| Coverage Policy Manual | |
| Policy #: | 2009037 |
| Category: | Laboratory |
| Initiated: | September 2009 |
| Last Review: | June 2023 |
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| Genetic Test: JAK2, MPL, and CALR Testing for Myeloproliferative Disorders | |
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| Description: |
Myeloproliferative neoplasms (MPNs) are a category of uncommon overlapping blood diseases characterized by the production of one or more blood cells. The most common forms of MPNs include chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). A common finding in many MPNs is clonality and a central pathogenic feature is detection of a somatic (acquired) pathogenic variant in disease-associated genes. Pathogenic variants in disease-associated genes result in constitutively activated tyrosine kinase enzyme or cell surface receptor.
The paradigm for use of this information to revolutionize patient management is CML. A unique chromosomal translocation t(9;22) (the Philadelphia chromosome) leads to a unique gene rearrangement (BCR-ABL) creating a fusion gene that encodes for a constitutively active Bcr-abl fusion protein. These findings led to the development of a targeted tyrosine kinase inhibitor drug treatment (imatinib) that produces long-lasting remissions. 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 JAK V617F variants in some of these cases (Jones, 2005). The remainder of this evidence review focuses only on the non-Ph or Ph-negative MPNs and genetic testing for JAK2, CALR, and MPL.
Diagnosis and monitoring of patients with Philadelphia chromosome-negative MPNs have been challenging because many of the laboratory and clinical features of the classic forms of these disease 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 morphologic bone marrow exam, and diagnosis can be complicated by changing disease patterns: PV and ET can evolve into PMF or undergo leukemic transformations. A complex set of clinical, pathologic, and biologic criteria was first introduced by the Polycythemia Vera Study Group in 1996 and by the World Health Organization (WHO) as a benchmark for diagnosis in 2002 and updated in 2008 and 2016 (Murphy, 1997; Pearson, 1996; Vardiman, 2002; Vardiman, 2009; Arber, 2016). Applying these criteria has been challenging because they involve complex diagnostic algorithms, rely on morphologic assessment of uncertain consistency, and require tests that are not well-standardized or widely available, such as endogenous erythroid colony formation. An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.
Varying combinations of these criteria are used to determine whether a patient has PV, ET, or PMF, ie, MPNs that are Ph-negative. An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.
Although the most common Ph-negative MPNs include what is 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 variants in some of these cases (Jones, 2005).
The JAK2 gene, located on chromosome 9, contains the genetic code for making the Janus kinase 2 protein, a nonreceptor tyrosine kinase. The Janus kinase 2 (JAK2) protein is part of the JAK/signal transduction pathway and activators of transcript (STAT) proteins that are important for the controlled production of blood cells from hematopoietic cells. Somatic (acquired) variants in the JAK2 gene are found in patients with PV, ET, and PMF (NIH Genetic Home Reference, 2014).
In 2005, 4 separate groups using different modes of discovery and different measurement techniques reported the presence of a novel somatic (acquired) single nucleotide variant in the conserved autoinhibitory pseudokinase domain of the gene coding for the gene coding Janus kinase 2 (JAK2) protein in patients with classic MPNs. The single nucleotide variant caused a valine-to-phenylalanine leading to a novel somatic gain-of-function single nucleotide variant that resulted in the loss of autoinhibition of the JAK2 tyrosine kinase. JAK2V617F is a constitutively activated kinase that recruits and phosphorylates 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.
The JAK2 V617F variant was present in blood and bone marrow from a variable portion of patients with classic BCR-ABL-negative (ie, Ph-negative) MPNs including 65% to 97% of patients with PV, 23% to 57% with ET, and 35% to 56% with PMF. The variant was initially reported to be absent in all normal subjects and patients with secondary erythrocytosis, although very low levels of cells carrying the variant have been reported in a small subset of healthy individuals (Baxter, 2005; Jones, 2005; Levine, 2005; James, 2005; Kralovics, 2005; Tefferi, 2005; Zhao, 2005; Campbell, 2005; Wolanskyj, 2005; Campbell, 2006; Tefferi, 2005; Xu, 2007; Sidon, 2006).
Although almost all studies were retrospective case series and/or cross-sectional studies, and although both the analytic and clinical performances appeared dependent on the laboratory method used to detect the variant, there has been consistency across studies in demonstrating that the JAK2 V617F variant is a highly specific marker for clonal evidence of an MPN.
