Highmark Commercial Medical Policy - Pennsylvania
Medical Policy: L-201-002
Topic: BCR-ABL Negative Myeloproliferative Neoplasm Testing
Section: Laboratory
Effective Date: November 13, 2017
Issue Date: November 13, 2017
Last Reviewed: March 2017

Primary myelofibrosis (PMF), polycythemia vera (PV) and essential thrombocythemia (ET) are a group of heterogeneous disorders of the hematopoietic system collectively known as Philadelphia chromosome-negative MPN.

The diagnosis and management of patients with MPN has evolved since the identification of mutations that activate the JAK pathway (JAK2, CALR, and MPL).  The development of targeted therapies has resulted in significant improvements in disease-related symptoms and quality of life.

JAK2 V617F mutations account for the majority of patients with PV (greater than 90%), ET or MF (60%). Most of the mutations occur in exon 14 with rare insertions/deletions in exon 12.

JAK2 exon 12 mutations have been seen in approximately 2-3% of patients with PV.  MPL mutations have been reported in 5-8% of patients with MF and 1- 4% of patients with ET. MPL mutations are associated with lower hemoglobin levels at diagnosis and increased risk of transfusion dependence in patients with MF.

CALR mutations are reported in approximately 20-35% of patients with ET and MF (accounting for approximately 60-80% of patients with JAK2/MPL-negative ET and MF). CALR deletion mutations are more commonly seen in patients with MF and are associated with a significantly higher risk of myelofibrosis transformation in ET.  CALR insertion mutations are associated with ET, low risk of thrombosis and an indolent course. CALR mutations are associated with a lower hemoglobin level, lower WBC count, higher platelet count and lower incidence of thrombosis than the JAK2 V617F mutation.

This policy is designed to address medical guidelines that are appropriate for the majority of individuals with a particular disease, illness, or condition. Each person's unique clinical circumstances may warrant individual consideration, based on review of applicable medical records.

Policy Position Coverage is subject to the specific terms of the member’s benefit plan.

JAK2 V617F mutation analysis may be considered medically necessary when the following criteria have been met:

JAK2 Exon 12 analysis may be considered medically necessary when the following criteria have been met:

CALR Exon 9 and MPL mutation analysis may be considered medically necessary when the following criteria have been met:

Analysis of ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and/or SF3B1 may be considered medically necessary when the following criteria have been met:

Procedure Codes
81219, 81270, 81402, 81403, 81479

Professional Statements and Societal Positions

Guidelines and Evidence

The World Health Organization (WHO, 2016) has established diagnostic criteria for PMF, PV, and ET.

  • Pre Primary Myelofibrosis (prePMF)
    Diagnosis requires meeting ALL 3 major criteria, and at least 1 minor criterion:
    • Major criteria:
      • Megakaryocytic proliferation and atypia, without reticulin fibrosis >grade 1, accompanied by increased age-adjusted BM cellularity, granulocytic proliferation, and often decreased erythropoiesis
      • Not meeting WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker*, or absence of minor reactive BM reticulin fibrosis
    • Minor criteria: Presence of at least 1 of the following, confirmed in 2 consecutive determinations:
      • Anemia not attributed to a comorbid condition
      • Leukocytosis ≥ 11 x 109/L
      • Palpable splenomegaly
      • LDH increased to above upper normal limit of institutional reference range
  • Overt Primary Myelofibrosis (overt PMF)
    Diagnosis requires meeting ALL 3 major criteria and at least 1 minor criterion]
    • Major criteria:
      • Megakaryocytic proliferation and atypia, accompanied by either reticulin and/or collagen fibrosis grades 2 or 3
      • Not meeting WHO criteria for BCR-ABL1+ CML, PV, ET, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation or in the absence of these mutations, presence of another clonal marker*, or absence of reactive BM myelofibrosis
    • Minor criteria: Presence of at least 1 of the following confirmed in 2 consecutive determinations:
      • Anemia not attributed to a comorbid condition
      • Leukocytosis greater than or equal to 11 x 109/L
      • Palpable splenomegaly
      • LDH increased to above upper normal limit of institutional reference range
      • Leukoerythroblastosis

*In the absence of ANY of the 3 major clonal mutations, the search for the most frequent accompanying mutations (e.g., ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, SF3B1) are of help in determining the clonal nature of the disease.

  • Polycythemia Vera (PV)
    Diagnosis requires meeting either all 3 major criteria, or the first 2 major criteria and the minor criterion**
    • Major criteria:
      • Hemoglobin greater than 16.5 g/dL in men, greater than 16.0 g/dL in women; or
      • Hematocrit greater than 49% in men, greater than 48% in women; or
      • Increased red cell mass (RCM), defined as greater than 25% above the mean normal predicted value
      • Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis) including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes (difference in size)
      • Presence of JAK2 V617F or JAK2 exon 12 mutation
    • Minor criteria:
      • Subnormal serum EPO level
  • Essential Thrombocythemia (ET)
    Diagnosis requires meeting ALL 4 major criteria or the first 3 major criteria and the minor criterion.
    • Major criteria:
      • Platelet count greater than or equal to 450 x 109/L
      • Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers
      • Not meeting WHO criteria for BCR-ABL1+ CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms
      • Presence of JAK2, CALR, or MPL mutation
    • Minor criteria:
      • Presence of a clonal marker or absence of evidence for reactive thrombocytosis

**Criterion number 2 (BM biopsy) may not be required in cases with sustained absolute erythrocytosis; hemoglobin levels greater than 18.5 g/dL in men (hematocrit, 55.5%) or greater than 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).

The National Comprehensive Cancer Network (NCCN, 2017) evidence and consensus-based guidelines recommend the following initial laboratory evaluations for individuals suspected to have MPN:

  • “Laboratory evaluations should include complete blood count (CBC), microscopic examination of the peripheral smear, comprehensive metabolic panel with serum uric acid, serum LDH, liver function tests, serum EPO level and serum iron studies.”
  • Fluorescence in situ hybridization (FISH) or a reverse transcriptase polymerase chain reaction (RT-PCR) on a peripheral blood specimen to detect BCR-ABL1 transcripts and exclude the diagnosis of CML is recommended for all patients, especially those with left-shifted leukocytosis and/or thrombocytosis with basophilia.”
  • “Molecular testing for JAKV617F mutations should be performed in all patients. If JAKV617F mutation is negative, molecular testing for MPL and CALR mutations should be performed for patients with MF and ET; molecular testing for JAK2 exon 12 mutation should be done for those with PV.”
  • “In the absence of JAK2, CALR and MPL mutations, the presence of another clonal marker is included as one of the major diagnostic criteria for PMF. Additional mutations in ASXL1, EZH2, TET2, IDH1, IDH2, SRSF2, and SF3B1 genes are noted to be of help in determining the clonal nature of the disease.”
  • “Bone marrow aspirate and biopsy with trichrome and reticulin stain and bone marrow cytogenetics (karyotype, with or without FISH) is necessary to accurately distinguish the bone marrow morphological features between the disease subtypes (early/prefibrotic PMF, ET and masked PV).”

Place of Service: Outpatient

BCR-ABL negative myeloproliferative neoplasm testing is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.


The policy position applies to all commercial lines of business


Denial Statements

Services that do not meet the criteria of this policy will not be considered medically necessary. A network provider cannot bill the member for the denied service unless: (a) the provider has given advance written notice, informing the member that the service may be deemed not medically necessary; (b) the member is provided with an estimate of the cost; and (c) the member agrees in writing to assume financial responsibility in advance of receiving the service. The signed agreement must be maintained in the provider’s records.

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