Corporate Medical Policy

JAK2 and MPL Mutations in Myeloproliferative Neoplasms

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jak2_and mpl_mutations_in_myeloproliferative_neoplasms
7/2011
11/2014
11/2015
11/2014

Description of Procedure or Service

Mutations in the gene coding for the Janus kinase 2 (JAK2) protein and in the gene
myeloproliferative leukemia virus oncogene (MPL) coding for the thrombopoietin receptor have
been associated with myeloproliferative neoplasms 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 myeloproliferative neoplasms. This
policy will also address the potential use of JAK2 mutations in the diagnosis or selection of
treatment in patients with 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. 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 findings led to the
development of 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 morphologic bone marrow exam, and diagnosis can be complicated by changing
disease patterns: PV and ET can evolve into PMF or undergo leukemic transformation. 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
morphologic assessment of uncertain consistency, and require tests that are not well standardized or
widely available, such as endogenous erythroid colony formation.
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 Janus kinase 2 ( JAK2) protein in
patients with classic MPNs. The mutation was noted to cause 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
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JAK2 and MPL Mutations in Myeloproliferative Neoplasms

findings were subsequently confirmed and additional mutations affecting the JAK2 gene mutations
in exon 12 or 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 syndromeassociated acute lymphoblastic leukemia (ALL).
Although 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.
2.
3.
4.

Diagnosis of patients with clinical, laboratory, or pathologic findings suggesting classic

MPNs (PV, ET, or PMF);
Diagnosis or selection of treatment for patients with Down syndrome ALL;
Phenotyping of disease subtypes in patients with MPNs to establish disease prognosis;
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 interassay and interlaboratory
variability in the generation of testing results.
***Note: This Medical Policy is complex and technical. For questions concerning the technical
language and/or specific clinical indications for its use, please consult your physician.

Policy
BCBSNC will provide coverage for tyrosine kinase mutation testing when it is determined to
be medically necessary because the medical criteria and guidelines shown below are met.

Benefits Application
This medical policy relates only to the services or supplies described herein. Please refer to the Member's
Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design;
therefore member benefit language should be reviewed before applying the terms of this medical policy.

When JAK2 and MPL Mutation Testing is covered

JAK2 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 myeloproliferative neoplasms (MPN), that is, polycythemia vera (PV), essential
thrombocythemia (ET), or primary myelofibrosis (PMF).

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JAK2 and MPL Mutations in Myeloproliferative Neoplasms

When JAK2 and MPL Mutation Testing is not covered
JAK2 tyrosine kinase and MPL mutation testing may be considered investigational in all other
circumstances including, but not limited to, the following situations.

Diagnosis of nonclassic forms of MPNs

Molecular phenotyping of patients with MPNs
Monitoring, management, or selecting treatment in patients with MPNs
Diagnosis or selection of treatment in patients with Down syndrome and acute
lymphoblastic leukemia

Policy Guidelines
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, e.g., 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.
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.

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it
will be reimbursed. For further information on reimbursement guidelines, please see Administrative
Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in
the Category Search on the Medical Policy search page.
Applicable service codes: 81270, 81402, 81403, G0452
BCBSNC may request medical records for determination of medical necessity. When medical records are
requested, letters of support and/or explanation are often useful, but are not sufficient documentation unless all
specific information needed to make a medical necessity determination is included.

Scientific Background and Reference Sources

Tyrosine Kinase Mutation Analysis in Myeloproliferative Neoplasms
BCBSA Medical Policy Reference Manual [Electronic Version]. 2.04.60, 1/13/2011
Medical Director 6/2011
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JAK2 and MPL Mutations in Myeloproliferative Neoplasms

Specialty Matched Consultant Advisory Panel 11/2011
JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms
BCBSA Medical Policy Reference Manual [Electronic Version]. 2.04.60, 1/12/12
Medical Director 3/2012
Specialty Matched Consultant Advisory Panel 12/2012
BCBSA Medical Policy Reference Manual [Electronic Version]. 2.04.60, 2/14/2013
Specialty Matched Consultant Advisory Panel 11/2013
BCBSA Medical Policy Reference Manual [Electronic Version]. 2.04.60, 2/13/2014
Specialty Matched Consultant Advisory Panel 11/2014

Policy Implementation/Update Information

Tyrosine Kinase Mutation Analysis in Myeloproliferative Neoplasms
7/19/11

New policy. JAK2 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 myeloproliferative neoplasms (MPN),
that is, polycythemia vera (PV), essential thrombocythemia (ET), or primary
myelofibrosis (PMF). JAK2 tyrosine kinase and MPL mutation testing may be
considered investigational in all other circumstances Notification given July 19, 2011.
Policy effective October 25, 2011. (btw)

1/10/12

Specialty Matched Consultant Advisory Panel review 11/30/11. No change to policy.

Added new 2012 CPT code, 81275, to the Billing/Coding section. (btw)

1/24/12

Removed 81275 from Billing/Coding section as it does not pertain to this policy. A dded
new 2012 CPT code, 81270 to Billing/Coding section. (btw)

JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms

4/17/12

Policy name changed from Tyrosine Kinase Mutation Analysis in Myeloproliferative

Neoplasms to JAK2 and MPL Mutation Analysis in Myeloproliferative Neoplasms.
MPL is not a tyrosine kinase. No change to policy intent. Policy Guidelines updated.
Medical Director review 3/29/12. Reference added. (btw)

12/28/12

Specialty Matched Consultant Advisory Panel review 12/4/2012. No change to policy

intent. Added CPT codes 81402, 81403, and G0452 to Billing/Coding section. (btw)

4/1/2013

Reference added. (btw)

12/10/13

Specialty Matched Consultant Advisory Panel review 11/20/2013. Policy Guidelines

revised. No change to policy intent. (btw)
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JAK2 and MPL Mutations in Myeloproliferative Neoplasms

4/15/14

Reference added. (btw)

12/9/14

Specialty Matched Consultant Advisory Panel review 11/24/2014. No change to policy

intent. (lpr)

Medical policy is not an authorization, certification, explanation of benefits or a contract. Benefits and eligibility are determined
before medical guidelines and payment guidelines are applied. Benefits are determined by the group contract and subscriber
certificate that is in effect at the time services are rendered. This document is solely provided for informational purposes only and
is based on research of current medical literature and review of common medical practices in the treatment and diagnosis of
disease. Medical practices and knowledge are constantly changing and BCBSNC reserves the right to review and revise its
medical policies periodically.

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