Scott et al identified 4 somatic gain-of-function variants in JAK2 exon 12 in 10 of 11 PV patients without the JAK2 V617F variant (Scott, 2007). Patients with a JAK2 exon 12 variant differed from those with the JAK2 V617F variant, presenting at a younger age with higher hemoglobin levels and lower platelet and white cell counts. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin, and mice treated with transfected bone marrow transplants developed a myeloproliferative syndrome.
Findings have been confirmed by a number of investigators who identified additional variants with similar functional consequences in patients with PV and patients with idiopathic erythrocytosis (Pardanani, 2007; Siemiatkowska, 2010). Based on these findings, it has been concluded that the identification of JAK2 exon 12 variants provides a diagnostic test for JAK2 V617F-negative patients who present with erythrocytosis. Of note, different variants in the same gene appear to have different effects on signaling, resulting in distinct clinical phenotypes (Scott, 2007).
The MPLgene, located on chromosome 1, contains the genetic code for making the thrombopoietin receptor, a cell surface protein that stimulates the JAK/STAT signal transduction pathway. The thrombopoietin receptor is critical for the cell growth and division of megakaryocytes, which produce platelets involved in blood clotting. Somatic variants in the MPL gene are associated with ET and PMF.
The CALR gene, located on chromosome 19, contains the genetic code for making the calreticulin protein, a multifunctional protein located in the endoplasmic reticulum, cytoplasm, and cell surface. The calreticulin protein is thought to play a role in cell growth and division and regulation of gene activity. Somatic variants in the CALR gene are associated with ET and PMF.
Ph-negative MPNs are characterized by their molecular genetic alterations. The driver genes and somatic variants associated with specific Ph-negative MPNs are listed below (Cazzola, 2014).
A more recent retrospective study of patients observed at the National Research Center for Hematology (Moscow, Russia) from October 2016 to November 2020 assessed the frequency of detection of JAK2 V617F, CALR, and MPL mutations in a Russian cohort of patients with BCR/ABL1 rearrangement negative (ie, Ph-negative) MPNs (Makarik, 2021). Patients (N=1958) with a diagnosis of ET, PV, PMF, or MPN-unclassified were examined. Below is a summary of the driver genes and somatic variants associated with specific Ph-negative MPNs:
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. More than a dozen commercial laboratories currently offer a wide variety of diagnostic procedures for JAK2, CALR, and MPL testing under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Coding
Effective in 2012, there is a specific CPT code for JAK2V617F testing:
81270: JAK2 (Janus kinase 2) (e.g., myeloproliferative disorder) gene analysis, p.Val617Phe (V617F) variant.
If further JAK2 testing is performed, the following code might be reported:
81403: Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR [polymerase chain reaction] in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) – which includes JAK2 (Janus kinase 2) (e.g., myeloproliferative disorder), exon 12 sequence and exon 13 sequence, if performed
Effective August 1, 2017, there is a code specific to the University of Iowa’s JAK2 mutation test –
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
Effective 1/1/2021, a new CPT code for JAK2 was added:
81279 JAK2 (Janus kinase 2) (eg, myeloproliferative disorder) targeted sequence analysis (eg, exons 12 and 13)
The following CPT code is available for MPL testing:
81402: Molecular pathology procedure, Level 3 (e.g., >10 SNPs [single-nucleotide polymorphism], 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T cell receptor gene rearrangements, duplication/deletion variants 1 exon) – which includes MPL (myeloproliferative leukemia virus oncogene, thrombopoietin receptor TPOR) (e.g., myeloproliferative disorder), common variants (e.g., W515A, W515K, W515L, W515R)
Effective 1/1/2021, 2 new codes for MPL testing were added:
81338 MPL (MPL proto oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; common variants (eg, W515A, W515K, W515L, W515R)
81339 MPL (MPL proto oncogene, thrombopoietin receptor) (eg, myeloproliferative disorder) gene analysis; sequence analysis, exon 10
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Policy/ Coverage: |
Effective July 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
JAK2 testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting classic forms of myeloproliferative neoplasms (MPNs), that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF).
MPL and CALR testing meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting essential thrombocythemia (ET) or primary myelofibrosis (PMF).
