Humana Janus Kinase 2 (JAK2) V617F, Exon 12 -15, Calreticulin (CALR) and MPL Mutation Analysis Form

Description

Janus kinase 2 (JAK2 V617F) variant analysis is a laboratory test used to assist in the diagnosis of the following myeloproliferative neoplasms (MPNs): essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). MPNs are a group of conditions characterized by an overproduction of specific types of blood or fiber cells in the bone marrow.

• ET is characterized by an overproduction of platelets due to a clonal process and may be suspected when an individual's platelet count is at least 450 x 109/L.2,79
• PV is differentiated from the other MPNs by the indication of increased red blood cell volume. An individual with the following laboratory results may require further evaluation with genetic testing: elevated red cell mass greater than 25% above the mean normal predicted value and/or elevated hemoglobin (greater than 16.5 g/dL for men or greater than 16 g/dL for women) and/or increased hematocrit (greater than 49% for men and greater than 48% for women).
• PMF is defined by the existence of bone marrow fibrosis that is not linked to another myeloid disorder such as chronic myeloid leukemia (CML), PV, ET or myelodysplastic syndromes (MDS). An individual with an increased white cell count (greater than 11 x 109/L) may require additional assessment.

Laboratory results for ET, PV and PMF remain persistent over time (typically a 4- month duration) and other reasons for the unexplained laboratory values, such as medications (including testosterone), dehydration and personal habits (eg, alcohol consumption), should be eliminated as a cause.

JAK2 Exon 12 to 15

While the detection of the JAK2 variant helps support a diagnosis of these MPNs, it does not distinguish between them. Because the variant is not always present, a negative result does not exclude the diagnosis. JAK2 exon 12, exon 13, exon 14 and exon 15 tests may be ordered to help diagnose cases in which PV is suspected but are negative for the JAK2 V617F variant. JAK2 exon 12, exon 13, exon 14 and exon 15 tests are often automatically initiated in the lab after a negative JAK2 V617F variant test, if ordered by a healthcare provider. This process is referred to as reflex testing.

CALR and MPL Gene Testing

Further investigation may be necessary by testing for pathogenic variants in the CALR and MPL genes. CALR and MPL variants may be detected in an individual diagnosed with ET or PMF but not in an individual with PV. Typically, these genes are tested following a negative JAK2 V617F variant result.

Qualitative vs Quantitative Testing

Some laboratories offer both qualitative and quantitative JAK2 V617F tests:

• A qualitative test expresses the result in terms of the presence (positive) or absence (negative) of a property or condition.
• A quantitative test expresses the results as a number and has been proposed for use in monitoring changes in the number of cells with the JAK2 V617F variant over time, which is purportedly useful in monitoring treatment effectiveness.

Refer to Coverage Limitations Section

For information about laboratory testing for hematological malignancies not addressed in this policy, please see the following:

Testing Methodology

• Comparative genomic hybridization/chromosomal microarray analysis
• Comprehensive molecular (genomic) profiling for Hematologic Malignancies and Solid Tumors
• Genetic testing of single genes (e.g., Multigene panel)

For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy:

• DNA banking or preservation
• General population screening
• Individual 17 years of age or younger for adult-onset conditions
• Interpretation and reporting for molecular pathology procedure
• Polygenic risk score (PRS) and single nucleotide polymorphisms (SNPs)
• Repeat germline or somatic genetic testing
• Retrieved archival tissue

Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis

Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 4 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Coverage Determination

Any state mandates for JAK2 V617F, Exon 12 to 15, CALR and MPL variant analysis take precedence over this medical coverage policy.

Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding plan coverage.

Apply General Criteria for Genetic and Pharmacogenomics Tests when disease- or gene-specific criteria are not available on a medical coverage policy. For information regarding general criteria for genetic and pharmacogenomics tests, please refer to Genetic Testing Medical Coverage Policy.

JAK2 V617F Genetic Testing

Humana members may be eligible under the Plan for qualitative JAK2 V617F genetic testing (81270) when the following criteria are met:

• Meets laboratory values established by World Health Organization (WHO) diagnostic criteria for myeloproliferative neoplasm (essential thrombocythemia [ET], polycythemia vera [PV] or primary myelofibrosis [PMF]); AND
• Philadelphia chromosome (BCR-ABL) testing is negative

JAK2 Exon 12 to 15 Genetic Testing

Humana members may be eligible under the Plan for qualitative JAK2 exon 12, JAK2 exon 13, JAK2 exon 14 and/or JAK2 exon 15 genetic testing (81279) (e.g., JAK2 Exons 12 to 15 Sequencing, Mayo Clinic [0027U]) when the following criteria are met:

• Meets laboratory values established by WHO diagnostic criteria for PV; AND
• Philadelphia chromosome (BCR-ABL) testing is negative; AND
• Qualitative JAK2 V617F testing is negative

CALR and MPL Genetic Testing

Humana members may be eligible under the Plan for qualitative CALR (81219) and MPL (81338, 81339) genetic testing when the following criteria are met:

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis
Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 5 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• Meets laboratory values established by WHO diagnostic criteria for ET or PMF; AND
• Philadelphia chromosome (BCR-ABL) testing is negative; AND
• Qualitative JAK2 V617F testing is negative

