Print JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms

JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms






Myeloproliferative Neoplasms (MPNs) are uncommon overlapping blood diseases characterized by the production of one or more blood cell lines and include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic masteocytosis, chronic eosinophilic leukemia and others. A common finding in many of the MPNs is clonality. A central pathogenic feature is a mutated version of a tyrosine kinase enzyme, such that it is abnormally constitutively activated. The paradigm for use of this information to revolutionalize patient management is CML. A unique chromosomal change (Ph) and an accompanying unique gene rearrangement (BCR-ABL) resulting in a continuously activated tyrosine kinase enzyme were identified. These findings led to the development of targeted tyrosine kinase inhibitor drug therapy (imatinib) that produces long-lasting remissions.

Diagnosis and monitoring of patients with Ph-negative MPNs have been challenging because many of the laboratory and clinical features of the classic forms of these diseases (PV, ET and PMF) can be mimicked by other conditions such as reactive or secondary erythrocytosis, thrombocytosis or myeloid fibrosis. In addition, these entities can be difficult to distinguish on morphological bone marrow exam and diagnosis can be complicated by changing disease patterns. For an example, PV and ET can evolve into PMF or undergo leukemic transformation. World Health Organization criteria were published as a benchmark for diagnosis in 2001 and updated in 2008. These have been challenging to use because they involve complex diagnostic algorithms, rely on morphological assessment of uncertain consistency, and require tests such as endogenous erthyroid colony formation that are not well-standardized or widely available.

In March and April of 2005, four separate groups using different modes of discovery and different measurement techniques reported the presence of a novel somatic point mutation in the conserved autoinhibitory pseudokinase domain of the gene encoding Janus Kinase 2 (JAK2) protein in patients with MPNs. The mutation caused a valine-to-phenylalanine substitution at amino acid position 617 (JAK2 V617F). Loss of JAK2 autoinhibition caused by JAK2 V617F, results in constitutive activation of the kinase and in recruitment and phosphorylation of substrate molecules including signal transducers and activators of transcript (STAT) proteins (so-called JAK-Stat signaling). The result is cell proliferation independent of normal growth factor control. These findings were subsequently confirmed and additional mutations affecting the JAK2 gene--mutations in exon 12 or in complementary pathways such as thrombopoietin receptor-pathway mutations in MPL exon 10--were identified. These mutations were seen with varying but reliable frequency in patients with classic MPNs, and with uncommon and erratic frequency in other MPNs. In addition, unique cases of JAK2 mutations were reported in subset of patients with Down syndrome-associated acute lymphoblastic leukemia (ALL).

While these mutations were of importance in better understanding of the biology of the MPNs, they were also of immediate interest as laboratory tools to aid in diagnosis and management of disease. To that end, at least four potential intended uses for mutation testing have been considered, including:

  1. Diagnosis of patients with clinical, laboratory or pathological findings suggesting classic MPNs (PV, ET or PMF);
  2. Diagnosis or selection of treatment for patients with Down syndrome ALL;
  3. Phenotyping of disease subtypes in patients with MPNs to establish disease prognosis;
  4. Identification, selection, and monitoring of treatment

Many diagnostic procedures are available for JAK2 testing and MPL mutation testing. Variable analytic and clinical performance has been reported, suggesting that nucleic acid amplification methodologies are more sensitive than mutation sequence analysis. It appears that there can be considerable interassay and interlaboratory variability in testing results.

More than a dozen commercial laboratories offer a wide variety of diagnostic procedures for JAK2 gene mutation testing and MPL testing. These tests are available as laboratory developed procedures under the Federal Drug and Administration enforcement discretion policy for laboratory-developed tests (LDTs). Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA), and laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, FDA does not require regulatory review of LDTs.



JAK2 tyrosine kinase and MPL mutation testing may be considered medically necessary in the diagnosis of patients presenting with clinical, laboratory or pathological findings suggesting classic forms of MPNs particularly PV, ET or PMF.

JAK2 tyrosine kinase and MPL mutation testing is considered investigational in all other circumstances including, but not limited to the following: 

  • Diagnosis of nonclassic forms of MPNs
  • Molecular phenotyping of patients with MPNs
  • Monitoring, management, or selecting treatment in patients with MPNs
  • Diagnosis or selection of treatment in patients with Down syndrome and acute lymphoblastic leukemia





The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.

Testing strategy

Patients suspected to have polycythemia vera (PV) should first be tested for the most common finding, JAK2 V617F. If testing is negative, further testing to detect other JAK2 tyrosine kinase mutations, eg, in exon 12, is warranted.

Patients suspected to have essential thrombocythemia (ET) or primary myelofibrosis (PMF) should first be tested for JAK2 mutations, as noted. If testing is negative, further testing to detect MPL mutations is warranted.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.



04/16/2010:  New policy added.

04/20/2011: Policy reviewed; no changes.

02/24/2012: Policy title changed from "Tyrosine Kinase Mutations in Myeloproliferative Neoplasms" to "JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms" because MPL is not a tyrosine kinase. Policy statement unchanged. Added 81270, 81402, and 81403 to the Code Reference section.

04/16/2013: Policy statement reorganized for clarity purposes; intent unchanged.

03/13/2014: Policy reviewed; no changes. Removed deleted CPT codes 83890 - 83906 and 83912 from the Code Reference section.

12/31/2014: Code Reference section updated to revise the description of the following CPT codes: 81402 and 81403.

03/18/2015: Policy description updated regarding laboratory testing. Policy statements unchanged. Policy guidelines updated to add the testing strategy for patients suspected to have PV, ET, or PMF.

08/18/2015: Medical policy revised to add ICD-10 codes.

06/06/2016: Policy number A.2.04.60 added. Policy Guidelines updated to add medically necessary and investigative definitions.



Blue Cross Blue Shield Association Policy # 2.04.60



This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

Code Number




JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant


Molecular pathology procedure, Level 3 (eg, > 10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants 1 exon), loss of heterozygosity [LOH], uniparental disomy [UPD]) (Revised 01-01-2015)


Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) (Revised 01-01-2015)



ICD-9 Procedure

ICD-10 Procedure




ICD-9 Diagnosis

ICD-10 Diagnosis


Polycythemia vera


Polycythemia vera


Essential thrombocythemia


Essential thrombocythemia


Myelofibrosis with myeloid metaplasia


Chronic myeloproliferative disease

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