Medical Policy: 02.04.62
Original Effective Date: August 2016
Reviewed: August 2020
Revised: August 2020
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
The Philadelphia chromosome (Ph), a derivative chromosome 22 resulting from a translocation between chromosomes 9 and 22 causing the BCR-ABL fusion, is present in approximately 95% of chronic myeloid leukemia (CML) and 25-30% of adult acute lymphoblastic leukemia (ALL) cases. In general, the ratio of the fusion to a reference control can be used for diagnosis, prognosis, and ongoing therapeutic monitoring. A BCR-ABL test is most often used to diagnose or rule out chronic myeloid leukemia (CML) or a specific form of acute lymphoblastic leukemia (ALL) (Ph-positive ALL). Ph-positive means a Philadelphia chromosome was found. The test is not used to diagnose other types of leukemia.
BCR-ABL cytogenetic testing detects the presence of the 9;22 translocation and the BCR-ABL fusion gene within somatic cells. This test may also identify an additional copy of Ph in cells or an atypical 9/22 translocation. Cytogenetic testing is indicated as an initial evaluation for patients suspected to have chronic myeloid leukemia (CML) or adult acute lymphoblastic leukemia (ALL) and then for monitoring disease status.
Qualitative BCR-ABL testing is indicated as an initial evaluation for patients known to have a positive FISH cytogenetic test for BCR-ABL. The qualitative BCR-ABL test can determine the specific type (isoform) of the Philadelphia chromosome present which is important for appropriate diagnosis and treatment.
Patients with CML are treated with the drug Imatinib, or a second generation tyrosine kinase inhibitor, at diagnosis. The treatment is highly effective however it is essential that any relapse in the disease is identified as soon as possible to ensure the best clinical outcome for the patient. As such the expression level of the fusion gene is monitored in patients over time.
For CML, inadequate initial response to tyrosine kinase inhibitors (TKIs) is defined as failure to achieve complete hematologic response at 3 months, only minor cytologic response at 6 months, or major (rather than complete) cytogenetic response at 12 months.
Unlike in CML, ALL resistance to TKIs is less well studied. In patients with ALL receiving a TKI, a rise in the BCR-ABL mRNA level while in hematologic complete response or clinical relapse warrants mutational analysis.
Loss of response to TKIs is defined as hematologic relapse, cytogenetic relapse, or 1-log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response.
For patients with increasing levels of BCR-ABL1 transcripts, there is no strong evidence to recommend specific treatment; possibilities include continuation of therapy with dasatinib or nilotinib at the same dose, or imatinib dose escalation as tolerated, or therapy change to an alternative second-generation TKI.
The ELN (European LeukemiaNet), European Society for Medical Oncology (ESMO), and National Comprehensive Cancer Network (NCCN) provide recommendations about when BCR-ABL1 KD mutation analysis should be performed in patients treated with TKIs. According to the ELN and the ESMO recommendations, mutation analysis is recommended at diagnosis only in AP-/BP-CML patients, before starting first-line therapy. However, in the absence of prospective studies based on mutation screening up front and the low rate of mutation detection, it is questionable whether this is sensible or cost-effective. The NCCN recommends mutation analysis in TKI-pretreated AP-/BP-CML patients
The ELN and the ESMO recommendations differentiate between first-line and second-line treatment, while the NCCN guidelines do not differentiate across lines of treatment. According to the ELN and the ESMO recommendations, BCR-ABL1 KD mutation analysis should be performed during second-line treatment in case of hematologic or cytogenetic failure, whereas based on the NCCN guidelines, mutation analysis should also be performed in case of loss of response, inadequate response, or increased BCR-ABL1 transcript levels.