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
JAK2, MPL, and CALR testing do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other circumstances including, but not limited to, the following:
For members with contracts without primary coverage criteria, JAK2, MPL, and CALR testing are considered investigational in all other circumstances including, but not limited to, the above criteria (listed as not meeting primary coverage criteria). Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to July 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
JAK2 tyrosine kinase and MPL mutation testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting classic forms of myeloproliferative disorders, that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF).
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
JAK2 tyrosine kinase and MPL mutation testing does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other circumstances including, but not limited to, the following:
For members with contracts without primary coverage criteria, JAK2 tyrosine kinase and MPL mutation testing in all other circumstances including, but not limited to, the above criteria (listed as not meeting primary coverage criteria) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to December 2020
JAK2 tyrosine kinase and MPL mutation testing meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the diagnosis of patients presenting with clinical, laboratory, or pathological findings suggesting classic forms of myeloproliferative disorders, that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF).
JAK2 tyrosine kinase and MPL mutation testing does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in all other circumstances including, but not limited to, the following:
For members with contracts without primary coverage criteria, JAK2 tyrosine kinase and MPL mutation testing in all other circumstances including, but not limited to, the above criteria (listed as not meeting primary coverage criteria) is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to August 2012
Testing for JAK2 Mutation for Myeloproliferative Disorders (Polycythemia vera, Essential thrombocythemia or Idiopathic myelofibrosis) does meet ABCBS Primary Coverage Criteria for Effectiveness
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| Rationale: |
Tyrosine Kinase Mutation Analysis and the Diagnosis of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms
Diagnosis of classic myeloproliferative neoplasms
Diagnosis of the various classic forms of myeloproliferative neoplasms (MPNs) 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 (Murphy, 1997; Pearson, 1996) or the World Health Organization (WHO) in 2001 (Vardiman, 2002). 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 polycythemia vera (PV), essential thrombocythemia (ET), or primary myelofibrosis (PMF): MPNs that are Philadelphia chromosome-negative. (An important component of the diagnostic process is a clinical and laboratory assessment to rule out reactive or secondary causes of disease.)
As noted in the Description section, some diagnostic methods (i.e., bone marrow microscopy) are not well-standardized, (Tefferi, 2009; Wilkins, 2008; Baxter 2005) and others (i.e., endogenous erythroid colony formation) are neither standardized nor widely available.
In March of 2005, a novel somatic gain-of-function point mutation was discovered in the conserved autoinhibitory pseudokinase domain of the Janus kinase 2 (JAK2) protein in patients with MPNs. The mutation was present in blood and bone marrow from a variable portion of patients with classic BCR-ABL-negative (i.e., Philadelphia chromosome-negative) MPNs including 65% to 97% of patients with PV, 23% to 57% with ET, and 35% to 56% with PMF . It was initially reported to be absent in all normal subjects and in patients studied with secondary erythrocytosis, (Baxter, 2005; Levine, 2005; James, 2005; Kravolics, 2005; Jones, 2005; Tefferi, 2005; Zhao, 2005; Campbell, 2005; Wolanskyj, 2005; Campbell, 2006; Tefferi, 2005) although recently very low levels of mutated cells have been reported to be found in a small subset of the healthy population (Xu, 2007; Sidon, 2006).
That the JAK2V617F-mutated protein was potentially causal for the disease was suggested by the demonstration that cell lines transfected with JAK2V617F could be maintained in culture for several weeks in the absence of growth factor and that dependency was restored by transduction of wild-type JAK2. In vivo, mice irradiated and then transplanted with bone marrow cells infected with retrovirus containing the mutation developed a myeloproliferative syndrome (James, 2005).
Although almost all studies reported were retrospective and/or cross-sectional case series and although both analytical and clinical performances appear dependent on the laboratory method used to detect the mutation, there has been impressive consistency across studies in demonstrating that the JAK2V617F mutation is a highly specific marker for clonal evidence of an MPN.
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 workups of secondary or reactive causes of the observed proliferative process in the JAK2V617F-positive patients (Steensma, 2006). 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.
In recognition of the value of use of this new marker in refining the diagnostic workup of patients suspected of having Philadelphia chromosome-negative MPNs, several reports recommending new algorithms for diagnosis were published (James, 2006) (McMullin, 2007). The 2001 World Health Organization (WHO) criteria were revised in 2008 to reflect incorporation of the test in patient workup (Tefferi, 2007; Vardiman, 2009).
