Medical Policy: 02.04.66
Original Effective Date: May 2017
Reviewed: May 2018
Revised: May 2018
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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. While large chromosomal abnormalities can be involved in the development of acute myeloid leukemia, about half the cases do not have these abnormalities; these are classified as CN-AML cytogenetically normal acute myeloid leukemia (CN-AML). In patients with cytogenetically normal AML, the identification of variants in several genes, including KIT, FLT3, NPM1, RUNX1, ASXL1, 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.
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 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
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.
Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (3.2017) 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 [internal tandem duplication], NPM1, CEBPA, and other mutations).”
“Molecular abnormalities (KIT, FLT3-ITD, NPM1, CEBPA, and other mutations) are important for prognostication in a subset of patients (category 2A) and may guide therapeutic intervention (category 2B). These are useful for patients with normal karyotype (especially FLT3-ITD, NPM1 mutations) or core binding factor leukemia (especially KIT mutation).”
The guideline defined the following risk status based on molecular abnormalities:
Large panel testing for leukemias has not been proven and is considered investigational.
Genetic testing for FLT3 internal tandem duplication (FLT3-ITD), NPM1, and CEBPA variants may be considered medically necessary in cytogenetically normal acute myeloid leukemia.
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 RUNX1 is considered medically necessary in the diagnosis and classification of leukemias and considered investigational for all other indications with the exception of myelodysplastic syndromes.
Genetic testing for ASXL1 mutations is considered medically necessary in the diagnosis and classification of leukemias and considered investigational for all other indications.
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May 2018 - Annual Review, Policy Revised
May 2017 - New Policy
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