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DESCRIPTIONVarious nucleic acid-based laboratory methods are used to detect the BCR-ABL1 fusion gene for confirmation of the diagnosis of chronic myelogenous leukemia (CML); for quantifying mRNA BCR-ABL1transcripts during and after treatment to monitor disease progression or remission; and for identification of ABL kinase domain point mutations related to drug resistance when there is inadequate response or loss of response to tyrosine kinase inhibitors (TKIs), or disease progression.
Chronic myelogenous leukemia (CML) is a clonal disorder of myeloid hematopoietic stem cells, accounting for 15% of adult leukemias. The disease occurs in chronic, accelerated, and blast phases, but is most often diagnosed in the chronic phase. If left untreated, chronic phase disease will progress within 3 to 5 years to the accelerated phase, characterized by any of several specific criteria such as 10-19% blasts in blood or bone marrow, basophils comprising 20% or more of the white blood cell count, very high or very low platelet counts, etc. From the accelerated phase, the disease progresses into the final phase of blast crisis, in which the disease behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed by the presence of either more than 20% myeloblasts or lymphoblasts in the blood or bone marrow, large clusters of blasts in the bone marrow on biopsy, or development of a solid focus of leukemia outside the bone marrow.
BCR-ABL1 is an abnormal fusion gene that is expressed in the malignant cells of patients with CML. The fusion gene is created in most cases by a reciprocal t(9;22) chromosomal translocation that fuses the ABL tyrosine kinase gene on chromosome 9 with the breakpoint cluster region (BCR) on chromosome 22 and usually results in the cytogenetically identifiable Philadelphia chromosome (Ph). In a minority of cases, the BCR-ABL1 fusion gene is formed by other genetic changes; in these cases the Ph is not seen in cytogenetic analysis but the fusion gene is detectable by molecular methods. Depending on the exact location of the fusion, the molecular weight of the protein can range from 185 to 210 kDa. Two clinically important variants are p190 and p210; p190 is generally associated with acute lymphoblastic leukemia, while p210 is most often seen in chronic myeloid leukemia. The product of BCR-ABL1 is also a functional tyrosine kinase; the kinase domain of the BCR-ABL protein is the same as the kinase domain of the normal ABL protein. However, the abnormal BCR-ABL protein is resistant to normal regulation. Instead, the enzyme is constitutively activated and drives unchecked cellular signal transduction resulting in excess cellular proliferation.
Treatment and Response
Imatinib (Gleevec®) was originally developed to specifically target and inactivate the ABL tyrosine kinase portion of the BCR-ABL1 fusion protein in order to treat patients with CML. In patients with chronic phase CML, early imatinib study data indicated a high response rate to imatinib compared to standard therapy, and long-term follow-up has shown that continuous treatment of chronic phase CML results in “durable responses in [a] large proportion of the patients with a decreasing rate of relapse.” As a result, imatinib became the primary therapy for most patients with newly diagnosed chronic phase CML.
Treatment response is evaluated initially by hematologic response (normalization of peripheral blood counts), then by cytogenetic response (percent of cells with Ph-positive metaphase [highly condensed] chromosomes in a bone marrow aspirate). Complete cytogenetic response (CCyR; 0% Ph-positive metaphases) is expected by 6-12 months after initial treatment with the TKI imatinib. Quantitative measurement of BCR-ABL1 gene expression transcript (messenger RNA) levels is the most sensitive method of monitoring treatment response and is recommended in conjunction with cytogenetic monitoring.
However, imatinib treatment does not usually result in complete eradication of malignant cells. Not uncommonly, malignant clones resistant to imatinib may be acquired or selected during treatment (secondary resistance), resulting in disease relapse. In addition, a small fraction of chronic phase malignancies that express the fusion gene do not respond to treatment, indicating intrinsic or primary resistance. The molecular basis for resistance is explained in the following section. When the initial response to treatment is inadequate or there is a loss of response, resistance mutation analysis is recommended to support a diagnosis of resistance (based on hematologic or cytogenetic relapse), and to guide the choice of alternative doses or treatments.
Structural studies of the ABL-imatinib complex have resulted in the design of second-generation ABL inhibitors, including dasatinib [Sprycel®] and nilotinib [Tasigna®], which were initially approved by the U.S. Food and Drug Administration (FDA) for treatment of patients resistant or intolerant to prior imatinib therapy. More recently, trials of both agents in newly diagnosed chronic phase patients showed that both are superior to imatinib for all outcomes measured after one year of treatment, including CCyR (primary outcome), time to remission, and rates of progression to accelerated phase or blast crisis. Although initial follow-up was short, early and sustained complete cytogenetic response was considered a validated marker for survival in CML. On June 17, 2010, the FDA approved nilotinib for the treatment of patients with newly-diagnosed chronic phase CML. Dasatinib was approved on October 28, 2010 for the same indication.