It is important to note that the 2008 WHO revision represents expert consensus and is not based on independent validation of the 2008 criteria compared to earlier diagnostic criteria or on clinical outcomes. Since these previous criteria were themselves based on expert consensus alone, the importance of such comparative studies may be a moot point. However, 2 small cross-sectional comparative studies have been performed that evaluate JAK2V617F testing directly against previously established PVSG or WHO criteria.
In 2005, James et al. (James, 2006) compared PV diagnosed using WHO or PVSG criteria with a streamlined diagnostic approach for PV using a 2-step algorithm (elevated hematocrit and the presence of the JAK2V617F mutation). Although the study group was small (45 patients with a PVSG diagnosis of PV and 61 patients meeting WHO criteria), use of the 2-step algorithm resulted in a correct diagnosis in 96% (PVSG criteria) or 93% (WHO criteria) of patients with PV.
In 2008, Kondo et al. (Kondo, 2008) compared the 2001 WHO classification and the 2008 classification in a small study of 75 patients undergoing evaluation for MPN. Using the 2001 criteria, 57 patients were diagnosed with MPNs, including 16 with PV, 37 with ET, and 4 with PMF. Using the 2008 criteria, 59 patients were diagnosed with MPNs. The PV and PMF categories were in complete agreement. The 2008 criteria caused reclassification of 2 patients (1 with erythrocytosis and 1 with thrombocytosis) into the ET category.
Ongoing studies of new drugs targeted to treat the mutated tyrosine kinase in patients with MPN are expected to cast additional light on the functionality of the observed JAK2V617F mutation and are likely to contribute not only to refined treatment choices but to improved insight into the diagnostic role of this important marker.
Diagnosis of nonclassical forms of MPNs
While the most common Philadelphia-negative MPNs include what are commonly referred to as classic forms of this disorder (PV, ET, and PMF), patients may rarely show unusual manifestations of this proliferative hematopoietic disorder including nonclassical forms of MPNs such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have appeared that identify JAK2V617 F mutations in some of these cases (Jones, 2005; Steensma, 2005). There is a paucity of data about the significance or use of JAK2V617F or MPL mutations in these disease settings.
Other tyrosine kinase or related mutations
In 2007, Scott et al. (Scott, 2007) identified 4 somatic gain-of-function mutations in the JAK2 exon 12 section of 10 of 11 PV patients without the JAK2V617F mutation. Patients with a JAK2 exon 12 mutation differed from those with the JAK2V617F mutations, presenting at a younger age with higher hemoglobin levels and lower platelet and white cell counts. Erythroid colonies could be grown from their blood samples in the absence of exogenous erythropoietin, and mice treated with transfected bone marrow transplants developed a myeloproliferative syndrome.
Findings were subsequently confirmed by a number of investigators who identified additional mutations with similar functional consequences in patients with PV and in patients with idiopathic erythrocytosis (Pardanani, 2007; Pikman, 2006). Based on these findings, it was concluded that the identification of JAK2 exon 12 mutations provides a diagnostic test for JAK2V617F -negative patients who present with erythrocytosis. Of note, different mutations in the same gene appear to have different effects on signaling, resulting in distinct clinical phenotypes (Scott, 2007). This perhaps explains the surprise findings of a series of JAK2 mutations in patients with Down syndrome-associated acute lymphoblastic lymphoma (ALL).
In 2006, Pikman et al. (Pikman, 2006) surveyed JAK2 mutation-negative patients with suspected ET and PMF to determine if mutations in pathways complementary to Janus kinase 2 signaling could be identified. A mutation of the thrombopoietin receptor gene (MPL) at codon 515 (exon 10) causing a change from tryptophan to leucine (MPLW515L) was discovered.
Subsequent studies identified additional mutations including MPLS505N, MPLW515Ki, and MPLW515Kii in a small but growing number of patients with ET and PMF (Pardanani, 2006; Beer, 2008; Pancrazzi, 2008; Ruan 2010). While this mutation can be found in both JAK2V617F- positive and negative patients, it is of particular value in the latter in helping to establish a clonal basis of the observed disease process.
Similar to the observations made on the JAK2V617F-negative mutations involving exon 12, the MPL exon 10 mutations appeared to demonstrate an autoinhibitory role leading to receptor activation in the absence of thrombopoietin binding. Expression of the MPL allele resulted in cytokine-independent growth of 3 independent cell lines and transplantation of mice with bone marrow expressing this allele results in a distinctive myeloproliferative disorder (Pardanani, 2006).
