable residual disease; NGS: next-generation sequencing; OS: overall survival; RT-qPCR: reverse-transcriptase quantitative polymerase chain reaction.

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 for MRD evaluation is limited to 1 retrospective analysis.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Outcomes Based on Measurable Residual Disease Assessment of Genetic Variants

Results from a retrospective analysis describing outcomes after preemptive interventions based on MRD are shown in Table 6. Bataller et al (2020) evaluated the use of protocol in NPM1-mutated AML that prospectively evaluated MRD status and allowed use of allogenic stem cell transplant in patients with identified molecular failure based on the presence of MRD, instead of waiting for patients to present with morphologic hematologic recurrence.^54,

Table 6. Retrospective Analyses of Results by Treatment of Patients Based on MRD Assessment of Genetic Variants

   allo: allogeneic; AML: acute myeloid leukemia; CR: complete remission; HCT: hematopoietic cell transplantation; MRD: measurable residual disease; OS: overall survival.

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

The prognostic value of NPM1 MRD evaluation has been evaluated retrospectively and found to be associated with higher risks for relapse and lower overall survival. Literature on the use of MRD assessment of genetic variants to direct treatment decisions is limited to 1 retrospective analysis, which found survival benefit in implementing pre-emptive treatment intensification based on NPM1 variant MRD monitoring.

Summary of Evidence

For individuals who have AML with a genetic variant in FLT3, NPM1, or CEBPA, the evidence for measurable residual disease (MRD) monitoring of these genetic variants is limited to retrospective observational studies. Relevant outcomes are overall survival, disease-specific survival, test validity, and treatment-related mortality and morbidity. Detection of MRD based on NPM1 variant presence is associated with higher risks for relapse and lower overall survival; prospective evaluations using MRD results to direct prognostic evaluation and treatment decisions are needed. For the use of genetic variants to detect MRD, the evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

SUPPLEMENTAL INFORMATION

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (v.3.2024 ) provide the following recommendations^9,:

For the evaluation for acute leukemia, bone marrow core biopsy and aspirate analyses (including immunophenotyping by immunohistochemistry (IHC) stains with flow cytometry) and cytogenetic analyses are needed to risk stratify patients and potentially guide therapy of AML.

“Several gene mutations are associated with specific prognoses in a subset of patients (category 2A) and may guide treatment decisions (category 2B). Presently, c-KIT, FLT3-ITD, FLT3-TKD, NPM1, in-frame bZIP mutation inCEBPA , IDH1/IDH2, RUNX1, ASXL1, TP53, BCR::ABL, and PML::RAR alpha are included in this group." "All patients should be tested for mutations s, and multiplex gene panels and comprehensive next-generation sequencing (NGS) analysis are recommended for the ongoing management of AML in various phases of treatment." "To appropriately stratify therapy options, test results of molecular and cytogenetic analyses of immediately actionable genes or chromosomal abnormalities should be expedited."

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

Table 7. Risk Factors Based on Genetic Abnormalities

  Adapted from NCCN guidelines for AML (v.3.2024 ). ITD: internal tandem duplication

The role of measurable (minimal) residual disease (MRD) assessment for prognosis and treatment is evolving and the use of MRD is still under investigation. Currently available evidence has "demonstrated the correlation between MRD and risks for relapse, as well as the prognostic significance of MRD measurements after initial induction therapy." Limitations of incorporating MRD into routine practice include "a lack of standardization and established cutoff values." The guideline notes that "the most frequently employed methods for MRD assessment include real-time quantitative polymerase chain reactions (RQ-PCR) assays (ie, NPM1, CBFB::MYH11, RUNX1::RUNX1T1) and multicolor flow cytometry (MFC) assays specifically designed to detect abnormal MRD immunophenotypes. The threshold to define MRD+ and MRD- samples depends on the technique and subgroup of AML. Next-generation sequencing (NGS)-based assays to detect mutated genes (targeted sequencing, 20 to 50 genes per panel) is not routinely used, as the sensitivity of PCR-based assays and flow cytometry is superior to what is achieved by conventional NGS."

