MolDX: Non-Next Generation Sequencing Tests for the Diagnosis of BCR-ABL Negative Myeloproliferative Neoplasms

Jurisdiction: J15 MAC Part B. States: Kentucky, Ohio. Type: Active LCD

Indications and Limitations of Coverage This policy provides limited coverage for multi-gene non-next generation sequencing (NGS) panel testing and limited coverage for single-gene testing for the diagnostic workup of patients with suspected BCR-ABL negative myeloproliferative neoplasms (MPNs). Classical BCR-ABL negative MPNs include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF), and non-classical BCR-ABL negative MPNs include Chronic Neutrophilic Leukemia (CNL) and Chronic Eosinophilic Leukemia, Not Otherwise Specified (CEL, NOS), among other rare entities. Myelodysplastic/Myeloproliferative neoplasms are considered a separate class outside the scope of this LCD. Testing myeloid and suspected neoplasms by NGS is covered by a separate LCD, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies (L38047). ALL of the following criteria must be met: 1. The patient is being evaluated for a BCR-ABL-negative MPN according to national or international consensus diagnostic criteria (i.e., World Health Organization (WHO); International Consensus Classification (ICC)). 2. Testing follows the assessment of BCR-ABL (this is required unless the patient is only suspected of having PV). 3. The test is comprised of one or more highly sensitive single- or multi- gene assays (i.e. quantitative polymerase chain reaction [PCR], digital droplet PCR [ddPCR]) that can accurately detect a minimum variant allele frequency (VAF) of 1% for JAK2 (and 1-3% for CALR and MPL when they are included in the testing). 4. If testing is performed using single gene tests, a sequential and reflexive approach is expected. Once a positive result is obtained and the appropriate diagnosis is established, further testing should stop unless required for subsequent management of the patient or as further described below.. When testing for the classical BCR-ABL-negative MPNs (PV, ET, or PMF) using single gene tests , reflex testing to the next gene will be considered reasonable and necessary according to the following sequence of tests for known driver mutations: BCR-ABL negative test results, progress to ii. Note: For the rare patient with high clinical suspicion of PV despite a positive BCR-ABL result, testing for a mutation in JAK2 mutation may still be performed. JAK2 V617F negative test results (this includes JAK2 V617F positive at JAK2, exon 12 (required when PV is suspected) Calreticulin (CALR) and Thrombopoietin Receptor (MPL) driver mutations (required when ET or PMF is suspected) Note: testing for CALR/MPL does NOT require a negative JAK2 exon 12, just a negative JAK2 V617F result. 5. If testing is performed using a panel (i.e., multiplex PCR) the panel must include at least the minimum necessary genes and gene alterations that would be reasonably expected by the test to achieve a diagnosis according to national or international consensus guidelines, given the specific MPN subtype suspected. For example: Molecular testing for mutations in JAK 2 (including V617F and exon 12), CALR and MPL genes is considered medically necessary for the identification of the classical MPNs. However, if the accelerated/blast phase of PMF is suspected at diagnosis, molecular testing should also include acute myeloid leukemia (AML)- associated mutations and would likely require the performance of a NGS panel; in this case, a panel that does not include the AML-associated mutations does not meet the minimum necessary gene requirements. Additional MPN-associated genes must also be included as appropriate for the identification of other non-classical BCR-ABL-negative MPNs. For example, when CNL is suspected, testing for the colony stimulating factor 3 receptor (CSF3R) is required. Note also that testing for CNL requires the exclusion of the classical BCR-ABL-negative MPNs. 6. Patients with high suspicion of a BCR-ABL negative MPN who test negative by a non-NGS test for mutations in JAK2 (including the detection of JAK2 V617F at a VAF 7. Clinical validity (CV) of analytes measured must be established through a study published in the peer-reviewed literature for the intended use of the test in the intended population. 8. The test is being used (a) in a patient who is part of the population in which the test was analytically validated and (b) according to the intended use of the test. 9. The test satisfactorily completes a technical assessment (TA) that will evaluate and confirm that analytical validity (AV), clinical validity (CV), and clinical utility (CU) have been demonstrated. 10. Tests utilizing a similar methodology or evaluating a similar molecular analyte to a test for which there is a generally accepted testing standard or for which existing coverage exists must demonstrate equivalent or superior test performance (i.e., sensitivity and/or specificity) when used for the same indication in the intended-use population. 11. Testing is performed for diagnosis and not as a test of cure or for monitoring minimal residual disease (MRD). Note: Testing by NGS falls outside of the scope of this LCD but must fulfill the criteria outlined in LCD L38047, MolDX: Next-Generation Sequencing Lab-Developed Tests for Myeloid Malignancies and Suspected Myeloid Malignancies.