Although the data sets are small, the JAK2 exon 12 and MPL exon 10 mutations are unique, appear to be associated with MPNs, and exhibit in vitro and murine model behavior consistent with a causative role in MPNs. The 2008 WHO criteria specifically cite testing for JAK2 exon 12 mutations in patients with suspected PV (presumably in patients who are JAK2V617F -negative), specifically cite testing for MPLW515L/Kin patients with PMF (presumably in patients who are JAK2V617F -negative), and suggest patients with ET be subject to testing for JAK2V617F or other clonal markers, such as MPL testing in patients with ET (see Policy Guidelines).
Mutations of JAK2 in acute lymphoblastic leukemias associated with Down syndrome
Children with Down syndrome have a 10- to 20-fold increased risk of developing acute leukemia. The mechanisms for this are unknown; the disease process appears to be exclusively B cell in origin. In 2007, Malinge et al. published a case report (Malinge, 2007) describing a novel JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic lymphoma (ALL). Speculating that this finding might relate to the role the JAK/signal transducer and activator of transcription (STAT) signaling pathway played in early B-cell development, Bercovich et al. (Bercovich, 2008) studied 88 patients with Down syndrome-acquired ALL for JAK2 mutations and compared these to 216 patients with sporadic ALL. Five mutant alleles were identified in 16 (18%) of the patients with Down syndrome, all at a highly conserved arginine residue (R683) on exon 16. These mutations immortalized primary mouse hematopoietic progenitor cells in vitro. Only a single non-Down syndrome patient exhibited this mutation, and this patient was found to have an isochromosome 21Q. This finding was subsequently confirmed by Gaikwad et al. (Gaikwad, 2009) who found that 20% of patients with Down syndrome with ALL exhibited a point mutation at this location . The role of this abnormality and efforts to consider treatment modifications based on its finding remain subject to future study
Molecular profiling – phenotype/genotype associations and impact on prognosis
While there has been great interest in the use of the JAK2V617F test as a front-line diagnostic test in the evaluation of myeloproliferative patients, there has also 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.
Since the vast majority of patients with PV do exhibit the mutation, attention has been focused in this disease on differences in its presence in the homozygous versus heterozygous state and on whether allele burden correlates with clinical or laboratory features, Studies have suggested a range of findings including association of homozygous states with older age, higher hemoglobin level at diagnosis, leukocytosis, more frequent pruritus, increased incidence of fibrotic transformation, and larger spleen volumes. (38, 39) Studies that compare quantitative measurements of allele burden with disease manifestations have demonstrated both a positive and a lack of association with thrombosis, fibrotic transformation, and need for chemotherapy (Vannuchi, 2007; Tefferi, 2007).
The impact of the presence of JAK2V617F in patients with ET is also controversial. In several studies, the presence of this mutation has been associated with advanced age, higher hemoglobin levels, increased leukocyte count, lower platelet count, and a higher rate of transformation to PV (Campbell, 2005) (Wolanskyj, 2005). Discrepant results have been reported for thrombotic events and for fibrotic transformation (Panani, 2009). A recent meta-analysis by Dahabreh et al. (Dahabreh, 2009) surveyed 394 studies on the subject of outcomes in ET. Dahabreh et al. concluded that thrombosis but not myelofibrosis or leukemia appeared to be influenced by the presence of JAK2 mutations. Dahabreh et al. cautioned that there was a need for prospective studies to determine how this information might be used in treatment choices.
Thrombotic effects have been reported to be most pronounced for splanchnic vascular events, (Valla, 2009) and there has been little support for use of testing in patients with more general thrombosis or primary thrombocytosis (Mannucci, 2008). Results for splanchnic events have been contradictory. In one retrospective study performed looking at JAK2V617F in patients treated for thrombosis in ET and in unselected patients with splanchnic vein thrombosis (Xavier, 2010) JAK2 V617F mutations did occur with increased frequency in patients with splanchnic vein thrombosis and appeared to identify a subset of patients who might benefit from antiplatelet therapy. However, the outcome of routine testing in both settings remained unclear. In recent international collaborative studies of patients with ET, patients with JAK2 V617F mutations appeared at risk for arterial thrombosis but not for venous thrombosis (Carrobbio, 2011).
A recent report by Hussein et al. (Hussein, 2009) demonstrated that although there was significant overlap in JAK2V617 F allele burden among various MPN entities, quantitative measurements suggested discriminatory differences between patients with ET and the prefibrotic stage of PMF.