|blank cell||At diagnosis||During first-line therapy with imatinib||During second-line therapy with dasatinib or nilotinib|
|European LeukemiaNet and European Society for Medical Oncology recommendations||Only in patients with accelerated phase-/blast phase-||
In case of hematologic or cytogenetic failure, including:
|National Comprehensive Cancer Network||In case of disease progression to accelerated phase or blast phase||In patients with chronic phase-chronic myeloid leukemia who have inadequate initial response, defined as failure of achieving partial cytogenetic response or BCR-ABL1/ABL1 ≤10% (on the international scale) at 3 months or complete cytogenetic responseat 12 and 18 months||In patients with chronic phase-chronic myeloid leukemia at any sign of loss of response, defined as hematologic or cytogenetic relapse or 1-log increase in BCR-ABL1 transcript level and loss of major molecular response|
ELN, European LeukemiaNet; ESMO, European Society for Medical Oncology; AP, accelerated phase; BP, blast phase; CML, chronic myeloid leukemia; MMR, major molecular response; CyR, cytogenetic response; PCyR, partial cytogenetic response; CP, chronic phase; NCCN, National Comprehensive Cancer Network; CCyR, complete cytogenetic response.
National Cancer Institute (NCI): Regarding BCR-ABL mutation analysis in individuals with chronic myelogenous leukemia (CML), the NCI notes “In case of treatment failure or suboptimal response, patients should undergo BCR/ABL kinase domain mutation analysis to help guide therapy with the newer tyrosine kinase inhibitors or with allogeneic transplantation (2016)
The National Comprehensive Cancer Network (NCCN, 2020) recommends bone marrow cytogenetics to confirm a diagnosis of CML. If bone marrow is not available, FISH on a peripheral blood specimen using probes for both BCR and ABL can confirm the diagnosis. NCCN recommends BCR-ABL transcript levels be obtained by quantitative RT-PCR:
These recommendations are category 2A: "based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate."
FISH has been inadequately studied for monitoring response to treatment. The recent update addressed FISH use and states "FISH can be used if cytogenic evaluation is not possible".
For patients with progression to accelerated phase or blast phase, consider myeloid mutation panel to identify the BCR-ABL1 independent resistance mutations in patients with no BCR-ABL1 kinase domain mutations.
On February 2019, the QXDx BCR-ABL % IS Kit (Bio-Rad Laboratories) was approved by the FDA through the 510(k) pathway (K181661). This droplet digital PCR (ddPCR) test may be used in patients with diagnosed t(9;22) positive CML, during monitoring of treatment with TKIs, to measure BCR-ABL1 to ABL1 mRNA transcript levels, expressed as a log molecular reduction value from a baseline of 100% on the IS. This test is not intended to differentiate between e13a2 or e14a2 fusion transcripts and is not intended for the diagnosis of CML. This test is intended for use only on the Bio-Rad QXDx AutoDG ddPCR System. FDA classification code: OYX.
On July 2016, QuantideX® qPCR BCR-ABL IS Kit (Asuragen) was approved by the FDA through the de novo 510(k) pathway (DEN160003). This test may be used in patients with diagnosed t(9;22) positive CML, during treatment with TKIs, to measure BCR-ABL mRNA transcript levels. It is not intended to diagnose CML. FDA classification code: OYX.
On December 2017, the MRDx® BCR-ABL Test (MolecularMD) was approved by the FDA through the 510(k) pathway (K173492). The test may be used in patients diagnosed with t(9;22) positive CML, during treatment with TKIs, to measure BCR-ABL mRNA transcript levels. It is also intended for use “in the serial monitoring for BCR-ABL mRNA transcript levels as an aid in identifying CML patients in the chronic phase being treated with nilotinib who may be candidates for treatment discontinuation and for monitoring of treatment-free remission.” FDA classification code: OYX.
Additionally, 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. The BCR-ABL1 fusion gene qualitative and quantitative genotyping tests and ABL SNV tests are available 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 FDA has chosen not to require any regulatory review of this test.
BCR/ABL1 qualitative testing for the presence of the fusion gene may be considered medically necessary for diagnosis of chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL).
BCR/ABL1 testing at baseline prior to initiation of treatment and at appropriate intervals during therapy may be considered medically necessary for monitoring treatment response and remission.
Testing for all other indications is considered not medically necessary.
To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes and / or diagnosis codes.
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