Description of Procedure or Service

Myeloproliferative neoplasms (MPN) are a heterogeneous group of clonal disorders characterized by overproduction of one or more differentiated myeloid lineages (Grinfeld, Nangalia, & Green, 2017). These include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The majority of MPN result from somatic mutations in the 3 driver genes, JAK2, CALR, and MPL, which represent major diagnostic criteria in combination with hematologic and morphological abnormalities (Rumi & Cazzola, 2017).

Myeloproliferative neoplasms arise from somatic mutation in hematopoietic stem cell (HSC) that clonally expand resulting in single or multilineage hyperplasia (Vainchenker & Kralovics, 2017). They are relatively rare affecting 0.84 (PV), 1.03 (ET), and 0.47(PMF) people per 100,000 worldwide (Titmarsh et al., 2014), however these may not be reflective of its true incidence due to the high heterogeneity of MPN.

Clinically, MPN share features of bone marrow hypercellularity, increased incidence of thrombosis or hemorrhage, and an increased rate of transformation to acute myeloid leukemia (Grinfeld et al., 2017). In the majority of cases, abnormalities in cytokine signaling pathways are a common factor, and most commonly lead to increased JAK-STAT signaling (Grinfeld et al., 2017). PV is characterized by erythrocytosis with suppressed endogenous erythropoietin production, bone marrow panmyelosis, and JAK2 mutation leading to constitutive activation. ET is defined by thrombocytosis, bone marrow megakaryocytic proliferation, and presence of JAK2, CALR, or MPL mutation. PMF is characterized by bone marrow megakaryocytic proliferation, reticulin and/or collagen fibrosis, and presence of JAK2, CALR, or MPL mutation(Rumi & Cazzola, 2017). Mutations in other genes involved in signal transduction (CBL, LNK/SH2B3), chromatin modification (TET@, EZH2, IDH1/2, ASXL1, DNM3TA), RNA splicing (SF3B1, SRSF2, U2AF1), and tumor suppressor function (TP53) have also been reported(NCCN, 2018).

The significance of JAK2, MPL, CALR, and other mutations in the genesis of the MPNs as well as their relative roles in determining disease phenotype in these disorders are unclear(Tefferi, 2018), however integrated genomic analyses suggest that regardless of diagnosis or JAK2 mutational status, are characterized by upregulation of JAK-STAT target genes, demonstrating the central importance of this pathway in the pathogenesis of the MPNs (Rampal et al., 2014) and lead to development of novel JAK2 therapeutics (Silvennoinen & Hubbard, 2015). Thus, mutation analysis at the time of diagnosis has value for determining prognosis as well as individual risk assessment and guide treatment-making decisions (Hussein, Granot, Shpilberg, & Kreipe, 2013; Tefferi, 2018).

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician.

Policy

BCBSNC will provide coverage for JAK2, CALR, or MPL Mutation Analysis in Myeloproliferative Neoplasms when it is determined to be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy.

When JAK2, CALR, or MPL1 Mutation Analysis is covered

1. JAK2, CALR or MPL mutation testing is considered medically necessary for the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting classic forms of myeloproliferative neoplasms (MPN), that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF) when ordered by a hematology and/or oncology specialist.
   1. Patients suspected to have polycythemia vera (PV) should first be tested for the most common finding JAK2V617F. If testing is negative, further testing to detect other JAK2 tyrosine kinase mutations, eg, in exon 12, is considered medically necessary. For patients suspected to have PV, JAK2 mutation testing is considered medically necessary only if one of the following testing criteria are met:
      1. Hemoglobin >16.5 g/dL in men; Hemoglobin >16.0 g/dL in women, or Hematocrit >49% in men; Hematocrit >48% in women, on two separate occasions or
         
         Increased red cell mass (More than 25% above mean normal predicted value), and no other known cause of erythrocytosis, or
         