JAK2V617F mutational status and allele burden appear particularly poorly defined in patients with PMF. In a series of confusing and non-congruent articles, it has been concluded that:
Treatment
Due to the strong epidemiologic and biologic literature linking JAK2 pathway mutations to occurrence of MPNs, there has been considerable recent attention on using JAK2 as a molecular target for drug discovery. In preclinical and early clinical studies, a number of promising JAK2 inhibitors have been identified, and reports have suggested some of these are useful in symptom relief (Kumar, 2009). Many patients with these diseases have a good response to other therapies with cytotoxic drugs, and the natural course of disease, particularly for PV and ET, can be quite indolent. Considerable study will be required to sort through issues of safety and efficacy of these new treatments before they enter routine clinical use. Several early phase and preliminary treatment trials evaluating the safety and efficacy of tyrosine kinase inhibitors in patients with JAK2V617F -positive myeloproliferative neoplasms have been reported. (53-55) It has recently been noted that benefits from tyrosine kinase therapy may not be specific for JAK2V617F -positive myeloproliferative neoplasms but may be observed in wild-type disease as well (Quintas-Cardama, 2011).
While the identification of a drug producing long-term remissions such as imatinib in chronic myeloid leukemia (CML) is the ultimate goal, it will likely be complicated by the complexity of molecular processes occurring in patients with these other MPNs and the fact that JAK2V617F alone does not appear to be a unique or absolutely necessary event in many patients with these diseases. The role of JAK2V617F in selecting or monitoring patients for new treatments or residual neoplasia remains undefined.
There are several reports that suggest JAK2V617F-positive patients are more sensitive to treatment with hydroxyurea than negative patients (Panani, 2009). In one study of hydroxyurea treatment in patients with PV or ET harboring the JAK2V617F gene, serial changes in allele burden were observed. However, the value of these findings was unclear, and the authors concluded serial testing in patients on this drug should be confined to clinical studies (Antonioli, 2010).
Summary
There is an extensive and growing body of literature providing information on the clinical validation of the JAK2V617F as a distinctive marker of patients with Philadelphia chromosome-negative classic MPNs. In almost a dozen reports (all case series), JAK2V617F has been found as a unique clonal finding in patients with PV, ET, or PMF.
While the association between defined diseases and the presence of the marker has been rather variable depending on the detection methods used and the study designs applied, test specificity is virtually 100%. Patients with PV tested using PCR methodology appear to have a test sensitivity that also may approach 100% (reports up to 97%), and in the subset of patients with suspected PV who are JAK2V617F -negative, there is compelling evidence in several case series to suggest other JAK2 mutations (involving exon 12) may be identified.
Given the difficulty in using classic criteria (morphology and complex tests such as erythropoietin measurements or measurements of endogenous erythroid colony formation), it is not surprising that there was widespread enthusiasm for use of this test in the workup of patients with PV. The presence of this marker biologically and clinically is a convincing substitute for the need to rule out reactive causes of erythrocytosis.
While multiple reports have replicated the finding of high specificity in patients with ET and PMF, unfortunately, these diseases appear more heterogeneous than PV, and the mutation can be identified in only 30% to 50% of cases. However, high specificity assures that even in the absence of high sensitivity, the predictive value of a positive test approaches 100%. As with PV, increasing numbers of cases of patients with ET and PMF are now being described with new additional mutations in the complementary thrombopoietin pathway (MPL genetic mutations of exon 10). Identification of an appropriate mutation obviates the need for clinical, morphological, or other evaluation to demonstrate a reactive cause of disease.
It is important to note that the testing done to establish clinical performance for these genetic markers is not without flaws. With rare exceptions, studies have been observational performed on retrospective or cross-sectional sampling. Given the rarity of the diseases of interest, most cases have been selected from patients referred to specialty centers of excellence. However, even these special centers are challenged by the vagaries of the existing Gold Standard for diagnosis—the comprehensive but complicated WHO 2001 diagnostic criteria. Reproducibility of these criteria is unknown, and in instances in which morphology is a basis for diagnostic truth, it is well-established that the Gold Standard is imperfect.