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, imatinib dose escalation from 400 mg to 800 mg daily, as tolerated or therapy change to an alternate second-generation TKI are all options.
Resistance is most often explained at the molecular level by genomic instability associated with the creation of the abnormal BCR-ABL1 gene, usually resulting in point mutations within the ABL1 gene kinase domain that affects protein kinase-TKI binding. BCR-ABL1 kinase domain (KD) point mutations account for 30-50% of secondary resistance*. At least 58 different KD mutations have been identified in CML patients. The degree of resistance depends on the position of the mutation within the kinase domain (i.e. active site) of the protein. Some mutations are associated with moderate resistance and are responsive to higher doses of TKIs, while other mutations may not be clinically significant. Two mutations, designated T315I and E255K (nomenclature indicates the amino acid change and position within the protein), are consistently associated with resistance. The T315I mutation is relatively common at frequencies ranging from 4-19%, depending on the patient population; it is more common in patients with advanced-phase CML than in patients with early chronic phase CML.
Compared to imatinib, fewer mutations are associated with resistance to dasatinib or nilotinib. For example, Guilhot et al. and Cortes et al. studied the use of dasatinib in imatinib-resistant CML patients in the accelerated phase and in blast crisis, respectively, and found that dasatinib response rates did not vary by the presence or absence of baseline tumor cell BCR-ABL1 mutations. However, neither dasatinib nor nilotinib are effective against resistant clones with the T315I mutation, and new agents and treatment strategies are in development for patients with T315I resistance.
In a recent follow-up study of nilotinib by le Coutre et al., 137 patients with accelerated phase CML were evaluated after 24 months. Sixty-six percent of patients maintained major cytogenetic responses at 24 months. The estimates of overall and progression-free survival rates at 24 months were 70% and 33%, respectively. Grade 3/4 neutropenia and thrombocytopenia were each observed in 42% of patients.
Rarely, other acquired cytogenetic abnormalities such as BCR-ABL gene amplification and protein overexpression have also been reported. Resistance unrelated to kinase activity may result from additional oncogenic activation or loss of tumor suppressor function, and may be accompanied by additional karyotypic changes.
The BCR/ABL1 qualitative and quantitative genotyping tests, and ABL kinase domain mutation tests, are not manufactured test kits and have not been reviewed by the U.S. Food and Drug Administration. Rather, they are laboratory-developed tests (LDT), offered by clinical laboratories licensed under Clinical Laboratory Improvement Amendments (CLIA) for high-complexity testing.
Note that new BCR-ABL KD mutations also occur in about 80-90% of cases of acute lymphoblastic leukemia in relapse after TKI treatment, and in CML blast transformation.
POLICYBCR/ABL1 qualitative testing for the presence of the fusion gene is considered medically necessary for diagnosis of chronic myeloid leukemia (see Policy Guidelines).
BCR/ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcriptionpolymerase chain reaction at baseline prior to initiation of treatment and at appropriate intervals during therapy (see Policy Guidelines) is considered medically necessary for monitoring of chronic myeloid leukemia treatment response and remission.
Evaluation of ABL kinase domain point mutations to evaluate patients for tyrosine kinase inhibitor resistance is considered medically necessary when there is inadequate initial response to treatment or any sign of loss of response (see Policy Guidelines); and/or when there is progression of the disease to the accelerated or blast phase.
Evaluation of ABL kinase domain point mutations is considered investigational for monitoring in advance of signs of treatment failure or disease progression.
POLICY GUIDELINESQualitative molecular confirmation of the cytogenetic diagnosis (i.e., detection of the Philadelphia chromosome) and distinction between molecular variants (i.e., p190 vs. p210) is necessary information for accurate diagnosis and for accurate results in subsequent monitoring assays.
Determination of BCR-ABL1 messenger RNA transcript levels should be done by quantitative real-time reverse transcription polymerase chain reaction-based assays, and reported results should be standardized according to the International Scale. Testing is appropriate at baseline before the start of imatinib treatment; every 3 months for 3 years, then every 3-6 months thereafter. Without attainment of a complete cytogenetic response, continued monitoring at 3-month intervals is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib as well and will likely also be applied to bosutinib and ponatinib.
Inadequate initial response to tyrosine kinase inhibitors is defined as failure to achieve complete hematologic response at 3 months, only minor cytological response at 6 months or major (rather than complete) cytogenetic response at 12 months.
Loss of response to tyrosine kinase inhibitors is defined as hematologic relapse, cytogenetic relapse or 1 log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response.
Kinase domain mutation testing is usually offered either as a single test to identify T315I mutation or as a panel (which includes T315I) of the most common and clinically important mutations.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.
SOURCE(S)Blue Cross and Blue Shield Association Policy # 2.04.85
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.