Medical Policy: 02.04.66
Original Effective Date: May 2017
Reviewed: May 2020
Revised: May 2020
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Treatment of acute myeloid leukemia (AML) is based on risk stratification, primarily related to patient age and tumor cytogenetics. AML has a highly heterogeneous clinical course, and treatment generally depends on the different risk-stratification categories. Depending on the risk-stratification category, treatment modalities may include intensive remission induction chemotherapy, hypomethylating agents, clinical trials with innovative compounds, palliative cytotoxic treatment, new medication regimes, or supportive care only. For patients who achieve complete remission (CR) after induction treatment, possible post remission treatment options include intensive consolidation therapy, maintenance therapy, or autologous or allogeneic hematopoietic cell transplant. CN-AML is classified as "cytogenetically normal" based on the type of genetic changes involved in its development.
Cytogenetically normal refers to the fact that this form of acute myeloid leukemia is not associated with large chromosomal abnormalities. About half of people with acute myeloid leukemia have this form of the condition; the other half have genetic changes that alter large regions of certain chromosomes. These changes can be identified by a test known as cytogenetic analysis. CN-AML is associated with smaller genetic changes that cannot be seen by cytogenetic analysis. In patients with cytogenetically normal AML (CN-AML), the identification of variants in several genes, including KIT, FLT3, NPM1, RUNX1, ASXL1, IDH1/IDH2, and CEBPA, has been proposed to allow for further segregation in the management of this heterogeneous disease. 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.
Data have suggested an overall survival benefit with transplantation for patients with FLT3-ITD, but do not clearly demonstrate an overall survival 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 most recent World Health Organization (WHO) 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 clinico-pathologic-genetic entities with diagnostic, prognostic, and therapeutic implications. Conventional cytogenetic analysis (karyotyping) is considered to be a mandatory component in the diagnostic evaluation of a patient with suspected acute leukemia, because the cytogenetic profile of the tumor is considered to be the most powerful predictor of prognosis in AML and is used to guide the current risk-adapted treatment strategies.
Molecular variants have been analyzed to subdivide AML with normal cytogenetics into prognostic subsets. In AML, 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 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 WHO classification of acute leukemias. AML with FLT3 variants is not considered a distinct entity in the 2016 classification. The 2008 WHO classification recommends determining the presence of FLT3 variants because of the prognostic significance.
For individuals who have cytogenetically normal AML (CN-AML) who receive genetic testing for variants in FLT3, NPM1, CEBPA to risk-stratify AML, the evidence includes retrospective observational studies and systematic reviews of these studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and treatment-related mortality and morbidity. FLT3 internal tandem duplication (FLT3-ITD) variants confer a poor prognosis, whereas NPM1 (without FLT3-ITD 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-ITD, but do not clearly demonstrate an overall survival benefit of transplantation for patients with NPM1 and CEBPA variants.
Research has shown that children with gene mutations nucleophosmin-1 (NPM1) and CEBPA have a better prognosis than those without these mutations. If the leukemia has these mutations, the doctor may recommend chemotherapy without stem cell transplantation.
RUNX1 mutation refers to an alteration in the RUNX1 gene. It is associated with blood cell cancers, such as cancer of the white blood cells (leukemia). The RUNX1 gene gives instructions for the RUNX1 protein. RUNX1 helps blood cells control the process of converting genetic material to proteins by turning on genes related to blood cell development. RUNX1 is thus essential in early blood cells. It acts in unison with other proteins, such as the CBFB protein, and helps form the CBF complex. Alterations to the RUNX1 gene may result in a RUNX1 protein that is defective. The mutated RUNX1 protein may be unable to properly regulate blood cell growth and development, and may cause uncontrolled growth, resulting in cancer. The RUNX1 mutation analysis test detects abnormalities in the RUNX1 gene. It helps diagnose cancer. It also aids in the treatment of cancer by guiding selection of chemotherapy drugs.
Mutations in the IDH1/IDH2 genes have been identified in some people with cytogenetically normal acute myeloid leukemia (CN-AML). The IDH1/2 gene mutations involved in CN-AML are called somatic mutations; they are found only in cells that become cancerous and are not inherited. While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half of cases do not have these abnormalities; these are classified as CN-AML. The identification of IDH1/2 mutations could be helpful in the diagnosis of leukemia but would not play a role in inheritance or family cancer susceptibility. Reports on prognostic effect of these mutations has been somewhat inconsistent.
The ASXL1 gene maps to chromosome 20q11 and regulates chromatin by interacting with the polycomb group repressive complex proteins (PRC1 and PRC2) variants have been found to negatively impact outcomes. Frequent ASXL1 mutation is seen in effectively risk-stratifying patients on the basis of clinical parameters and the presence or absence of 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, treatment intensity, and medication selection. The U.S. Food and Drug Administration recently approved Rydapt (midostaurin) for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) who have a specific genetic mutation (FLT3), in combination with chemotherapy.
Bruton tyrosine kinase (BTK) mutation. The BTK gene provides instructions for making a protein called Bruton tyrosine kinase (BTK), which is essential for the development and maturation of B cells. The BTK protein transmits important chemical signals that instruct B cells to mature and produce antibodies. BTK is used in the diagnosis of x-linked agammaglobulinemia or XLA. In the diagnosis and treatment of cancer the testing of BTK is used frequently for treatment stratification. Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. Mutations in BTK appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.
Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (2.2020) provide the following recommendations.
For the evaluation for acute leukemia, “bone marrow with cytogenetics (karyotype ± FISH [fluorescence in situ hybridization]) and molecular analyses (KIT, FLT3 [ITD and TKD], NPM1, CEBPA, IDH1, IDH2, TP53, and other mutations).”