European LeukemiaNet

The European LeukemiaNet international expert panel recommendations for the diagnosis and management of adults with AML were updated in 2017 and again in 2022.^57,58, The most recent update reflects the 2022 changes to the World Health Organization classification of AML. The panel 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 8 outlines the risk stratification by genetic variants, and Table 9 summarizes recommended conventional care regimens based on patient fitness and risk characteristics, including mutations and other considerations.

The European LeukemiaNet MRD Working Party is an international expert panel convened with the objective of providing guidelines for technical assessment and clinical use of immunophenotypic and molecular MRD testing in AML; the panel's first consensus recommendations were published in 2018, and updated recommendations were published in 2021.^59,7, In the 2021 update, the panel recommended that molecular MRD be assessed by real-time quantitative or digital polymerase chain reaction in patients with NPM1, CBFB-MYH11, or RUNX1-RUNX1T1 mutations, and by MFC in all other patients. NGS-based MRD monitoring is considered by the panel to be "useful to refine prognosis in addition to MFC but, to date, there are insufficient data to recommend NGS-MRD as a stand-alone technique." The panel also defined MRD positivity thresholds according to whether

Table 8. Risk Stratification by Genetic Variant

  Adapted from Döhner et al (2022).58, ITD: internal tandem duplication.

Table 9. Selected Conventional Care Regimens by Fitness and Risk Characteristics

  Adapted from Döhner et al (2022).58, *Examples include intermediate- or adverse-risk disease and/or inadequate clearance of measurable residual disease. allo: allogeneic, AML: acute myeloid leukemia, HCT: hematopoietic cell transplant.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Select currently ongoing and unpublished trials that might influence this review are listed in Table 10.

