JAK2, MPL, and CALR Testing for Myeloproliferative Neoplasms

POLICY NUMBER

A.2.04.60

DESCRIPTION

Somatic (acquired) genetic variants in JAK2, MPL, and CALR genes have been implicated as the underlying molecular genetic drivers for the pathogenesis of myeloproliferative neoplasms (MPNs). This policy addresses the use of genetic testing of JAK2, MPL, and CALR genes for the diagnosis, prognosis, and treatment selection of patients with MPN.

Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPNs) are rare overlapping blood diseases characterized by the production of one or more blood cell lines. The most common forms of MPNs include polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukemia. A common finding in many MPNs is clonality and a central pathogenic feature in the detection of a somatic (acquired) pathogenic variant in disease-associated genes. Pathogenic variants in disease-associated genes result in constitutively activated tyrosine kinase enzyme or cell surface receptor.

The paradigm for the use of molecular genetics to revolutionize patient management is chronic myeloid leukemia. A unique chromosomal translocation t(9;22), the Philadelphia chromosome (Ph), leads to a unique gene rearrangement (BCR-ABL) creating a fusion gene that encodes for a constitutively active Bcr-abl fusion protein. These findings led to the development of targeted tyrosine kinase inhibitor drug therapy (imatinib) that produces long-lasting remissions. Rarely, patients may show unusual manifestations of nonclassic forms of MPNs, such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have identified JAK2 V617F variants in some of these cases. The remainder of this policy focuses only on the non-Ph or Ph-negative MPNs and genetic testing for JAK2, CALR, and MPL.

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 can be mimicked by other conditions such as reactive or secondary erythrocytosis, thrombocytosis, or myeloid fibrosis. Additionally, these entities can be difficult to distinguish on morphologic bone marrow exam, and diagnosis can be complicated by changing disease patterns: PV and ET can evolve into PMF or undergo leukemic transformation. A complex set of clinical, pathologic, and biologic criteria first introduced by the Polycythemia Vera Study Group in 1996 and by the World Health Organization as a benchmark for diagnosis in 2002 and updated in 2008 and 2016. In 2022, both the World Health Organization 5th edition and an International Consensus Classification were published. Applying these criteria has been challenging because they involve complex diagnostic algorithms, rely on morphological assessment of uncertain consistency, and require tests that are not well-standardized or widely available, such as endogenous erythroid colony formation. An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.

Chronic Myeloid Leukemia and Philadelphia Chromosome

Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Classic Myeloproliferative NeoplasmsVarying combinations of these criteria are used to determine whether a patient has PV, ET, or PMF (ie, MPNs that are Ph-negative). An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.

As noted, some diagnostic methods (eg, bone marrow microscopy) are not well-standardized, and others (eg, endogenous erythroid colony formation) are neither standardized nor widely available.

Nonclassic Forms of Myeloproliferative NeoplasmsAlthough the most common Ph-negative MPNs include what is commonly referred to as classic forms of this disorder (PV, ET, PMF), rarely, patients may show unusual manifestations of nonclassic forms of MPNs, such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have identified JAK2 V617F variants in some of these cases.

Molecular Genetics of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

JAK2 Gene

The JAK2 gene, located on chromosome 9, contains the genetic code for making the Janus kinase 2 (JAK2) protein, a nonreceptor tyrosine kinase. The JAK2 protein is part of the JAK/signal transducer and activator of transcription (STAT) proteins that are important for the controlled production of blood cells from hematopoietic cells. Somatic (acquired) variants in the JAK2 gene are found in patients with PV, ET, and PMF.

JAK2 V617F VariantIn 2005, 4 separate groups using different modes of discovery and different measurement techniques reported on the presence of a novel somatic (acquired) single nucleotide variant in the conserved autoinhibitory pseudokinase domain of the gene encoding JAK2 protein in patients with classic MPNs. The single nucleotide variant caused a valine-to-phenylalanine substitution at amino acid position 617 (JAK2 V617F) leading to a novel somatic gain-of-function single nucleotide variant that resulted in the loss of autoinhibition of the JAK2 tyrosine kinase. JAK2 V617F is a constitutively activated kinase that recruits and phosphorylates substrate molecules including STAT proteins (so-called JAK-STAT signaling). The result is cell proliferation independent of normal growth factor control.