Coverage Limitations

Humana members may NOT be eligible under the Plan for JAK2 V617F genetic testing, including exons 12, 13, 14 and 15, CALR and MPL gene testing for any indications other than those listed. This is considered experimental/investigational as it is not identified as widely used and generally accepted for any other proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for quantitative JAK2 V617F genetic testing. This is considered experimental/investigational as it is not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for JAK2 exons 12, 13, 14 and 15 genetic testing for any of the following indications or methodologies:

• JAK2 V617F test result is positive or assessed quantitatively; OR
• Quantitative assessment of JAK2 exons 12, 13, 14 and 15

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Humana members may NOT be eligible under the Plan for CALR and MPL gene testing for any of the following indications or methodologies:

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis
Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 6 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

• JAK2 V617F test result is positive or assessed quantitatively; OR
• JAK2 exons 12, 13, 14 or 15 test result is positive or assessed quantitatively; OR
• Quantitative assessment of CALR and MPL

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Additional Information

Additional information about myeloproliferative neoplasms may be found from the following websites:

Background

• National Cancer Institute
• National Comprehensive Cancer Network
• National Library of Medicine

Additional information about essential thrombocythemia, polycythemia vera and primary myelofibrosis may be found from the following websites:

• National Heart, Lung, and Blood Institute
• National Library of Medicine

Medical Alternatives

Physician consultation is advised to make an informed decision based on an individual’s health needs.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure.

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis
Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 7 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled.

Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

CPT® Category III Code(s)

Description

Comments

No code(s) identified

HCPCS Code(s)

Description

Comments

No code(s) identified

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis

Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 8 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

References

1. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018; 8(2):15. https://www.ncbi.nlm.nih.gov/pmc/articles. Accessed July 17, 2023.
2. ECRI Institute. ECRIgene (ARCHIVED). Ipsogen JAK2 RGQ PCR (Qiagen Gmbh) for informing diagnosis of myeloproliferative neoplasms. https://www.ecri.com. Published October 2018. Accessed July 4, 2023.
3. Hayes, Inc. Clinical Utility Evaluation. Genetic testing for the diagnosis and treatment monitoring of primary myelofibrosis (PMF). https://evidence.hayesinc.com. Published April 12, 2018. Updated June 17, 2022. Accessed July 4, 2023.
4. Hayes, Inc. Clinical Utility Evaluation. Genetic testing for the diagnosis and treatment of polycythemia vera (PV). https://evidence.hayesinc.com. Published April 2, 2018. Updated June 17, 2022. Accessed July 4, 2023.
5. Hayes, Inc. Clinical Utility Evaluation. Genetic testing for the diagnosis of essential thrombocytophenia (ET). https://evidence.hayesinc.com. Published April 2, 2018. Updated June 17, 2022. Accessed July 4, 2023.
6. Hayes, Inc. Genetic Test Evaluation (GTE) Synopsis (ARCHIVED). Myeloproliferative leukemia virus oncogene (MPL) testing in myeloproliferative neoplasms (MPN). https://evidence.hayesinc.com. Published December 5, 2011. Accessed July 4, 2023.
7. MCG Health. Myeloproliferative neoplasms – CALR gene. 27th edition. https://www.mcg.com. Accessed July 4, 2023.
8. MCG Health. Myeloproliferative neoplasms – JAK2 gene. 27th edition. https://www.mcg.com. Accessed July 4, 2023.

1. Myeloproliferative neoplasms – MPL gene. 27th edition. https://www.mcg.com. Accessed July 4, 2023.

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis
Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 9 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

10. National Cancer Institute (NCI). Chronic myeloproliferative neoplasms treatment (PDQ) – health professional version. https://www.cancer.gov. Updated November 4, 2020. Accessed July 5, 2023.
11. National Comprehensive Cancer Network (NCCN). NCCN Biomarkers Compendium. CALR, JAK2, MPL. https://www.nccn.org. Updated 2023. Accessed July 5, 2023.
12. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Myeloproliferative neoplasms. https://www.nccn.org. Updated May 19, 2023. Accessed July 5, 2023.
13. UpToDate, Inc. Approach to the patient with thrombocytosis. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
14. UpToDate, Inc. Clinical manifestations and diagnosis of polycythemia vera. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
15. UpToDate, Inc. Clinical manifestations and diagnosis of primary myelofibrosis. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
16. UpToDate, Inc. Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS). https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
17. UpToDate, Inc. Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
18. UpToDate, Inc. Diagnostic approach to the patient with erythrocytosis/polycythemia. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
19. UpToDate, Inc. Molecular pathogenesis of congenital erythrocytoses and polycythemia vera. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
20. UpToDate, Inc. Overview of the myeloproliferative neoplasms. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
21. UpToDate, Inc. Pathogenetic mechanisms in primary myelofibrosis. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
22. UpToDate, Inc. Prognosis and treatment of essential thrombocythemia. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
23. UpToDate, Inc. Prognosis and treatment of polycythemia vera and secondary polycythemia. https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.
24. UpToDate, Inc. Prognosis of primary myelofibrosis.https://www.uptodate.com. Updated June 2023. Accessed July 4, 2023.

Janus Kinase 2 (JAK2), Calreticulin (CALR) and Myeloproliferative Leukemia (MPL) Variant Analysis
Effective Date: 12/14/2023
Revision Date: 12/14/2023
Review Date: 07/27/2023
Policy Number: HUM-0513-019
Page: 11 of 11

Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version.

Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

Appendix A

World Health Organization Diagnostic Criteria for Myeloproliferative Neoplasm: Laboratory Values