BlueCross and BlueShield of Montana Medical Policy/Codes
JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms
Chapter: Genetic Testing
Current Effective Date: July 18, 2013
Original Effective Date: May 03, 2012
Publish Date: July 18, 2013
Revised Dates: April 10, 2013
Description

Mutations in the gene coding for the Janus kinase 2 (JAK2) protein and in the gene MPL (myeloproliferative leukemia virus oncogene) coding for the thrombopoietin receptor that result in constitutive activation of the kinase have been associated with myeloproliferative neoplasms (MPNs) and with acute lymphoblastic leukemia (ALL) in Down syndrome patients. This policy addresses the use of JAK2 and MPL gene mutation testing for diagnosis, prognosis, and treatment selection in patients with MPNs. This policy will also address the potential use of JAK2 mutations in the diagnosis or selection of treatment in patients with Down syndrome ALL.

MPNs are a category of uncommon overlapping blood diseases characterized by the production of one or more blood cells—chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), systemic mastocytosis, chronic eosinophilic leukemia, and others. A common finding in many of the MPNs is clonality, and a central pathogenic feature is the presence of a mutated version of the tyrosine kinase enzyme, such that it is abnormally constitutively activated. The paradigm for use of this information to revolutionize patient management is CML. A unique chromosomal change (the Philadelphia chromosome) and an accompanying unique gene rearrangement (BCR-ABL) resulting in a continuously activated tyrosine kinase enzyme were identified. These led to discovery of a targeted tyrosine kinase inhibitor drug treatment (imatinib) that produces long-lasting remissions.

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 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: PV and ET can evolve into PMF or undergo leukemic transformations. World Health Organization (WHO) criteria were published as a benchmark for diagnosis in 2001. 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 erythroid 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 coding for the JAK2 protein in patients with classic MPNs. The mutation was noted to cause a valine-to-phenylalanine substitution at amino acid position 617 (JAK2V617F). Loss of JAK2 autoinhibition caused by JAK2V617F 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 involved in complementary pathways such as the 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 a subset of patients with Down syndrome ALL.

While these mutations were of importance in better understanding 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:

  1. Diagnosis of patients with clinical, laboratory or pathological findings suggesting classic MPNs (PV, ET, or PMF);
  2. Diagnosis or selection of treatment for patients with Down syndrome ALL;
  3. Phenotyping of disease subtypes in patients with MPNs to establish disease prognosis; and
  4. Identification, selection and monitoring of treatment.

More than a dozen commercial laboratories currently 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 U.S. Food and Drug Administration (FDA) enforcement discretion policy for laboratory developed tests. Variable analytical and clinical performance has been reported, suggesting that the nucleic acid amplification methodologies are more sensitive than mutation sequence analysis. It appears that there can be considerable inter-assay and inter-laboratory variability in the generation of testing results.

Policy

Prior authorization is recommended.  To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624.  A retrospective review is performed if services are not prior authorized.

Medically Necessary

BCBSMT may consider JAK2 (Janus kinase 2 ) tyrosine kinase mutation testing (e.g., JAK2, JAK2V617F) and MPL (myeloproliferative leukemia virus oncogene) mutation testing medically necessary in 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).

NOTE:  Generally, patients suspected to have PV should first be tested for the most common finding, JAK2V617F. If testing is negative, further testing to detect other JAK2 tyrosine kinase mutations, e.g., in exon 12, is warranted. Also, patients suspected to have ET or PMF should first be tested for a JAK2 mutation. If testing is negative, further testing to detect MPL mutations is warranted.

Investigational

BCBSMT considers JAK2 tyrosine kinase and MPL mutation testing experimental, investigational and unproven in all other circumstances including, but not limited to, the following situations:

  • Diagnosis of nonclassic forms of myeloproliferative neoplasms (MPNs);
  • Molecular phenotyping of patients with MPNs;
  • Monitoring, management, or selecting treatment in patients with MPNs; or
  • Diagnosis or selection of treatment in patients with Down syndrome and acute lymphoblastic leukemia (ALL).

Federal Mandate

Federal mandate prohibits denial of any drug, device, or biological product fully approved by the FDA as investigational for the Federal Employee Program (FEP). In these instances coverage of these FDA-approved technologies are reviewed on the basis of medical necessity alone. Call the BCBSMT FEP Customer Service Department at 1-800-634-3569 for benefit information.

Policy Guidelines

Effective in 2012, there are new specific CPT codes:

81270 is a Tier 1 code that is specific for JAK2V617F testing.

81403 is a Tier 2 code that may be used if further JAK2 testing is performed (e.g., exon 12 and exon 13 sequences).

81402 is a Tier 2 code that is available for MPL testing.

Rationale for Benefit Administration

This medical policy was developed through consideration of peer reviewed medical literature, FDA approval status, accepted standards of medical practice in Montana, Technology Evaluation Center evaluations, and the concept of medical necessity. BCBSMT reserves the right to make exceptions to policy that benefit the member when advances in technology or new medical information become available.