The JAK2 V617F variant was present in blood and bone marrow from a variable portion of patients with classic BCR-ABL–negative (ie, Ph-negative) MPNs including 65% to 97% of patients with PV, 23% to 57% with ET, and 35% to 56% with PMF (see the table below). The variant was initially reported to be absent in all normal subjects and patients with secondary erythrocytosis, although very low levels of cells carrying the variant have been reported in a small subset of healthy individuals.

Although almost all studies were retrospective case series and/or cross-sectional studies, and although both the analytic and clinical performances appeared dependent on the laboratory method used to detect the variant, there has been consistency across studies in demonstrating that the JAK2 V617F variant is a highly specific marker for clonal evidence of an MPN.

Frequency of the JAK2 V617F Variant in Patients with Classic Philadelphia Chromosome-Negative Myeloproliferative Neoplasm From Case Series

Values are n/N (%).ET: essential thrombocythemia; NR: not reported; PCR: polymerase chain reaction; PMF: primary myelofibrosis; PV: polycythemia vera.In vivo, mice irradiated and then given transplanted bone marrow cells infected with a retrovirus containing the variant developed a myeloproliferative syndrome.

JAK2 Exon 12 VariantsScott et al (2007) identified 4 somatic gain-of-function variants in JAK2 exon 12 in 10 of 11 PV patients without the JAK2 V617F variant. Patients with a JAK2 exon 12 variant differed from those with the JAK2 V617F variant, presenting at a younger age with higher hemoglobin levels and lower platelet and white cell counts. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin, and mice treated with transfected bone marrow transplants developed a myeloproliferative syndrome.

Findings have been confirmed by a number of investigators who identified additional variants with similar functional consequences in patients with PV and patients with idiopathic erythrocytosis. Based on these findings, it has been concluded that the identification of JAK2 exon 12 variants provides a diagnostic test for JAK2 V617F–negative patients who present with erythrocytosis. Of note, different variants in the same gene appear to have different effects on signaling, resulting in distinct clinical phenotypes.

MPL Gene

The MPL gene, located on chromosome 1, contains the genetic code for making the thrombopoietin receptor, a cell surface protein that stimulates the JAK/STAT signal transduction pathway. The thrombopoietin receptor is critical for the cell growth and division of megakaryocytes, which produce platelets involved in blood clotting. Somatic variants in the MPL gene are associated with ET and PMF.

CALR Gene

The CALR gene, located on chromosome 19, contains the genetic code for making the calreticulin protein, a multifunctional protein located in the endoplasmic reticulum, cytoplasm, and cell surface. The calreticulin protein is thought to play a role in cell growth and division and regulation of gene activity. Somatic variants in the CALR gene are associated with ET and PMF.

Frequency of JAK2, CALR, and MPL Somatic Variants in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Philadelphia chromosome-negative MPNs are characterized by their molecular genetic alterations. The table below summarizes the driver genes and somatic variants associated with specific Ph-negative MPNs.

Table 2. Frequency of JAK2, CALR, and MPL Somatic Variants in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Indels: insertions and deletions; MPN: myeloproliferative neoplasm; Ph: Philadelphia chromosome.

A more recent retrospective study of patients observed at the National Research Center for Hematology (Moscow, Russia) from October 2016 to November 2020 assessed the frequency of detection of JAK2 V617F, CALR, and MPL mutations in a Russian cohort of patients with BCR/ABL rearrangement negative (ie, Ph-negative) MPNs. Patients (N=1958) with a diagnosis of ET, PV, PMF, or MPN-unclassified were examined. Table 3 summarizes the driver genes and somatic variants associated with specific Ph-negative MPNs.

Table 3. Frequency of JAK2, CALR, and MPL Genes in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

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. More than a dozen commercial laboratories offer a wide variety of diagnostic procedures for JAK2, CALR, and MPL testing under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by 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.

