Medical Policy: 02.04.61 

Original Effective Date: August 2016 

Reviewed: August 2018 

Revised: August 2018 

 

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.

 

Description:

This policy addresses the use of JAK2, MPL, and CALR mutation testing for diagnosis, prognosis, and treatment selection in patients with myeloproliferative neoplasms. This policy also will address the potential use of mutations in the diagnosis or selection of treatment in patients with other conditions, including Down syndrome and acute lymphoblastic leukemia.

 

Myeloproliferative neoplasms (MPNs) are uncommon overlapping blood diseases characterized by the production of one or more blood cells and includes chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis, chronic eosinophilic leukemia, and others.

 

Diagnosis of the various classic forms of myeloproliferative neoplasms has been most recently based on a complex set of clinical, pathological and biological criteria first introduced by the Polycythemia Vera Study Group (PVSG) in 1996 or the World Health Organization (WHO) in 2001, updated in 2008 and again in 2016. Both of these classifications use a combination of clinical, pathological and/or biological criteria to arrive at a definitive diagnosis. Varying combinations of these criteria are used to determine if a patient has PV, ET or PMF. An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.

 

Early reports suggested that specificity was 100% although sensitivity was variable (as high as 97% in patients with PV but only 30% to 50% in patients with ET or PMF). A result of the extraordinary specificity observed was that in the setting of evaluating a patient with a suspected Philadelphia Chromosome negative MPN, the predictive value of a positive test also approached 100%. It was recognized within months of the discovery of this mutation, that JAK2V617F (Exon 13) testing could dramatically expedite diagnosis by reducing the need for complex work-ups of secondary or reactive causes of the observed proliferative process in the JAK2V617F positive patients.

 

Two important caveats should be noted in use of this test. A negative result cannot be used to rule out a classic MPN. A positive result is excellent evidence that a classic MPN is present but alone is insufficient to sub classify the disease category present.

 

Although there has been great interest in the use of the JAK2 V617F test as a front-line diagnostic test in the evaluation of myeloproliferative patients, there also has been a growing effort to link the presence of this mutation and the quantitative measurement of its allele burden with clinical features and biological behavior. Unfortunately, due to differences in disease definitions, differences in methods of testing, differences in sample type (bone marrow versus circulating blood cells), and differences in study design, the literature in this area is conflicting and inconclusive.

 

CALR/MPL Testing

This testing provides an analysis of the mutational status of exon 9 of the CALR gene. The test targets patients in whom essential thrombocythemia or myelofibrosis is suspected and who have tested negative for the mutation in JAK2 V617F.

 

MPL (myeloproliferative leukemia virus oncogene homology) belongs to the hematopoietin superfamily and enables its ligand, thrombopoietin, to facilitate both global hematopoiesis and megakaryocyte growth and differentiation. MPL W515 mutations are present in patients with primary myelofibrosis (PMF) and essential thrombocythemia (ET) at a frequency of approximately 5% and 1%, respectively. The S505 mutation is detected in patients with hereditary thrombocythemia.

 

Diagnosis of Nonclassic Forms of MPNs

Although the most common Ph-negative MPNs include what are commonly referred to as classic forms of this disorder (PV, ET, PMF), rare 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 mutations in some of these cases. Due to the paucity of data about the significance of JAK2 V617F or MPL mutations in these disease settings, testing in patients with these diseases should not currently be seen as the standard of care.

 

In recognition of the value of use of this new marker in refining the diagnostic work-up of patients suspected to have Philadelphia-negative MPNs, several reports recommending new algorithms for diagnosis were published. The 2001 WHO criteria were revised in 2008 to reflect incorporation of the test in patient work-up.

 

WHO Criteria for MPN (2016)

Polycythemia Vera (PV)

PV – Major criteria: presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation

 

WHO PV 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 (RCM)
  2. BM 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

 

WHO PV minor criterion

Subnormal serum erythropoietin level

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

*More than 25% above mean normal predicted value.

Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels >18.5 g/dL in men (hematocrit, 55.5%) or >16.5 g/dL in women (hematocrit, 49.5%) if major criterion 3 and the minor criterion are present. However, initial myelofibrosis (present in up to 20% of patients) can only be detected by performing a BM biopsy; this finding may predict a more rapid progression to overt myelofibrosis (post-PV MF).

 

Essential Thrombocythemia (ET)

ET- Major Criteria: demonstration of JAK2V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis

WHO ET major criteria
  1. Platelet count ≥450 × 109/L
  2. BM 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

 

WHO ET minor criterion

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

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

 

Primary Myelofibrosis (PMF)

PMF- Major criteria: Demonstration of JAK2V617F or other clonal marker (e.g. MPLW515K or MPLW515L) or in the absence of a clonal marker, no evidence of bone marrow fibrosis due to underlying inflammatory or other neoplastic disease.

 

WHO prePMF 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, or absence of minor reactive BM reticulin fibrosis

 

WHO prePMF minor criteria

Presence of at least 1 of the following, confirmed in 2 consecutive determinations:

  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

 

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

 

In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.

 

Minor (grade 1) reticulin fibrosis secondary to infection, autoimmune disorder or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

 

WHO overt PMF criteria

WHO overt PMF 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, or absence of reactive myelofibrosis

 

WHO overt PMF minor criteria

Presence of at least 1 of the following, confirmed in 2 consecutive determinations:

  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

 

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

 

In the absence of any of the 3 major clonal mutations, the search for the most frequent accompanying mutations (eg, ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.

