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In the treatment of Philadelphia (Ph) chromosome-positive leukemias, various nucleic acid-based laboratory methods may be used to detect the BCR-ABL1 fusion gene for confirmation of the diagnosis; for quantifying mRNA BCR-ABL1 transcripts 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
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, or very high or very low platelet counts. 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.
Extensive clinical data have led to the development of congruent recommendations and guidelines developed both in North America and in Europe on the use of various types of molecular tests relevant to the diagnosis and management of CML. These tests are useful in the accelerated and blast phases of this malignancy.
Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. ALL is the most common childhood tumor, and represents 75% to 80% of acute leukemias in children. ALL represents only 20% of all leukemias in the adult population. The median age at diagnosis is 14 years; 60% of patients are diagnosed at younger than 20 years of age. Current survival rates for patients with ALL have improved dramatically over the past, primarily in children, largely due to better understanding of the molecular genetics of the disease, incorporation of risk-adapted therapy, and new targeted agents. Current treatment regimens have a cure rate among children of about 80%. Long-term prognosis among adults is poor, with cure rates of 30% to 40%. Prognosis variation is explained, in part, by different subtypes among age groups, including the BCR-ABL fusion gene, which has a poor prognosis and is much less common in childhood ALL.
Philadelphia (Ph) chromosome-positive leukemias are characterized by the expression of the oncogenic fusion protein product BCR-ABL1, resulting from reciprocal translocation between chromosomes 9 and 22. This abnormal fusion product characterizes CML. In ALL, with increasing age, the frequency of genetic alterations associated with favorable outcomes declines and alterations associated with poor outcomes, such as BCR-ABL1, are more common. In ALL, the Ph chromosome is found in 3% of children and 25% to 30% of adults. 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 CML. 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.
Although CML is diagnosed primarily by clinical and cytogenetic methods, qualitative molecular testing is needed to confirm the presence of the BCR-ABL1 fusion gene, particularly if the Ph chromosome was not found, and to identify the type of fusion gene, because this information is necessary for subsequent quantitative testing of fusion gene messenger RNA transcripts. If the fusion gene is not confirmed, then the diagnosis of CML is called into question.
Determining the qualitative presence of the BCR-ABL1 fusion gene is not necessary to establish a diagnosis of ALL.
Treatment and Response and Minimal Residual Disease
Before initiation of therapy for CML or ALL, quantification of the BCR-ABL transcript is necessary to establish baseline levels for subsequent quantitative monitoring of response during treatment.
Quantitative determination of BCR-ABL1 transcript levels during treatment allows for a very sensitive determination of the degree of patient response to treatment. Evaluation of trial samples has consistently shown the degree of molecular response correlates with risk of progression. In addition, the degree of molecular response at early time points predicts improved rates of progression-free and event-free survival. Conversely, rising BCR-ABL1 transcript levels predicts treatment failure and the need to consider a change in management. Quantitative polymerase chain reaction (PCR)‒based methods and international standards for reporting have been recommended and adopted for treatment monitoring.
Imatinib (Gleevec), a tyrosine kinase inhibitor (TKI), was originally developed to specifically target and inactivate the ABl tyrosine kinase portion of the Bcr-ABl1 fusion protein 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.
With the established poor prognosis of Ph-positive ALL, standard ALL chemotherapy alone has long been recognized as a suboptimal therapeutic option, with 60% to 80% of patients achieving a complete response, significantly lower than that achieved in Ph-negative ALL. The inclusion of TKIs to frontline induction chemotherapy has improved complete response rates, exceeding 90%.
Treatment response is evaluated initially by hematologic response (normalization of peripheral blood counts), then by cytogenetic response (percent of cells with Ph-positive metaphase 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. It is well established that most “good responders” who are considered to be in morphologic remission but relapse may still have considerable levels of leukemia cells, referred to as minimal residual disease (MRD.) Among children with ALL who achieve a complete response (CR) by morphologic evaluation after induction therapy, approximately 25% to 50% may still have detectable MRD based on sensitive assays. Current methods used for MRD detection include flow cytometry (sensitivity of MRD detection, 0.01%), or polymerase chain reaction (PCR)‒based analyses (Ig and T-cell receptor gene rearrangements or analysis of BCR-ABL transcripts), which are the most sensitive methods of monitoring treatment response (sensitivity, 0.001%. Most ALL patients can be tested with Ig and T-cell receptor gene arrangement analysis, whereas only Ph-positive patients can be tested with PCR analysis of BCR-ABL transcripts.