The purpose of medical policy is to guide coverage decisions and is not intended to influence treatment decisions. Providers are expected to make treatment decisions based on their medical judgment. Blue Cross and Blue Shield of Montana recognizes the rapidly changing nature of technological development and welcomes provider feedback on all medical policies.

When using this policy to determine whether a service, supply or device will be covered, please note that member contract language will take precedence over medical policy when there is a conflict.

Rationale

Tyrosine Kinase Mutation Analysis and the Diagnosis of Philadelphia Chromosome-Negative Myeloproliferative Neoplasms (MPNs)

Diagnosis of classic MPNs

Diagnosis of the various classic forms of 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 (1, 2) or the World Health Organization (WHO) in 2001. (3) 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, some diagnostic methods (i.e., bone marrow microscopy) are not well-standardized (4-6) and others (i.e., endogenous erythroid colony formation) are neither standardized nor widely available.

As noted, 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 IMF (see Table 1). It was initially reported to be absent in all normal subjects and in patients studied with secondary erythrocytosis, (6-16) although recently very low levels of mutated cells have been reported to be found in a small subset of the healthy population. (17, 18)

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. (8)

Table 1: Frequency of JAK2V617F Mutations in Patients with Classic Philadelphia Chromosome-Negative MPN

STUDY

MUTATION DETECTION METHOD

PV

ET

PMF

NORMAL

SECONDARY ERYTHRO-CYTOSIS

COMMENT

Baxter 2005

(6)

DNA* sequencing, PCR testing

71/73 (97%)

29/51 (57%)

8/16 (50%)

90/90 (100%)

 

Case series

Levine 2005 (7)

DNA sequencing

121/164 (74%)

37/115 (32%)

16/46 (35%)

0/269 (0%)

 

Case series

James 2005 (8)

DNA sequencing

40/45 (88%)

9/21 (43%)

3/7 (43%)

0/15

(0%)

0/35

(0%)

Case series

Kravolics 2005 (9)

DNA sequencing 

83/128 (65%)

21/94 (23%)

13/23 (56%)

0/142 (0%)

0/11

(0%)

Case series 

Jones 2005 (10)

PCR** testing

58/72 (81%)

24/59 (41%)

15/35 (43%)

0/160 (0%)

0/4

(0%)

Case series 

Tefferi 2006 (11)

PCR testing

36/38 (95%)

12/46 (55%)

3/10 (30%)

 

0/19

(0%)

Case series 

Zhao 2005 (12)

DNA sequencing 

20/24 (83%)

 

 

0/12

(0%)

 

Case series 

Campbell 2005 (13)

PCR testing   

 

414/776 (53%)

 

 

 

Prospective, case series  

Wolanski 2005 (14)

PCR testing   

 

73/150 (49%)

 

 

 

Case series 

Campbell 2005 (15)

PCR testing     

 

 

83/152 (55%)

 

 

Case series 

Tefferi 2005 (16)

PCR testing

 

 

80/157 (51%)

 

 

Case series

*DNA—Deoxyribonucleic acid

**PCR—Polymerase chain reaction

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. (19) 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. (20,21) The 2001 World Health Organization (WHO) criteria were revised in 2008 to reflect incorporation of the test in patient workup. (22, 23)

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, two small cross-sectional comparative studies have been performed evaluating JAK2V617F testing directly against previously established PVSG or WHO criteria.

In 2005, James et al. (20) compared PV diagnosed using WHO or PVSG criteria with a streamlined diagnostic approach for PV using a two-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 two-step algorithm resulted in a correct diagnosis in 96% (PVSG criteria) or 93% (WHO criteria) of patients with PV.

In 2008, Kondo et al. (24) 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 four 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 two patients (one with erythrocytosis and one 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 also to improved insight into the diagnostic role of this important marker.

Diagnosis of non-classical 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 non-classical forms of MPNs such as chronic myelomonocytic leukemia, hypereosinophilic syndrome, systemic mastocytosis, chronic neutrophilic leukemia, or others. Reports have appeared identifying JAK2V617F F mutations in some of these cases. (10, 25) Due to the paucity of data about the significance or use of JAK2V617F or MPL mutations in these disease settings, use of the test in patients with these diseases should be considered experimental, investigational and unproven.

Other tyrosine kinase or related mutations

In 2007, Scott et al. (26) identified four 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. (27, 28) 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. (26) This perhaps explains the surprise findings of a series of JAK2 mutations in patients with Down syndrome ALL.

In 2006, Pikman et al. (29) surveyed JAK2 mutation-negative patients with suspected ET and PMF to determine if mutations in pathways complementary to JAK2 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 (see Table 2). (30-33) While this mutation can be found in both JAK2V617-positive and -negative patients, it is obviously of particular value in the latter in helping to establish a clonal basis of the observed disease process.

