JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms
DESCRIPTIONMyeloproliferative 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:
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.
POLICYJAK2 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:
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.
Investigative service is defined as the use of any treatment procedure, facility, equipment, drug, device or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member’s specific benefit plan language.
POLICY HISTORY04/16/2010: 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.
SOURCESBlue Cross Blue Shield Association Policy # 2.04.60
CODE REFERENCEThis 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.