POLICY

JAK2testing may be considered medically necessary in the diagnosis of individuals presenting with clinical, laboratory, or pathologic findings suggesting polycythemia vera, essential thrombocythemia, or primary myelofibrosis. Based on criteria from the World Health Organization and the International Consensus Classification for diagnosis of PV, documentation of a serum erythropoietin level below the reference range for normal is recommended before JAK2 testing (See Policy Guidelines).

MPL and CALR testing may be considered medically necessary in the diagnosis of individuals presenting with clinical, laboratory, or pathologic findings suggesting essential thrombocythemia or primary myelofibrosis.

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

• Diagnosis of nonclassic forms of myeloproliferative neoplasms (MPNs)

• Molecular phenotyping of individuals with MPNs

• Monitoring, management, or selecting treatment in patients with MPNs.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

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

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

Individuals suspected to have essential thrombocythemia or primary myelofibrosis should first be tested for JAK2 variants, as noted. If testing is negative, further testing to detect MPL and CALR variants is warranted.

Criteria for Polycythemia Vera Testing

Based on the World Health Organization (WHO) and International Consensus Classification major and minor criteria (see the table below), documentation of serum erythropoietin level below the reference range for normal meets a minor criterion for polycythemia vera. Therefore, serum erythropoietin testing is recommended before JAK2 testing.

World Health Organization 5th Edition and the International Consensus Classification Diagnostic Criteria for Polycythemia Vera

The diagnosis of PV requires the presence of all 3 major criteria or the presence of the first 2 major criteria together with the minor criterion.^aThe World Health Organization 2022 5th edition removed red cell mass as a major criterion since this is not commonly evaluated in clinical practice. The International Consensus Classification still includes increased red blood cell mass as a major criterion.

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 Mental Health Disorders, 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 medical necessity, “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.

POLICY HISTORY

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.

06/27/2017: Code Reference section updated to revise code description for CPT code 81403, effective 07/01/2017.

12/15/2017: Policy title changed from "JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms" to "JAK2, MPL, and CALR Testing for Myeloproliferative Neoplasms." Policy description updated regarding molecular genetics of Ph-Negative MPNs. First policy statement revised to remove MPL mutation testing. Added statement regarding recommendation for documentation of serum erythropoietin levels before JAK2 testing. Added statement that MPL and CALR testing may be considered medically necessary in the diagnosis of patients presenting with clinical, laboratory or pathologic findings suggesting ET or PMF. Investigational statement updated to include CALR testing as investigational in all other circumstances and to remove "diagnosis or selection of treatment in patients with Down syndrome and acute lymphoblastic leukemia" from the criteria. Policy Guidelines updated regarding criteria for polycythemia testing, genetics nomenclature, and genetic counseling information. Code Reference section updated to add CPT code 81219. Revised description for CPT code 81403 effective 01/01/2018.

01/25/2018: Code Reference section updated to add new 2018 CPT code 0027U.

08/07/2018: Policy description updated regarding myeloproliferative neoplasms and the JAK2 gene. Policy statements unchanged. Policy Guidelines updated regarding genetic counseling.

09/04/2019: Policy description updated regarding myeloproliferative neoplasms. Policy statements unchanged.

09/08/2020: Minor edit made to investigational statement. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

12/16/2020: Code Reference section updated to add new CPT codes 81279, 81338, and 81339, effective 01/01/2021.

12/08/2021: Policy description updated to add table regarding the frequency of JAK2, CALR, and MPL genes in Ph-Negative MPNs. Policy statements unchanged. Policy Guidelines updated regarding diagnosing PV and to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

09/09/2022: Policy description updated. Policy statements updated to change "patients" to "individuals."

09/12/2023: Policy description updated. Policy statement updated to reference the International Consensus Classification for diagnosis of polycythemia vera (PV). Policy Guidelines updated regarding diagnostic criteria for PV.

09/12/2024: Policy reviewed. Policy statement updated to change "patients" to "individuals."

09/22/2025: Policy description updated. Policy statements unchanged.

SOURCE(S)

Blue Cross Blue Shield Association Policy #2.04.60

CODE REFERENCE

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

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