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 have shown 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.
Molecular resistance is most often as genomic instability associated with the creation of the abnormal BCR-ABL1 gene, usually resulting in point mutations within the ABL1 gene kinase domain (KD) 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.
The presence of ABL KD point mutations is associated with treatment failure. A large number of mutations have been detected, but extensive analysis of trial data with low-sensitivity mutation detection methods has identified a small number of mutations consistently associated with treatment failure with specific TKIs; guidelines recommend testing for, and use of information on these specific mutations in subsequent treatment decisions. The recommended method is sequencing with or without denaturing high-performance liquid chromatography screening to reduce the number of samples to be sequenced. Targeted methods that detect the mutations of interest for management decisions are also acceptable if designed for low sensitivity. High-sensitivity assays are not recommended.
Unlike imatinib, fewer mutations are associated with resistance to dasatinib or nilotinib. For example, Guilhot and colleagues and Cortes and colleagues 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 and colleagues, 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.
Unlike in CML, resistance in ALL to TKIs is less well studied. In patients with ALL receiving a TKI, a rise in the BCR-ABL level while in hematologic complete response or clinical relapse warrants mutational analysis.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). The BCR/ABL1 qualitative and quantitative genotyping tests and ABL kinase domain mutation tests are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.
Chronic Myelogenous Leukemia
BCR/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 transcription-polymerase 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.
Acute Lymphoblastic Leukemia
BCR/ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) at baseline prior to initiation of treatment and at appropriate intervals during therapy (see Policy Guidelines section) is considered medically necessary for monitoring of Philadelphia chromosome-positive acute lymphoblastic 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.
Evaluation of ABL kinase domain point mutations is considered investigational for monitoring in advance of signs of treatment failure or disease progression.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
Diagnosis of CML and ALL
Qualitative molecular confirmation of the cytogenetic diagnosis (i.e., detection of the Philadelphia chromosome) is necessary for accurate diagnosis of CML. Identification of the Philadelphia chromosome is not necessary for the diagnosis of ALL, however, molecular phenotyping is generally performed at the initial assessment (See Determining baseline RNA transcript levels and subsequent monitoring).
Distinction between molecular variants (i.e., p190 vs. p210) is necessary for accurate results in subsequent monitoring assays.
Determining baseline RNA transcript levels and subsequent monitoring
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.
For CML, testing is appropriate at baseline before the start of imatinib treatment and testing is appropriate every 3 months when the patient is responding to treatment. After a complete cytogenetic response is achieved, testing is recommended every 3 months for 2 years and then every 3-6 months thereafter.
Without 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 and will likely also be applied to bosutinib and ponatinib.
For ALL, the optimal timing remains unclear and depends upon the chemotherapy regimen used.
Tyrosine Kinase Inhibitor Resistance
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.
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.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Nervous/Mental Conditions, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of Medically Necessary, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.
09/16/2014: Policy title changed from "BCR-ABL1 Testing for Diagnosis, Monitoring, and Drug Resistance Mutation Detection in Chronic Myelogenous Leukemia" to "BCR-ABL1 Testing in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia." Policy description updated regarding acute lymphoblastic leukemia, disease genetics, and treatment and response and minimal residual disease. Policy statement section updated to add "Chronic Myelogenous Leukemia" and "Acute Lymphoblastic Leukemia." Added three policy statements under acute lymphoblastic leukemia heading regarding BCR/ABL1 testing and the evaluation of ABL kinase domain point mutations. Policy guidelines updated to clarify the timing of testing in patients who are responding to treatment or who have a complete cytogenetic response. Added and updated the following headings in the Policy Guidelines: Diagnosis of CML and ALL, Determining baseline RNA transcript levels and subsequent monitoring, and TKI resistance. Added ICD-9 diagnosis codes 204.00-204.02 to the Code Reference section.
04/21/2015: Policy reviewed. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigational definitions.
08/21/2015: Code Reference section updated for ICD-10.
12/31/2015: Code Reference section updated to add new 2016 CPT code 81170.
06/09/2016: Policy number A.2.04.85 added. Policy description updated regarding diagnosis, treatment, and response of CML and ALL. Policy statements unchanged. Policy guidelines section updated regarding determining baseline RNA transcript levels and subsequent monitoring: For CML, after a complete cytogenetic response is achieved, recommended testing changed from "every 3 months for 3 years" to "every 3 months for 2 years."
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.
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.