         
      2. Bone marrow biopsy showing hypercellularity for age with trilineage hyperplasia including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
   2. Patients suspected to have essential thrombocythemia (ET) should first be tested for JAK2 mutations. If testing is negative, further testing to detect CALR and MPL mutations is considered medically necessary. For patient suspected to have ET, testing for JAK2, CALR and MPL mutations is considered medically necessary only if one of the following testing criteria are met:
      1. Platelet count ≥450 × 10⁹ /L greater than 3 months or
      2. Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.
   3. Patients suspected to have primary myelofibrosis (PMF) should first be tested for JAK2 mutations. If testing is negative, further testing to detect CALR and MPL mutations is considered medically necessary. For patient suspected to have PMF, testing for JAK2, CALR and MPL mutations is considered medically necessary if any the following testing criteria are met:
      1. Patient has demonstrated leukocytosis of greater or equal to 11 x 10 (9) on two separate occasions in the absence of other conditions that can cause leukocytosis or
      2. Enlarged spleen or
      3. BM biopsy shows megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis or
      4. BM biopsy shows presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
2. JAK2 mutation testing is considered medically necessary in individuals diagnosed with Budd-Chiari Syndrome.

When JAK2, CALR, or MPL1 Mutation Analysis is not covered

JAK2 tyrosine kinase, CALR, and MPL mutation testing is considered investigational in all other cases.

Policy Guidelines

Applicable State/Federal Regulations

On March 27, 2017 the FDA approved ipsogen^® JAK2 RGQ PCR KIT (FDA, 2017) to detect Janus Tyrosine Kinase 2 (JAK2) gene mutation G1849T (V617F) with an allele-specific, quantitative, polymerase chain reaction (PCR) using an amplification refractory mutation system (ARMS). This is the first FDA-authorized test intended to help physicians in evaluating patients for suspected Polycythemia Vera (PV).

The device marketing authorization was based on data from a clinical study of 216 suspected patients with PV. The study compared results from the ipsogen JAK2 RGQ PCR Kit to results obtained with Sanger sequencing according to the WHO criteria for evaluating a patient for PV. The study found that the ipsogen JAK2 RGQ PCR Kit test detected PV with 94.6 percent sensitivity and 98.1 percent specificity (FDA, 2017).

Guidelines and Recommendations

World Health Organization

The 2016 edition of the World Health Organization’s classification of myeloid neoplasm and acute leukemia proposed the following criteria for the diagnosis of PV, ET and PMF (Arber et al., 2016).

WHO Criteria for PV

Diagnosis of PV requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion:

Major Criteria:

1. Hemoglobin >16.5 g/dL in men; Hemoglobin >16.0 g/dL in women, or Hematocrit >49% in men; Hematocrit >48% in women, or Increased red cell mass (More than 25% above mean normal predicted value)
2. Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (differences in size)
3. Presence of JAK2V617F or JAK2 exon 12 mutation

Minor Criteria:

Subnormal serum erythropoietin level

WHO Criteria for ET

Diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria and the minor criterion:

Major Criteria:

1. Platelet count ≥450 × 109 /L
2. Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers
3. Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
4. Presence of JAK2, CALR, or MPL mutation

Minor Criteria:

Presence of a clonal marker or absence of evidence for reactive thrombocytosis

WHO Criteria for PrePMF

Diagnosis of prePMF requires meeting all 3 major criteria, and at least 1 minor criterion:

Major Criteria:

1. Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis
2. Not meeting the WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms
3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker (e.g. ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1), or absence of minor reactive BM reticulin fibrosis

Minor Criteria:

1. Anemia not attributed to a comorbid condition
2. Leukocytosis ≥11 × 10⁹/L
3. Palpable splenomegaly
4. LDH increased to above upper normal limit of institutional reference range

WHO Criteria for Overt PMF

Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion

Major Criteria:

1. Presence of megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
2. Not meeting WHO criteria for ET, PV, BCR-ABL1+ CML, myelodysplastic syndromes, or other myeloid neoplasms
3. Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker (e.g. ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1), or absence of reactive myelofibrosis

