Medical Policy: 02.04.66 

Original Effective Date: May 2017 

Reviewed: May 2019 

Revised: May 2019 



This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.


Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.


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.


National Comprehensive Cancer Network

Current National Comprehensive Cancer Network guidelines for acute myeloid leukemia (AML) (2.2019) 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 implication."


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

  • NPM1 without FLT3-ITD: favorable risk
  • Isolated biallelic CEBPA: favorable risk
  • FLT3-ITD: poor risk


Current National Comprehensive Cancer Network guidelines for Chronic Lymphocytic leukemia (CLL)/small lymphocytic lymphoma (2.2019) provide the following recommendations.

  • Acalabrutinib has no activity against CLL cells with BTK mutations and should not be administered to patients with ibrutinib-refractory disease who have this mutation present in their tumor cells.
  • Testing for BTK and PLCG2 mutations may be useful in patients receiving ibrutinib and suspected of having progression. BTK and PLCG2 mutation status alone is not an indication to change treatment.


American Society of Hematology Guideline (2019)


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).


Panel Testing

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.


Prior Approval:

Not applicable



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 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.


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.


Large panel testing for leukemia’s ( e.g. myAML, myHEME) has not been proven and is considered investigational.


Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.

  • 81120 IDH1 (isocitrate dehydrogenase 1 [NADP+], soluble) (eg, glioma), common variants (eg, R132H, R132C)
  • 81121 IDH2 (isocitrate dehydrogenase 2 [NADP+], mitochondrial) (eg, glioma), common variants (eg, R140W, R172M)
  • 81218 CEBPA (CCAAT/enhancer binding protein [C/EBP], alpha) (eg, acute myeloid leukemia), gene analysis, full gene sequence
  • 81245 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; internal tandem duplication (ITD) variants (ie, exons 14, 15)
  • 81246 FLT3 (fms-related tyrosine kinase 3) (eg, acute myeloid leukemia), gene analysis; tyrosine kinase domain (TKD) variants (eg, D835, I836)
  • 81310 NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, exon 12 variants.
  • 81175 ASXL1 (additional sex combs like 1, transcriptional regulator) (eg, myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; full gene sequence
  • 81176 ASXL1 (additional sex combs like 1, transcriptional regulator) (eg, myelodysplastic syndrome, myeloproliferative neoplasms, chronic myelomonocytic leukemia), gene analysis; targeted sequence analysis (eg, exon 12)
  • 81233 BTK (Bruton's tyrosine kinase) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, C481S, C481R, C481F)
  • 81320 PLCG2 (phospholipase C gamma 2) (eg, chronic lymphocytic leukemia) gene analysis, common variants (eg, R665W, S707F, L845F)
  • 81334 RUNX1 (runt related transcription factor 1) (eg, acute myeloid leukemia, familial platelet disorder with associated myeloid malignancy), gene analysis, targeted sequence analysis (eg, exons 3-8)
  • 0023U Oncology (acute myelogenous leukemia), DNA, genotyping of internal tandem duplication, p.D835, p.I836, using mononuclear cells, reported as detection or non-detection of FLT3 mutation and indication for or against the use of midostaurin
  • 0046U FLT3 (fms-related tyrosine kinase 3) eg, acute myeloid leukemia) internal tandem duplication (ITD) variants, quantitative
  • 0049U NPM1 (nucleophosmin) (eg, acute myeloid leukemia) gene analysis, quantitative
  • 0050U Targeted genomic sequence analysis panel, acute myelogenous leukemia, DNA analysis, 194 genes, interrogation for sequence variants, copy number variants or rearrangements
  • 0056U Hematology (acute myelogenous leukemia), DNA, whole genome next-generation sequencing to detect gene rearrangement(s), blood or bone marrow, report of specific gene rearrangement(s)
  • 0120U Oncology (B-cell lymphoma classification), mRNA, gene expression profiling by fluorescent probe hybridization of 58 genes (45 content and 13 housekeeping genes), formalin-fixed paraffin-embedded tissue, algorithm reported as likelihood for primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma (DLBCL) with cell of origin subtyping in the latter


Selected References:

