Medical Policy: 02.04.61
Original Effective Date: August 2016
Reviewed: August 2017
Revised: August 2017
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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.
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 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 subclassify 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.
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.
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.
PV – Major criteria: presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation
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).
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
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.
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
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.
Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
Diagnosis of overt PMF requires meeting all 3 major criteria, and at least 1 minor criterion
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.
Molecular testing for the JAK2 V617F mutation in individuals with 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 mutations are considered not medically necessary in all other circumstances including, but not limited to, the following situations:
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:
MPL and CALR exon mutation testing is considered not medically necessary in all other circumstances including, but not limited to, the following situations:
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.
National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: myelodysplastic syndromes.
UpToDate, Inc. Molecular pathogenesis of congenital polycythemic disorders and polycythemia vera.
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