Minor Criteria:

1. Anemia not attributed to a comorbid condition
2. Leukocytosis ≥11 × 10⁹/L
3. Palpable splenomegaly
4. LDH increased to above upper normal limit of institutional reference range
5. Leukoerythroblastosis

National Comprehensive Cancer Network

The NCCN Guidelines Version 2.2018 for Myeloproliferative Neoplasms (NCCN, 2018) recommends “molecular testing for JAK2 V617F mutation; if negative test for CALR and MPL (for patients with ET and MF) and JAK Exon 12 mutations (for patients with PV). Prognostic models incorporating other mutations have been proposed to identify patients who may be at risk of leukemic transformation. The role of next generation sequencing to identify high risk mutations and the use of the Molecular International Prognostic Scoring System (MIPSS) is less well established. NGS remains a research tool in many situations. However, it may be useful to establish clonality in selected circumstances.”

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Applicable service codes: 81175, 81176, 81219, 81270, 81402, 81403, 81450, 81455

BCBSNC may request medical records for determination of medical necessity. When medical records are requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Arber, D. A., Orazi, A., Hasserjian, R., Thiele, J., Borowitz, M. J., Le Beau, M. M., . . . Vardiman, J. W. (2016). The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood, 127(20), 2391-2405. doi:10.1182/blood-2016-03-643544

FDA. (2017). Approved Drugs - Ipsogen JAK2 RGQ PCR Kit (WebContent). from Center for Drug Evaluation and Research https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm551474.htm

Grinfeld, J., Nangalia, J., & Green, A. R. (2017). Molecular determinants of pathogenesis and clinical phenotype in myeloproliferative neoplasms. Haematologica, 102(1), 7-17. doi:10.3324/haematol.2014.113845

Hussein, K., Granot, G., Shpilberg, O., & Kreipe, H. (2013). Clinical utility gene card for: familial polycythaemia vera. Eur J Hum Genet, 21(6). doi:10.1038/ejhg.2012.216

NCCN. (2018). NCCN Clinical Practice Guidelines in Oncology; Myeloproliferative Neoplasms v2.2018. https://www.nccn.org/professionals/physician_gls/default.aspx

Rampal, R., Al-Shahrour, F., Abdel-Wahab, O., Patel, J. P., Brunel, J. P., Mermel, C. H., . . . Levine, R. L. (2014). Integrated genomic analysis illustrates the central role of JAK-STAT pathway activation in myeloproliferative neoplasm pathogenesis. Blood, 123(22), e123-133. doi:10.1182/blood-2014- 02-554634

Rumi, E., & Cazzola, M. (2017). Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood, 129(6), 680-692. doi:10.1182/blood-2016-10-695957

Silvennoinen, O., & Hubbard, S. R. (2015). Molecular insights into regulation of JAK2 in myeloproliferative neoplasms. Blood, 125(22), 3388-3392. doi:10.1182/blood-2015-01-621110

Tefferi, A. (2018). Overview of the myeloproliferative neoplasms - UpToDate. In A. Rosmarin (Ed.), UpToDate. Retrieved from https://www.uptodate.com/contents/overview-of-themyeloproliferativeneoplasms?search=myeloproliferative%20disorders&usage_type=default&source=search_result &selectedTitle=1~150&display_rank=1#H15.

Titmarsh, G. J., Duncombe, A. S., McMullin, M. F., O'Rorke, M., Mesa, R., De Vocht, F., . . . Anderson, L. A. (2014). How common are myeloproliferative neoplasms? A systematic review and metaanalysis. Am J Hematol, 89(6), 581-587.

Vainchenker, W., & Kralovics, R. (2017). Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms. Blood, 129(6), 667-679. doi:10.1182/blood-2016-10-695940

Policy Implementation/Update Information

1/1/2019 New policy developed. BCBSNC will provide coverage for JAK2, CALR, MPL mutation analysis in myeloproliferative neoplasms when it is determined to be medically necessary and criteria are met. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (lpr)