  • National Comprehensive Cancer Network (NCCN). NCCN Clinical Practive Guidelies in Oncology: Acute Myeloid Leukemia. Version 2.2019.
  • Port M, Bottcher 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):1279-1286. PMID 24801015
  • 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):573-580. PMID 26847745
  • 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):121-128. PMID 27435859
  • Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia. N Engl J Med. May 1 2008;358(18):1909-1918. PMID 18450602
  • 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):1576-1582. PMID 23863898
  • 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):219-228. PMID 24297940
  • 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):1278-1284. PMID 25260824
  • 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):149-160. PMID 25430616
  • 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):1951-1957. PMID 26644412
  • 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):301-310. PMID 26537612
  • 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
  • Bornhäuser M, Illmer T, Schaich M, et al. Improved outcome after stem-cell transplantation in FLT3/ITD-positive AML. Blood. Mar 1 2007;109(5):2264-2265; author reply 2265. PMID 17312001
  • 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):1404-1409. PMID 21324374
  • Guieze 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):1052-1056. PMID 22911473
  • Meshinchi S, Alonzo TA, Stirewalt DL, et al. Clinical implications of FLT3 mutations in pediatric AML. Blood. Dec 01 2006;108(12):3654-3661. PMID 16912228
  • Liersch R, Muller-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
  • John Hopkins University, Targeting FLT3 to treat leukemia. Expert Opin Ther Targets: Jan 2016; 19(1): 37-54. Doi:10.1517/14728222.2014
  • Fey M, Buske C, Acute myeloblastic leukaemias in adult patients: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Annals of Oncology. Aug 2013. Doi: 10.1093/annonc/mdt320.
  • FDA US Food and Drug Administration Rydapt approval label.
  • Arber DA, Borowitz MJ, Cessna M, et al. Initial diagnostic workup of acute leukemia: guideline from the College of American Pathologists and the American Society of Hematology [published online February 22, 2017]. Arch Pathol Lab Med. doi:10.5858/arpa.2016-0504-CP
  • Fu L, Fu H, Tian L, et al. High expression of RUNX1 is associated with poorer outcomes in cytogenetically normal acute myeloid leukemia. Oncotarget. 2016;7(13):15828-15839. doi:10.18632/oncotarget.7489.
  • Zerkalenkova E, Panfyorova A, Kazakova A, Baryshev P, Shelihova L, Kalinina I, Novichkova G, Maschan M, Maschan A, Olshanskaya Y. Ann Hematol. 2018 Jun;97(6):977-988. doi: 10.1007/s00277-018-3267-z. Epub 2018 Feb 9.
  • Mrinal M. Patnaik, MD, and Ayalew Tefferi, MD. Chronic Myelomonocytic Leukemia: Focus on Clinical Practice. Mayo Clin Proc. February 2016;91(2):259-272
  • Abdel-Wahab O, Pardanani A, Patel J, et al. Concomitant analysis of EZH2 and ASXL1 mutations in myelofibrosis, chronic myelomonocytic leukemia and blast-phase myeloproliferative neoplasms. Leukemia. 2011;25(7):1200-1202.
  • L. Dang, K. Yen, E. C. Attar, IDH mutations in cancer and progress toward development of targeted therapeutics, Annals of Oncology, Volume 27, Issue 4, April 2016, Pages 599–608.
  • Nassereddine, S., Lap, C. J., Haroun, F., & Tabbara, I. (2017). The role of mutant IDH1 and IDH2 inhibitors in the treatment of acute myeloid leukemia. Annals of Hematology, 96(12), 1983–1991.
  • Cerrano, M. & Itzykson, R. Curr Oncol Rep (2019) 21: 16. New Treatment Options for Acute Myeloid Leukemia in 2019. 
  • Valérie de Haas, Nofisat Ismaila, Anjali Advani, Daniel A. Arber, Raetasha S. Dabney, Dipti Patel-Donelly, Elizabeth Kitlas, Rob Pieters, Ching-Hon Pui, Kendra Sweet, and Ling Zhang Initial Diagnostic Work-Up of Acute Leukemia: ASCO Clinical Practice Guideline Endorsement of the College of American Pathologists and American Society of Hematology Guideline Journal of Clinical Oncology 2019 37:3, 239-253
  • Maciejko L, Smalley M, Goldman A. Cancer Immunotherapy and Personalized Medicine: Emerging Technologies and Biomarker-Based Approaches. J Mol Biomark Diagn. 2017;8(5):350. doi:10.4172/2155-9929.1000350
  • Kim J. Unravelling the genomic landscape of leukemia using NGS techniques: the challenge remains. Blood Res. 2017;52(4):237–239. doi:10.5045/br.2017.52.4.237
  • Patnaik MM, Tefferi A. Chronic myelomonocytic leukemia: 2018 update on diagnosis, risk stratification and management. Am J Hematol. 2018;93:824–40.


Policy History:

  • May 2019 - Annual Review, Policy Revised
  • May 2018 - Annual Review, Policy Revised
  • May 2017 - New Policy

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