 

BM fibrosis secondary to infection, autoimmune disorder, or other chronic inflammatory conditions, hairy cell leukemia or other lymphoid neoplasm, metastatic malignancy, or toxic (chronic) myelopathies.

 

More than a dozen commercial laboratories currently offer a wide variety of diagnostic procedures for JAK2 testing. These tests are available as laboratory developed procedures under the U.S. Food and Drug Administration (FDA) enforcement discretion policy for laboratory developed tests.

 

Prior Approval:

Not applicable

 

Policy:

Molecular testing for the JAK2 V617F (exon 13) mutation in individuals with suspected polycythemia vera (PV), essential thrombocytopenia (ET) and primary myelofibrosis (PMF) testing is considered medically necessary to confirm diagnosis of these diseases, based on criteria established by the World Health Organization (WHO).

 

JAK2 V617F (exon 13) mutations testing are considered not medically necessary in all other circumstances including, but not limited to, the following situations:

  • Diagnosis of non-classic forms of MPNs
  • Monitoring, management, or selecting treatment in patients with MPNs
  • Diagnosis or selection of treatment in patients with Down Syndrome and acute lymphoblastic leukemia (ALL)

 

JAK2 (exon 12, 14, and 15) MPL and CALR exon 9 mutations are considered medically necessary for the diagnosis of ET, PMF, and PV when ALL of the following conditions are met:

  • Genetic testing would impact medical management.
  • Criteria for JAK2 V617F are met.
  • JAK2 V617F mutation analysis was previously completed and was negative.

 

JAK2 (exon 12, 14, and 15), MPL and CALR exon mutation testing  is considered not medically necessary in all other circumstances including, but not limited to, the following situations:

  • Diagnosis of non-classic forms of MPNs
  • Monitoring, management, or selecting treatment in patients with MPNs
  • Diagnosis or selection of treatment in patients with Down Syndrome and acute lymphoblastic leukemia (ALL)

 

Procedure Codes and Billing Guidelines:

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

  • 81219 CALR (calreticulin) (eg, myeloproliferative disorders), gene analysis, common variants in exon 9
  • 81270 Jak2 (Janus Kinase 2) (e.g., myeloproliferative disorder) gene analysis, p.val617phe (v617f) variant
  • 0017U Oncology (hematolymphoid neoplasia), JAK2 mutation, DNA, PCR amplification of exons 12-14 and sequence analysis, blood or bone marrow, report of JAK2 mutation not detected or detected
  • 0027U Jak2 (Janus Kinase 2) gene analysis, targeted sequence analysis exons 12-15
  • 81402 Molecular Pathology Procedure Level 3 (Used for MPL)
  • 81403 Molecular Pathology Procedure Level 4 (Used for JAK2 exons)

 

Selected References:

  • Verstovsek S, Kantarjian H, Mesa RA et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 2010; 363(12):1117-27
  • Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood 2009; 114: 937-951.
  • Tefferi A, Thiele J and Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: Order out of chaos. Cancer, September 2009; 115(17): 3842-3847.
  • Bench AJ, White HE, Foroni L et al. Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol 2013; 160(1):25-34.
  • Gaikwad A, Rye CL, Devidas M, et al. Prevalence and clinical correlates of JAK2 mutations in Down syndrome acute lymphoblastic leukaemia. Br J Haematol. Mar 2009;144(6):930-932. PMID 19120350
  • Fantasia F, Di Capua EN, Cenfra N, et al. A highly specific q-RT-PCR assay to address the relevance of the JAK2WT and JAK2V617F expression levels and control genes in Ph-negative myeloproliferative neoplasms. Ann Hematol. Oct 31 2013. PMID 24173087
  • Furtado LV, Weigelin HC, Elenitoba-Johnson KS, et al. Detection of MPL mutations by a novel allele-specific PCR-based strategy. J Mol Diagn. Nov 2013;15(6):810-818. PMID 23994117
  • Tefferi A, Lasho TL, Finke CM, et al: CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia advance online publication 21 January 2014
  • Rumi E, Pietra D, Ferretti V, et al: JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Published online before print December 23, 2013
  • Nangalia J, Massie CE, Baxter EJ, et al: Somatic CALR mutation in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013;369:2391-2405
  • Baxter EJ, Scott LM, Campbell PJ, et al: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 2005 March 16;365(9464):1054-1061
  • James C, Ugo V, Le Couedic JP, et al: A unique clonal JAK2 mutation leading to constitutive signaling causes polycythaemia vera. Nature 2005 April 28;434(7037):1144-114
  • Steensma DP, Dewald GW, Lasho TL, et al: The JAK2 V617F activating tyrosine kinase mutation is an infrequent event in both "atypical" myeloproliferative disorders and the myelodysplastic syndrome. Blood 2005;106:1207-1209
  • Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. Mar 1 2012;366(9):787-798. PMID 22375970
  • Arber D., Orazi A., Hasserjian R., et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391-2405.
  • Bain BJ, Ahmad S. Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities? Br J Haematol. 2014;166(6): 809-817.
  • National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: myelodysplastic syndromes.
  • UpToDate, Inc. Molecular pathogenesis of congenital polycythemic disorders and polycythemia vera.
  • Genetic Home Reference. A service of the U.S. National library of Medicine. JAK2. 2014.
  • National Comprehensive Cancer Network (NCCN). NCCN Clinical Practie Guidelines in Oncology: Myeloproliferative neoplasms. Version.2.2018.

 

Policy History:

  • August 2018 - Annual Review, Policy Revised
  • August 2017 - Annual Review, Policy Revised
  • August 2016 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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