In 2007, an ad hoc group of experts in the area of MPNs formed a working group to reformulate the 2001 WHO diagnostic criteria for classic cases of MPN. This group recommended the use of JAK2 testing for diagnosis of all 3 common Philadelphia chromosome-negative MPN variants—PV, ET, and PMF. Revised criteria were published by WHO in 2008.
This reformulation of diagnostic criteria was performed using expert consensus. Since identification of a mechanistic basis for disease is now the target for therapeutic intervention, it is likely that additional information on testing and its clinical use will be gathered. It is not clear if targeted therapies directed at functional aberrations caused by the JAK2 mutation will require testing for patient selection, for assessment of patient phenotype (disease prognosis), and/or or for monitoring treatment. In fact the value of treatment itself remains uncertain and is likely to be complicated by the finding that the JAK2 mutation alone may not be necessary or sufficient to cause clinically relevant disease.
Reports have appeared in the literature linking JAK2 mutations to patients with Down syndrome developing ALL. This information is of uncertain diagnostic value and to date has no prognostic or therapeutic use.
While measurements of JAK2 and related mutations (MPL mutations) have been studied in a somewhat nonstandardized manner using different methodologies and different study designs, the consensus-driven WHO criteria appear to be supported by multiple epidemiologic, biologic, and clinical studies of classic MPN disorders. Testing for these mutations appears medically necessary in the diagnosis of patients with signs and symptoms of suspected PV, ET, or PMF.
Testing in patients with Down syndrome-associated ALL is not needed to establish this diagnosis and has no known prognostic or treatment use.
Mutations testing to establish disease phenotype (such as disease prognosis) or to select or monitor therapy remains an area of intense interest with a growing number of studies, in particular drug trials. Recently multiple additional mutations have been identified in patients with various MPN disorders. These appear to have less specificity than the JAK2 and MPL mutations, and their use in understanding, diagnosing and treating disease remains a matter requiring further study. It is currently unclear if these carry a broad, albeit nonspecific pathogenetic relevance to MPNs or whether they are simply passenger mutations with little or no functional relevance.
Practice Guidelines and Position Statements
WHO criteria for MPN (2008)
PV – Major criteria: presence of JAK2 V617F or other functionally similar mutation such as JAK2 exon 12 mutation
ET- Major Criteria: demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis
PMF- Major criteria: demonstration of JAK2 V617F 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
2014 Update
A literature search conducted through July 2014 did not reveal any new information that would prompt a change in the coverage statement.
In 2013, European LeukemiaNet and MPN&MPNr (related diseases)-EuroNet undertook a joint systematic evaluation of JAK2V617F quantitative polymerase chain reaction (qPCR) assays to identify “an assay that, beyond being robust enough for routine diagnostic purposes, also showed the best performance profile when used for predicting outcome following an allogeneic transplant.”(Jovanovic, 2013). Effective assays can detect an allele burden as low as 1% (Bench, 2013). Investigators assessed 3 unpublished laboratory-developed tests and 6 published assays in 12 laboratories in 7 countries. The detection limit of each assay was determined in 7 quality control rounds comprising serial dilutions of centrally-distributed wild-type and mutated cell line DNA and plasmid standards. DNA detection was verified by pyrosequencing. Sensitivity and specificity of the 2 best-performing assays were further assessed in serial samples from 28 patients who underwent allogeneic hematopoietic stem cell transplantation (HSCT) for JAK2V617F-positive disease and in 100 peripheral blood samples from healthy controls, respectively. The most sensitive assay performed consistently across various qPCR platforms and detected mutant allele (ie, minimal residual disease) in transplant recipients a median of 22 weeks (range, 6-85 weeks) before relapse. The authors suggested that the assay could be used to guide management of patients undergoing allogeneic HSCT. Although the study supports the analytic validity of the assay, given the inconsistency of outcomes when JAK2V617F testing is used for treatment monitoring (described earlier), utility of this assay or any JAK2V617F test for treatment monitoring is uncertain.
2015 Update
A literature search conducted through January 2015 did not reveal any new information that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The National Comprehensive Cancer Network published guidelines (v.1.2021) on the workup, diagnosis, and treatment of suspected MPNs (NCCN, 2021). For patients with suspicion of MPNs, the guidelines recommend "molecular testing (blood) for JAK2 V617F mutation; if negative, test for CALR and MPL mutations (for patients with ET and MF) and JAK2 Exon 12 mutations (for patients with PV) or molecular testing using multigene NGS panel that includes JAK2, CALR, and MPL."
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
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