Table 10. Summary of Key Trials

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

References

1. American Cancer Society (ACS). Key Statistics for Acute Myeloid Leukemia (AML). 2024; https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html. Accessed November 27, 2024.
2. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. Jul 2022; 36(7): 1703-1719. PMID 35732831
3. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. May 19 2016; 127(20): 2391-405. PMID 27069254
4. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. Jan 21 2010; 115(3): 453-74. PMID 19880497
5. Newell LF, Cook RJ. Advances in acute myeloid leukemia. BMJ. Oct 06 2021; 375: n2026. PMID 34615640
6. Ehinger M, Pettersson L. Measurable residual disease testing for personalized treatment of acute myeloid leukemia. APMIS. May 2019; 127(5): 337-351. PMID 30919505
7. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. Dec 30 2021; 138(26): 2753-2767. PMID 34724563
8. Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013?. Hematology Am Soc Hematol Educ Program. 2013; 2013: 220-6. PMID 24319184
9. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute Myeloid Leukemia. Version 3.2024. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed November 27, 2024.
10. Whitman SP, Maharry K, Radmacher MD, et al. FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study. Blood. Nov 04 2010; 116(18): 3622-6. PMID 20656931
11. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. Mar 22 2012; 366(12): 1079-89. PMID 22417203
12. Polak TB, Van Rosmalen J, Dirven S, et al. Association of FLT3-internal tandem duplication length with overall survival in acute myeloid leukemia: a systematic review and meta-analysis. Haematologica. Oct 01 2022; 107(10): 2506-2510. PMID 35796012
13. Daver N, Schlenk RF, Russell NH, et al. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. Feb 2019; 33(2): 299-312. PMID 30651634
14. Bazarbachi A, Bug G, Baron F, et al. Clinical practice recommendation on hematopoietic stem cell transplantation for acute myeloid leukemia patients with FLT3 -internal tandem duplication: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica. Jun 2020; 105(6): 1507-1516. PMID 32241850
15. Liersch R, Müller-Tidow C, Berdel WE, et al. Prognostic factors for acute myeloid leukaemia in adults--biological significance and clinical use. Br J Haematol. Apr 2014; 165(1): 17-38. PMID 24484469
16. Martelli MP, Sportoletti P, Tiacci E, et al. Mutational landscape of AML with normal cytogenetics: biological and clinical implications. Blood Rev. Jan 2013; 27(1): 13-22. PMID 23261068
17. Ohgami RS, Ma L, Merker JD, et al. Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod Pathol. May 2015; 28(5): 706-14. PMID 25412851
18. Cagnetta A, Adamia S, Acharya C, et al. Role of genotype-based approach in the clinical management of adult acute myeloid leukemia with normal cytogenetics. Leuk Res. Jun 2014; 38(6): 649-59. PMID 24726781
19. Li HY, Deng DH, Huang Y, et al. Favorable prognosis of biallelic CEBPA gene mutations in acute myeloid leukemia patients: a meta-analysis. Eur J Haematol. May 2015; 94(5): 439-48. PMID 25227715
20. Tarlock K, Lamble AJ, Wang YC, et al. CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group. Blood. Sep 30 2021; 138(13): 1137-1147. PMID 33951732
21. Taube F, Georgi JA, Kramer M, et al. CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome. Blood. Jan 06 2022; 139(1): 87-103. PMID 34320176
22. Port M, Böttcher M, Thol F, et al. Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis. Ann Hematol. Aug 2014; 93(8): 1279-86. PMID 24801015
23. Dickson GJ, Bustraan S, Hills RK, et al. The value of molecular stratification for CEBPA(DM) and NPM1(MUT) FLT3(WT) genotypes in older patients with acute myeloid leukaemia. Br J Haematol. Feb 2016; 172(4): 573-80. PMID 26847745
24. Wu X, Feng X, Zhao X, et al. Prognostic significance of FLT3-ITD in pediatric acute myeloid leukemia: a meta-analysis of cohort studies. Mol Cell Biochem. Sep 2016; 420(1-2): 121-8. PMID 27435859
25. Kuwatsuka Y, Tomizawa D, Kihara R, et al. Prognostic value of genetic mutations in adolescent and young adults with acute myeloid leukemia. Int J Hematol. Feb 2018; 107(2): 201-210. PMID 29027108
26. Rinaldi I, Louisa M, Wiguna FI, et al. Prognostic Significance of Fms-Like Tyrosine Kinase 3 Internal Tandem Duplication Mutation in Non-Transplant Adult Patients with Acute Myeloblastic Leukemia: A Systematic Review and Meta-Analysis. Asian Pac J Cancer Prev. Oct 01 2020; 21(10): 2827-2836. PMID 33112537
27. Issa GC, Bidikian A, Venugopal S, et al. Clinical outcomes associated with NPM1 mutations in patients with relapsed or refractory AML. Blood Adv. Mar 28 2023; 7(6): 933-942. PMID 36322818
28. Knapper S, Russell N, Gilkes A, et al. A randomized assessment of adding the kinase inhibitor lestaurtinib to first-line chemotherapy for FLT3-mutated AML. Blood. Mar 02 2017; 129(9): 1143-1154. PMID 27872058
29. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation. N Engl J Med. Aug 03 2017; 377(5): 454-464. PMID 28644114
30. Voso MT, Larson RA, Jones D, et al. Midostaurin in patients with acute myeloid leukemia and FLT3-TKD mutations: a subanalysis from the RATIFY trial. Blood Adv. Oct 13 2020; 4(19): 4945-4954. PMID 33049054
31. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3 -Mutated AML. N Engl J Med. Oct 31 2019; 381(18): 1728-1740. PMID 31665578
32. Cortes JE, Khaled S, Martinelli G, et al. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial. Lancet Oncol. Jul 2019; 20(7): 984-997. PMID 31175001
33. Schlenk RF, Döhner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. May 01 2008; 358(18): 1909-18. PMID 18450602
34. Schlenk RF, Taskesen E, van Norden Y, et al. The value of allogeneic and autologous hematopoietic stem cell transplantation in prognostically favorable acute myeloid leukemia with double mutant CEBPA. Blood. Aug 29 2013; 122(9): 1576-82. PMID 23863898
35. Willemze R, Suciu S, Meloni G, et al. High-dose cytarabine in induction treatment improves the outcome of adult patients younger than age 46 years with acute myeloid leukemia: results of the EORTC-GIMEMA AML-12 trial. J Clin Oncol. Jan 20 2014; 32(3): 219-28. PMID 24297940
36. Chou SC, Tang JL, Hou HA, et al. Prognostic implication of gene mutations on overall survival in the adult acute myeloid leukemia patients receiving or not receiving allogeneic hematopoietic stem cell transplantations. Leuk Res. Nov 2014; 38(11): 1278-84. PMID 25260824
37. Ma Y, Wu Y, Shen Z, et al. Is allogeneic transplantation really the best treatment for FLT3/ITD-positive acute myeloid leukemia? A systematic review. Clin Transplant. Feb 2015; 29(2): 149-60. PMID 25430616
38. Tarlock K, Alonzo TA, Gerbing RB, et al. Gemtuzumab Ozogamicin Reduces Relapse Risk in FLT3/ITD Acute Myeloid Leukemia: A Report from the Children's Oncology Group. Clin Cancer Res. Apr 15 2016; 22(8): 1951-7. PMID 26644412
39. Ahn JS, Kim JY, Kim HJ, et al. Normal karyotype acute myeloid leukemia patients with CEBPA double mutation have a favorable prognosis but no survival benefit from allogeneic stem cell transplant. Ann Hematol. Jan 2016; 95(2): 301-10. PMID 26537612
40. Brunner AM, Li S, Fathi AT, et al. Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission. Br J Haematol. Nov 2016; 175(3): 496-504. PMID 27434660
41. Versluis J, In 't Hout FE, Devillier R, et al. Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio. Leukemia. Jan 2017; 31(1): 26-33. PMID 27416910
42. Döhner H, Wei AH, Roboz GJ, et al. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine. Blood. Oct 13 2022; 140(15): 1674-1685. PMID 35960871
43. Bornhäuser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. Mar 01 2007; 109(5): 2264-5; author reply 2265. PMID 17312001
44. DeZern AE, Sung A, Kim S, et al. Role of allogeneic transplantation for FLT3/ITD acute myeloid leukemia: outcomes from 133 consecutive newly diagnosed patients from a single institution. Biol Blood Marrow Transplant. Sep 2011; 17(9): 1404-9. PMID 21324374
45. Doubek M, Muzík J, Szotkowski T, et al. Is FLT3 internal tandem duplication significant indicator for allogeneic transplantation in acute myeloid leukemia? An analysis of patients from the Czech Acute Leukemia Clinical Register (ALERT). Neoplasma. 2007; 54(1): 89-94. PMID 17233551
46. 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): 3658-65. PMID 16076872
47. Guièze R, Cornillet-Lefebvre P, Lioure B, et al. Role of autologous hematopoietic stem cell transplantation according to the NPM1/FLT3-ITD molecular status for cytogenetically normal AML patients: a GOELAMS study. Am J Hematol. Dec 2012; 87(12): 1052-6. PMID 22911473
48. Labouré G, Dulucq S, Labopin M, et al. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD. Biol Blood Marrow Transplant. Dec 2012; 18(12): 1845-50. PMID 22766221
49. Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. Dec 01 2006; 108(12): 3654-61. PMID 16912228
50. Ivey A, Hills RK, Simpson MA, et al. Assessment of Minimal Residual Disease in Standard-Risk AML. N Engl J Med. Feb 04 2016; 374(5): 422-33. PMID 26789727
51. Balsat M, Renneville A, Thomas X, et al. Postinduction Minimal Residual Disease Predicts Outcome and Benefit From Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia With NPM1 Mutation: A Study by the Acute Leukemia French Association Group. J Clin Oncol. Jan 10 2017; 35(2): 185-193. PMID 28056203
52. Dillon R, Hills R, Freeman S, et al. Molecular MRD status and outcome after transplantation in NPM1-mutated AML. Blood. Feb 27 2020; 135(9): 680-688. PMID 31932839
53. Grob T, Sanders MA, Vonk CM, et al. Prognostic Value of FLT3 -Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia. J Clin Oncol. Feb 01 2023; 41(4): 756-765. PMID 36315929
54. Loo S, Roberts AW, Anstee NS, et al. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG. Blood. Dec 07 2023; 142(23): 1960-1971. PMID 37647654
55. Levis MJ, Hamadani M, Logan B, et al. Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3. J Clin Oncol. May 20 2024; 42(15): 1766-1775. PMID 38471061
56. Bataller A, Oñate G, Diaz-Beyá M, et al. Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease. Br J Haematol. Oct 2020; 191(1): 52-61. PMID 32510599
57. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. Jan 26 2017; 129(4): 424-447. PMID 27895058
58. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood. Sep 22 2022; 140(12): 1345-1377. PMID 35797463
59. Schuurhuis GJ, Heuser M, Freeman S, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood. Mar 22 2018; 131(12): 1275-1291. PMID 29330221

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