"Molecular abnormalities (KIT, FLT3-ITD, NPM1, CEBPA, and other mutations) are important for risk assessment and prognostication in a subset of patients (category 2A) and may guide treatment decisions (category 2B). More comprehensive panel arrays are available and institutions may have established sequencing panels that include markers with unknown impact on prognosis or which do not determine clinical trial eligibility."
"A variety of gene mutations are associated with specific prognosis and may guide medical decision making. Other mutations, such as, FLT3-ITD, FLT3-TKD, IDH ½, NPM1, and c-KIT may have therapeutic implications."
The guideline defined the following risk status based on molecular abnormalities:
Current National Comprehensive Cancer Network guidelines for Chronic Lymphocytic leukemia (CLL)/small lymphocytic lymphoma (2.2019) provide the following recommendations.
For pediatric and adult patients with suspected or confirmed AML of any type, the pathologist or treating clinician should ensure that testing for FLT3-ITD is performed. The pathologist or treating clinician may order mutational analysis that includes, but is not limited to, IDH1, IDH2, TET2, WT1, DNMT3A, and/or TP53 for prognostic and/or therapeutic purposes. (Strong recommendation for testing for FLT3-ITD; Recommendation for testing for other mutational analysis).
Following recent progress in molecular genetic findings and 2016 WHO classification of acute leukemias, the College of American Pathologists (CAP) and the American Society of Hematology (ASH) have formed an expert panel to review and establish guidelines for appropriate laboratory testing. The published guideline provides twenty-seven guideline statements ranging from recommendations on what testing is appropriate for the diagnostic and prognostic evaluation of leukemias to where the testing should be performed and how results should be reported.
The appropriate molecular genetic testing for AML is discussed starting from 16th guideline statement. Expert panel strongly recommends testing for FLT3-ITD in adult and pediatric patients with suspected or confirmed AML of any type. They also recommend testing for other mutational analysis that could include, but not limited to, IDH1, IDH2, TET2, WT1, DNMT3A, and/or TP53 for prognostic and/or therapeutic purposes (Statement 16).
In the 17th guideline statement, expert panel strongly recommends testing for KIT mutation in adult patients with confirmed core-binding factor (CBF) AML (AML with t(8;21)(q22;q22.1); RUNX1- RUNX1T1 or inv(16)(p13.1q22) /t(16;16)(p13.1;q22); CBFB-MYH11). It is only an expert consensus opinion for testing KIT mutation in pediatric patients with confirmed core binding factor AML (AML with t(8;21)(q22;q22.1); RUNX1- RUNX1T1 or inv(16)(p13.1q22) /t(16;16)(p13.1;q22); CBFBMYH11) which is not a strong recommendation (Statement 17).
The strong recommendation is also given for patients other than those with confirmed core binding factor AML, APL, or AML with myelodysplasia-related cytogenetic abnormalities that testing is needed for mutational analysis for NPM1, CEBPA, and RUNX1 (Statement 19).
In the 20th guideline statement, expert panel is providing no recommendation on either for or against the use of global/gene specific methylation, micro RNA (miRNA) expression, or gene expression analysis for diagnosis or prognosis in patients with confirmed acute leukemia.
Finally, in their last statement, expert panel strongly recommends the use of current WHO terminology for the final diagnosis and classification of acute leukemias.
The MyAML™ panel identifies single nucleotide variants (SNVs), insertion-deletion variants (indels) and the entire range of structural variants, including partial tandem duplications (PTDs) and translocations.
The MyHEME™ panel sequences the coding and non-coding exons of 571 genes. The data and report include sequences of mutations, which facilitates both minimal residual disease testing and temporal and longitudinal studies.
For additional information on panel testing see policy Expanded Genetic Panels to Identify Cancer Risk 02.04.64
Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA variants may be considered medically necessary in cytogenetically normal acute myeloid leukemia (CN-AML).
Genetic testing for FLT3, NPM1, and CEBPA variants to detect minimal residual disease is considered investigational.
Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA variants is considered investigational in all other situations.
Genetic testing for FLT3 tyrosine kinase domain (FLT3-TKD) variants is considered investigational for all indications.
Genetic testing for Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutation is considered medically necessary in the diagnosis and classification of leukemia’s and in diagnosis of chondrosarcomas, or gliomas and glioblastomas. It is considered investigational for all other indications.
Genetic testing for RUNX1 is considered medically necessary in the diagnosis and classification of leukemia's and in diagnosis of myelodysplastic syndromes. It is considered investigational for all other indications.
Genetic testing for ASXL1 mutations is considered medically necessary in the diagnosis and classification of leukemias and considered investigational for all other indications.
Genetic testing for BTK (Bruton’s tyrosine kinase) and PLCG2 mutations is considered medically necessary in the diagnosis and classification of B-cell disorders including Chronic Lymphocytic Leukemia (CLL), x-linked agammaglobulinemia (XLA), other B-cell disorders and mantle cell lymphoma. It is necessary to determine use of ibrutinib in treatment of in CLL. It is considered not medically necessary for all other indications.
KIT testing targeted sequence analysis may be considered medically necessary in cytogenetically normal acute myeloid leukemia (CN-AML) Testing for KIT D816 variant in cytogenetically normal acute myeloid leukemia (CN-AML) is considered investigational.
Large panel testing for leukemia’s ( e.g. myAML, myHEME) has not been proven and is considered investigational.
The use of micro RNA (miRNA) expression analysis for diagnosis or prognosis in patients with confirmed or suspected leukemia is considered investigational.
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