TABLE 2: Frequency of MPL 515 Mutations in Patients with Philadelphia Chromosome-Negative MPN

STUDY

MUTATION DETECTION METHOD

PV

ET

PMF

NORMALS

OTHER MPNs

COMMENT

Pikman 2006  (29)

DNA sequencing 

0/10 (0%) 

0/50

(0%)

4/45 (8.8%)

0/270

(0%)

 

JAK2 Negative  

Pardanani 2006  (30)

Site 1: PCR with DNA sequencing; Site 2: DNA sequencing  

0/38 (0%)

 

0/204 (0%) 

2/167

(1%)

 

2/151

(1%)

8/198

(4%)

 

5/92

(5%)

0/64

(0%)

3/118 (2.5%)

 

Beer (2008)  (31)

PCR testing

 

Preliminary 3/88 (3.4%) Prospective 32/776 (4.1%)

Preliminary 8/112 (7.1%)

 

 

 

Pancrazzi (2008) (32)

PCR testing 

0/50 (0%)

 

19/217 (8.7%)

0/60

(0%)

 

 

Ruan (2009) (33)

PCR testing 

0/32 (0%) 

7/199 (3.5%)

3/24 (12.5%)

0/52

(0%)

0/29 (0%)

 

Schnittger (2009) (34)

PCR testing 

 

19/356 (5.3%)

10/193 (5.2%)

 

2/269 (0.8%)

 

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 three independent cell lines and transplantation of mice with bone marrow expressing this allele results in a distinctive myeloproliferative disorder. (30)

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/K in 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.

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; interestingly, the disease process appears to be exclusively B cell in origin. In 2007 Malinge et al. published a case report (35) describing a novel JAK2 mutation in a patient with Down syndrome and B-cell precursor acute lymphoblastic lymphoma. Speculating that this finding might relate to the role the JAK-STAT signaling pathway played in early B-cell development, Bercovich et al. (36) 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 Down syndrome patients, 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. (37) who found 20% of Down syndrome patients 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 subjects for 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, the literature in this area is conflicting and inconclusive, due to differences in disease definitions, in methods of testing, in sample type (bone marrow versus circulating blood cells), and 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 comparing 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. (40, 41)

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. (13, 14) Discrepant results have been reported for thrombotic events and for fibrotic transformation. (42) A recent meta-analysis by Dahabreh et al. (43) surveyed some 394 studies on the subject of outcomes in ET. Dahabreh concluded thrombosis but not myelofibrosis or leukemia appeared to be influenced by the presence of JAK2 mutations. Dahabreh 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, (44) and there has been little support for use of testing in patients with more general thrombosis or primary thrombocytosis. (45) 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 (46) JAK2V617F 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 JAK2V617F mutations appeared at risk for arterial thrombosis but not for venous thrombosis. (47)

A recent report by Hussein et al. (48) demonstrated that although there was significant overlap in JAK2V617F 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:

  • Patients with JAK2V617F mutations required fewer blood transfusions but exhibited poorer overall survival than those without the mutation. (15)
  • Patients with JAK2V617F mutations did not show differences in the incidence of thrombosis, overall survival, or leukemia-free survival. (29)
  • Patients with homozygous JAK2V617F mutations show an increased evolution toward large splenomegaly, need of splenectomy and leukemic transformation. (49)
  • Patients with low allele burdens appeared to exhibit shortened survival, perhaps because they represented a myelodepleted subset of affected patients. (29, 50)

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. (51) 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. (52-54) 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. (55)

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 suggesting JAK2V617F-positive patients are more sensitive to treatment with hydroxyurea than negative patients. (42) 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. (56)

Practice Guidelines and Position Statements

WHO criteria for MPN (2008)

  • PV — Major criteria: presence of JAK2V617F or other functionally similar mutation such as JAK2 exon 12 mutation
  • ET — Major criteria: demonstration of JAK2V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis
  • 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

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 MLNs. 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 (see Table 1) 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 three 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 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 non-standardized 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 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. Based on current data, use of testing for these purposes is considered experimental, investigational and unproven. 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.

Coding

Disclaimer for coding information on Medical Policies         

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.           

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.           

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps. 

Rationale for Benefit Administration
 
ICD-9 Codes

202.60, 202.61, 202.62, 202.63, 202.64, 202.65, 202.66, 202.67, 202.68, 205.10, 205.11, 205.12, 238.4, 238.71, 238.76

ICD-10 Codes

C92.10-C92.12, C96.2, D45, D47.3, D47.4

Procedural Codes: 81270, 81402, 81403
References
  1. Murphy S, Peterson P, Iland H et al. Experience of the Polycythemia Vera Study Group with essential thrombocythemia: a final report on diagnostic criteria, survival, and leukemic transition by treatment. Semin Hematol 1997; 34(1):29-39.
  2. Pearson TC, Messinezy M. The diagnostic criteria of polycythaemia rubra vera. Leuk Lymphoma 1996; 22 Suppl 1:87-93.
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April 2012  New policy for BCBSMT. May be considered medically necessary in the diagnosis of PV, ET, PMF; all other uses investigational
April 2013 Policy formatting and language revised.  Policy statement unchanged.  Removed codes 83890-83906, 83912.
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JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms