CAM 20485

BCR-ABL1 Testing in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Category:Laboratory   Last Reviewed:July 2019
Department(s):Medical Affairs   Next Review:July 2020
Original Date:August 2013    

Description
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.  

The evidence for BCR/ABL1 fusion gene qualitative testing to confirm diagnosis and establish baseline for monitoring treatment in individuals who have suspected chronic myelogenous leukemia (CML) includes validation studies. Relevant outcomes are test accuracy and test validity. The sensitivity of testing with reverse transcription-polymerase chain reaction is high compared with conventional cytogenetics. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for quantitative BCR/ABL1 quantitative testing at appropriate intervals during therapy for monitoring treatment response and remission in individuals who have a diagnosis of CML or at baseline prior to and during treatment to monitor treatment response and remission in individuals who have acute lymphoblastic leukemia (ALL) includes a randomized trial and case series. Relevant outcomes are disease-specific survival, test accuracy and validity and change in disease status. Studies have shown a high sensitivity of this type of testing and a strong correlation with outcomes, including risk of disease progression and survival, and may stratify patients to different treatment options. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for evaluation of ABL kinase domain (KD) point mutations to assess for TKI resistance in individuals who have a diagnosis of CML or who have Ph chromosome‒positive ALL and signs of treatment failure or disease progression includes a systematic review of pharmacogenetic testing for TKIs and case series reporting the presence of KD mutations detected at imatinib failure. Relevant outcomes are test accuracy and validity and medication use. Studies have shown a correlation between certain types of mutations, treatment response and the selection of subsequent treatment options. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Background
Disease
Chronic Myelogenous Leukemia
Chronic myelogenous leukemia (CML) is a clonal disorder of myeloid hematopoietic 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% to 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.1 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. Median age at diagnosis is 14 years; 60% of patients are diagnosed before 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.  

Disease Genetics
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.2 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 ALL, 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.  

Diagnosis
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 predict 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 with 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."3 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.4 The inclusion of TKIs to frontline induction chemotherapy has improved complete response rates, exceeding 90%.4 

Treatment response is evaluated initially by hematologic response (normalization of peripheral blood counts), then by cytogenetic response (percentage of cells with Ph-positive metaphase chromosomes in a bone marrow aspirate). Complete cytogenetic response (CCyR; 0% Ph-positive metaphases) is expected by 6 to 12 months after initial treatment with the TKI imatinib.3 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 by morphologic evaluation after induction therapy, 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 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%).5 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 is.  

Resistance
Imatinib treatment does not usually result in completely eradicated 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.3,6    

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 1 year of treatment, including CCyR (primary outcome), time to remission and rates of progression to accelerated phase or blast crisis.7,8 Although initial follow-up was short, early and sustained CCyR was considered a validated marker for survival in CML. On June 17, 2010, FDA approved nilotinib for the treatment of patients with newly diagnosed chronic phase CML. Dasatinib was approved on Oct. 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, or imatinib dose escalation from 400 to 800 mg daily, as tolerated, or therapy change to an alternative second-generation TKI.3

Molecular Resistance
Molecular resistance is most often explained 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 KD point mutations account for 30% to 50% of secondary resistance.6 At least 58 different KD mutations have been identified in CML patients.9 The degree of resistance depends on the position of the mutation within the KD (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% to 19%, depending on the patient population; it is more common in patients with advanced phase CML than in patients with early chronic phase CML.10-12

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.13,14 For example, Guilhot et al.15 and Cortes et al.16 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,15,9 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.,17 137 patients with accelerated phase CML were evaluated after 24 months. Sixty-six percent 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.18 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.6

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.  

Regulatory Status 
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.

Related Policies
None

Policy 

  1. Qualitative or quantitative RT-PCR testing for identification of the BCR-ABL1 fusion gene transcript type is considered MEDICALLY NECESSARY for the differential diagnosis of CML or ALL.
  2. Quantitative testing on blood or bone marrow for the BCR-ABL1 fusion gene transcript in individuals with CML, using the International Scale reporting convention, for patients prior to initiation or undergoing treatment with TKI therapy, is considered MEDICALLY NECESSARY:
    1. As a baseline measurement prior to initiation of TKI therapy
    2. Every 3 months after initiation of therapy after MMR (BCR-ABL1 (IS) < 1% (>0.1%-1%)) has been achieved
    3. Every 3 months for 2 years and every 3-6 months thereafter
    4. If there is a 1-log increase in BCR-ABL1 transcript levels with MMR, repeat in 1-3 months
  3. Quantitative testing on blood or bone marrow for the BCR-ABL1 fusion gene transcript in individuals with CML, using the International Scale reporting convention, for patients undergoing treatment discontinuation with TKI therapy and who remain in MMR after discontinuation of therapy, is considered MEDICALLY NECESSARY.
  4. Evaluation of BCR-ABL kinase domain point mutations in patients with CML is considered MEDICALLY NECESSARY when:
    1. There is insufficient response to TKI therapy, OR
    2. There is loss of response to TKI therapy, OR
    3. 1-log increase in BCR-ABL1 transcript levels and loss of MMR, OR
    4. The disease progresses to accelerated or blast phase.
  5. Quantitative or qualitative testing on blood or bone marrow for the BCR-ABL1 fusion gene transcript, including determination of transcript size (ie, p190 vs. p210), in individuals diagnosed with B-ALL, using the International Scale reporting convention, is considered MEDICALLY NECESSARY for optimal risk stratification, treatment planning, surveillance, and MRD assessment.
  6. Evaluation of BCR-ABL kinase domain point mutations in patients with ALL is considered MEDICALLY NECESSARYwhen there is relapsed or refractory disease in Ph positive ALL patients.
  7. Testing of both bone marrow and blood for monitoring purposes is considered NOT MEDICALLY NECESSARY.

Policy Guidelines
Diagnosis of CML and ALL
Qualitative molecular confirmation of the cytogenetic diagnosis (i.e., detection of the Philadelphia chromosome) is necessary information for the 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 time of initial assessment (See Determining baseline RNA transcript levels and subsequent monitoring).

Distinction between molecular variants (i.e., p190 vs. p210) is necessary information 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 RT-PCR-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, every three months for three years, then every three to six months thereafter. Without attainment of a complete cytogenetic response, continued monitoring at three-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 (see Rationale section for more information). For ALL, the optimal timing remains unclear and depends upon the chemotherapy regimen used.

TKI Resistance
For CML, inadequate initial response to TKIs is defined as failure to achieve complete hematologic response at three months, only minor cytologic response at six months or major (rather than complete) cytogenetic response at 12 months.

Unlike in CML, resistance in ALL to TKIs is less well studied. In patients with ALL who are receiving a TKI, a rise in the BCR-ABL level while in hematologic CR or clinical relapse warrants mutational analysis.

Loss of response to TKIs is defined as hematologic relapse, cytogenetic relapse or one log increase in BCR-ABL1 transcript ratio and, therefore, loss of major molecular response (MMR).

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.

There is specific CPT coding for BCR-ABL1 testing:

81206: BCR/ABL1 (t(9;22)) (e.g., chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative

81207: minor breakpoint, qualitative or quantitative

81208: other breakpoint, qualitative or quantitative

Testing for ABL kinase domain point mutations to evaluate patients for TKI resistance would be reported with the following codes:

CPT code 81401 includes the following test:

ABL (c-abl oncogene 1, receptor tyrosine kinase) (e.g., acquired imatinib resistance), T315I variant

CPT code 81403 includes the following test:

ABL1 (c-abl oncogene 1, receptor tyrosine kinase) (e.g., acquired imatinib tyrosine kinase inhibitor resistance), variants in the kinase domain

Benefit Application
Blue Card®/National Account Issues
None identified

Rationale
Various types of laboratory tests for BCR-ABL1 detection are associated with chronic myelogenous leukemia (CML) and have different clinical uses. Briefly, they are:

  1. Diagnosis: Patients who do not have the BCR-AB1L fusion gene by definition do not have CML. In contrast, identification of the BCR-ABL1 fusion gene is necessary, although not sufficient, for diagnosis. Relevant test technologies are cytogenetics (karyotyping; recommended) or fluorescence in situ hybridization (FISH; acceptable in the absence of sufficient sample for karyotyping).
  2. Monitoring BCR-ABL1 RNA transcripts for residual disease during treatment/disease remission; relevant, standardized test technology is quantitative reverse-transcription polymerase chain reaction (RT-PCR). Note that a baseline measurement after confirmation of CML diagnosis, and before treatment begins is strongly recommended.
  3. Identification and monitoring of mutations for drug resistance at response failure or disease progression; various test technologies are in use (not standardized).

Diagnosis/Pretreatment Workup
Chronic Myelogenous Leukemia
While the diagnosis of CML is based on the presence of characteristic cellular abnormalities in bone marrow, the presence of the Philadelphia (Ph) chromosome and/or confirmation of the BCR-ABL1 fusion gene is essential. The initial evaluation of chronic phase CML should include bone marrow cytogenetics, not only to detect the Ph chromosome, but also to detect other possible chromosomal abnormalities.19 If bone marrow is not available, FISH analysis with dual probes for BCR and ABL genes or qualitative RT-PCR can provide qualitative confirmation of the fusion gene and its type.19 Baseline measurement of BCR-ABL transcript levels are recommended as part of the initial evaluation, providing confirmation of the fusion gene, ensuring that it is detectable (rare variants requiring nonstandard probes may occur), and providing baseline for monitoring response to treatment.19

Acute Lymphoblastic Leukemia
The diagnosis of acute lymphoblastic leukemia (ALL) is made by demonstrating 20% or greater bone marrow lymphoblasts; demonstration of the BCR-ABL fusion gene is not essential. However, identification of specific molecular subtypes is recommended at the time of diagnosis for optimal risk evaluation and treatment planning. The initial evaluation of ALL patients should include bone marrow sample for RT-PCR for BCR-ABL to establish the presence or absence of BCR-ABL, as well as baseline transcript quantification.4

Monitoring for Residual Disease During Treatment and Disease Remission
Chronic Myelogenous Leukemia
Quantitative RT-PCR (qRT-PCR) measurement of BCR-ABL1 RNA transcript levels is the method of choice for assessing response to treatment because of the high sensitivity of the method and strong correlation with outcomes.3 Compared with conventional cytogenetics, qRT-PCR is more than 3 logs more sensitive20 and can detect 1 CML cell in the background of 100,000 or more normal cells. qRT-PCR testing can be conducted on peripheral blood, eliminating the need for bone marrow sampling. The goal of treatment is complete molecular response (CMR; no detectable BCR-ABL transcript levels by qRT-PCR). However, only a small minority of patients achieve CMR on imatinib.21 More often, patients achieve a major molecular response (MMR; a 3-log reduction from the standardized baseline of the International Scale (IS; not from the actual baseline level of the individual patient). Results from the IRIS trial showed that patients who had a CMR or MMR had a negligible risk of disease progression at 1 year, and a significantly lower risk of disease progression at 5 years than patients who had neither.22 At 8-year follow-up, none of the patients who achieved an MMR at 1 year progressed to the accelerated phase of disease or to a blast crisis. Similar near absence of progression in patients who achieved an MMR has been reported in registration studies of nilotinib and dasatinib.7,8,21

The degree of molecular response has been reported to correlate with risk of progression in patients treated with imatinib.23 Timing of the molecular response is also important; the degree of molecular response at early time points predicts the likelihood of achieving CMR or MMR and predicts improved rates of progression-free and event-free survival.24-27 While early and strong molecular response predicts durable long-term remission rates and progression-free survival, studies have not been conclusive that molecular response is predictive of overall survival.28-30

Based on imatinib follow-up data, it is recommended that, for patients with a complete cytogenetic response (CCyR), molecular response to treatment be measured every 3 months for 2 years, then every 3 to 6 months thereafter.3,31 Without CCyR, 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,3 and will likely also be applied to bosutinib and ponatinib.

Rising BCR-ABL1 transcript levels are associated with increased risk of mutations and of treatment failure.32-37 However, what constitutes a clinically significant rise to warrant mutation testing is not known. Factors affecting the clinically significant change include the variability of the specific assay used by the laboratory and the level of molecular response achieved by the patient. Thresholds used include 2- to 10-fold increases, and increases of 0.5 to 1 log, respectively.33,38 Because of potential variability in results and lack of agreement across studies for an acceptable threshold, rising transcript levels alone are not viewed as sufficient to trigger mutation testing or changes in treatment.39

Standardization of BCR-ABL1 Quantitative Transcript Testing
A substantial effort has been made to standardize the BCR-ABL1 qRT-PCR testing and reporting across academic and private laboratories. In 2006, the National Institutes of Health Consensus Group proposed an IS for BCR-ABL1 measurement.40 The IS defines 100% as the median pretreatment baseline level of BCR-ABL1 RNA in early chronic phase CML; as determined in the pivotal IRIS trial, MMR is defined as a 3-log reduction relative to the standardized baseline, or 0.1% BCR-ABL1 on the IS.41 In the assay, BCR-ABL1 transcripts are quantified relative to 1 of 3 recommended reference genes (e.g., ABL) to control for the quality and quantity of RNA and to normalize for potential differences between tests.42,43 Percent ratios on the IS are determined at local labs by a test-specific conversion factor: IS percent ratio = local percent ratio conversion factor. Until reference standards become broadly available, patient specimens must be exchanged between the local laboratory and an IS reference laboratory to establish a laboratory-specific conversion factor (available online at www.whereareyouontheis.com/Default.aspx). In the United States, many laboratories offer BCR-ABL quantitative testing (e.g., Quest, ARUP, LabCorp, Mayo), and most specify on their websites that results are standardized to the IS.

Acute Lymphoblastic Leukemia
Despite significantly higher complete response (CR) rates with tyrosine kinase inhibitors (TKIs) in Ph-positive ALL, the response is typically short-lived and relapses are common.4 The principal aim of after remission therapy is to eradicate minimal residual disease (MRD), which is the prime cause for relapse.4

Studies in children and adults with ALL have demonstrated a strong correlation between MRD and risk for relapse, as well as the prognostic significance of measuring MRD during and after initial induction therapy. A commonly used cutoff to define MRD positivity is 0.01%, with patients who attain an MRD less than 0.01% early during therapy having high odds of remaining in continuous CR with contemporary postremission therapy.44

A study of 3184 B-cell ALL children enrolled in the AIEOP-BFM ALL 2000 treatment protocol demonstrated that a risk classification algorithm based on MRD measurements using PCR on days 33 and 78 of treatment was superior to that of other risk stratification criteria based on white blood cell count, age, early response to prednisone and genetic subtype.44,45 Patients with an MRD less than 0.01% on day 33 (42%) had a 5-year event-free survival of 92.3%.

NCCN recommendations state that the timing of testing for MRD depends on the ALL chemotherapy regimen used and may occur during or after completion of induction therapy or at additional time points.

MRD is also a strong prognostic factor for children and adolescents with first-relapse ALL who achieve a second remission.44 Patients with an MRD of 0.01% or more are eligible for allogeneic hematopoietic cell transplantation, whereas achievement of MRD negativity may be an indication for chemotherapy.44

Identification of ABL Kinase Domain Mutations (Mutations Associated With TKI Resistance)
Chronic Myelogenous Leukemia
Screening for BCR-ABL1 kinase domain (KD) point mutations (i.e., single-nucleotide polymorphisms) in chronic phase CML is recommended for patients with (1) inadequate initial response to TKI treatment, (2) with evidence of loss of response or (3) who have progressed to accelerated or blast phase CML.3 Testing for KD point mutations, in the setting of potential treatment failure, helps to select from among other possible TKI treatments or allogeneic cell transplantation. The following discussion focuses only on KD point mutations.

In 2010, the Agency for Healthcare Research and Quality published a systematic review on BCR-ABL1 pharmacogenetic testing for TKIs in CML.46 The report concluded that the presence of any BCR-ABL1 mutation does not predict differential response to TKI therapy, although the presence of the T315I mutation uniformly predicts TKI failure. The review was strongly criticized by respected pathology organizations for insufficient attention to several issues. Importantly, the report grouped studies that used KD mutation screening methods with those that used targeted methods, and grouped studies that used mutation detection technologies with very different sensitivities. The report discounted issues related to analytic validity. However, in this clinical scenario, assays used for different reasons (screening vs. targeted) and assays with very different sensitivities may lead to different clinical conclusions.

Point Mutation Detection Methods
Currently, methods for detecting drug resistance mutations are not standardized; clinical laboratories may choose among different methods. Some can detect specific, known mutations (e.g., targeted mutation analysis) or screen for all possible mutations (e.g., direct sequencing); sensitivity also varies by method.

Particular methods to detect BCR-ABL KD mutations will greatly influence the detection frequency, analytic sensitivity and the clinical impact of testing. The various mutation detection methods available have widely differing analytic sensitivities, from the least sensitive direct Sanger sequencing to the highly sensitive mutation-specific quantitative PCR methods.

Direct Sanger sequencing screens for all possible mutations but has low sensitivity, detecting a mutation present in approximately 1 in 5 BCR-ABL1 transcripts. Denaturing high-performance liquid chromatography (DHPLC) is a screening method with initially higher sensitivity to detect the presence or absence of mutations. Follow-up Sanger sequencing of positive samples is required to identify the mutations present; final sensitivity of this method is the sensitivity of sequencing. Targeted methods, used either to screen for only the most common, clinically relevant mutations or to monitor already identified mutations after a therapy change, can offer either limited sensitivity (e.g., pyrosequencing) or very high sensitivity (e.g., allele-specific PCR).

KD Point Mutations and Treatment Outcomes
Branford et al. summarized available evidence in 2009 regarding KD mutations detected at imatinib treatment failure, and subsequent treatment success or failure with dasatinib or nilotinib.47 Studies referenced used direct Sanger sequencing, with or without DHPLC screening, to identify mutations at low sensitivity. The authors conducted a survey of mutations detected in patients at imatinib failure at their own institution and compared results with a collation of mutations derived from the literature. For both, the T315I mutation was most common; although about 100 mutations have been reported, the 7 most common (at residues T315, Y253, E255, M351, G250, F359 and H396) accounted for 60% to 66% of all mutations in both surveys. Detection of the T315I mutation at imatinib failure is associated with lack of subsequent response to high-dose imatinib or to dasatinib or nilotinib. For these patients, allogeneic cell transplantation was the only available treatment until the approval of new agents (e.g., ponatinib).48 Most common, however, does not necessarily correspond to clinically significant. Based on the available clinical studies, most imatinib-resistant mutations remain sensitive to dasatinib and nilotinib. However, pre-existing or emerging mutations T315A, F317L/I/V/C and V299L are associated with decreased clinical efficacy with dasatinib treatment following imatinib failure. Similarly, pre-existing or emerging mutations Y253H, E255K/V and F359V/C have been reported to have decreased clinical efficacy with nilotinib treatment following imatinib failure. In the Branford survey, 42% of patients tested had T315I or one of the dasatinib- or nilotinib-resistant mutations.47 As a result, guidelines recommend mutation analysis only at treatment failure, and use of the T315I mutation and the identified dasatinib- and nilotinib-resistant mutations to select subsequent treatment.3,39 Absent any of these actionable mutations, various treatment options are available. Note that these data were obtained from studies of patients all initially treated with imatinib. No data are available on mutations developing during first-line therapy with dasatinib or nilotinib.49

ABL KD mutational analysis is recommended if there is inadequate initial response (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) or any sign of loss of response (defined as hematologic relapse, cytogenetic relapse or 1-log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response). Mutation testing is also recommended for progression to accelerated or blast phase CML. Treatment recommendations based on mutation(s) are shown in Table 1.  

Table 1. Treatment Options Based on BCR-ABL1 KD Point Mutation Status at Imatinib Treatment Failure

Mutation   Treatment Recommendation  
T315I   Ponatinib,a HSCT or clinical trial  
V299L, T315A, F317L/V/I/C   Consider nilotinib or bosutiniba rather than dasatinib  
Y253H, E255K/V, F359V/C/I   Consider dasatinib or bosutiniba rather than nilotinib  
Any other mutation   Consider high-dose imatinib, or dasatinib, nilotinib, or bosutiniba 

HSCT: hematopoietic stem cell transplantation; KD: kinase domain.
a Recently approved; added in advance of National Comprehensive Cancer Network update, from which guidelines in this table have been modified. Ponatinib active in treatment-resistant patients with T3151 mutation.48,50 Bosutinib is active across BCR-ABL1 mutations including dasatinib- and nilotinib-resistant mutations except T315I, and after treatment failure with imatinib, dasatinib, or nilotinib.51,52  

Because only a small number of mutations have been recommended as clinically actionable, targeted assays may also be used to screen for the presence of actionable mutations at treatment failure. Quantitative, targeted assays may also be used to monitor levels of already identified clinically significant mutations after starting a new therapy because of initial treatment failure. Targeted assays use different technologies that can be very sensitive and pick up mutated cell clones at very low frequencies in the overall malignant population. Banked samples from completed trials have been studied with high-sensitivity assays to determine if monitoring treatment can detect low-level mutations that predict treatment failure well in advance of clinical indications. Some results have been positive, but not all mutations detected in advance predict treatment failure; more study is recommended before these assays are used for monitoring in advance of treatment failure.39,47 A direct correlation between low-sensitivity and high-sensitivity assays and a limited correlation with clinical outcomes support recommendations of sequencing, with or without DHPLC screening, for identification of mutations.53 Although high-sensitivity assays identified more mutations than did sequencing, the clinical impact of identifying additional mutations is uncertain.

Mutations other than point mutations can be detected in the BCR-ABL1 gene, including alternate splicing, insertions, deletions and/or duplications. The clinical significance of such altered transcripts is unclear, and reporting such mutations is not recommended.6,49  

Acute Lymphoblastic Leukemia
Unlike in CML, resistance in ALL to TKIs is less well studied. Resistance does not necessarily arise from dominant tumor clone(s), but possibly in response to TKI-driven selective pressure and/or competition of other coexisting subclones.4 In patients with ALL receiving a TKI, a rise in the BCR-ABL protein level while in hematologic CR or clinical relapse warrants mutational analysis. 

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 2. 

Table 2. Summary of Key Trials

NCT No. Trail Name Planned Enrollment Completion Date
Ongoing
NCT01343173  Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib  220  Jul 2017 
NCT01578213 Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients (ISAV)  100  Nov 2018 
Unpublished    
NCT00760877ª  An Open Label, Randomized Study of Nilotinib vs. Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response for CML-CP Patients With Evidence of Persistent Leukemia by RQ-PCR  206  Jul 2015 (completed)
NTC01580059ª  Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in Chronic Phase  419  Nov 2014 (completed)
NCT01342679 A Study of Complete Molecular Response for Chronic Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib  21  Sep 2014 (completed) 

NCT: national clinical trial.
a Denotes industry-sponsored or cosponsored trial.  

Summary of Evidence
The evidence for BCR/ABL1 fusion gene qualitative testing to confirm diagnosis and establish baseline for monitoring treatment in individuals who have suspected chronic myelogenous leukemia (CML) includes validation studies. Relevant outcomes are test accuracy and test validity. The sensitivity of testing with reverse transcription-polymerase chain reaction is high compared with conventional cytogenetics. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for quantitative BCR/ABL1 quantitative testing at appropriate intervals during therapy for monitoring treatment response and remission in individuals who have a diagnosis of CML or at baseline prior to and during treatment to monitor treatment response and remission in individuals who have acute lymphoblastic leukemia (ALL) includes a randomized trial and case series. Relevant outcomes are disease-specific survival, test accuracy and validity and change in disease status. Studies have shown a high sensitivity of this type of testing and a strong correlation with outcomes, including risk of disease progression and survival, and may stratify patients to different treatment options. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

The evidence for evaluation of ABL kinase domain (KD) point mutations to assess for tyrosine kinase inhibitor resistance in individuals who have a diagnosis of CML or who have Philadelphia chromosome‒positive ALL and signs of treatment failure or disease progression includes a systematic review of pharmacogenetic testing for TKIs and case series reporting the presence of KD mutations detected at imatinib failure. Relevant outcomes are test accuracy and validity and medication use. Studies have shown a correlation between certain types of mutations, treatment response and the selection of subsequent treatment options. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.  

Practice Guidelines and Position Statements
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (NCCN) practice guidelines (v.1.2016) on chronic myelogenous leukemia outline recommended methods for diagnosis and treatment management of CML, including BCR-ABL1 tests for diagnosis, monitoring and ABL KD mutations, and were referred to extensively in this document.3   

The NCCN practice guidelines (v.2.2015) on ALL state that, if minimal residual disease (MRD) is being evaluated, the initial measurement should be performed on completion of induction therapy; additional time points for MRD evaluation may be useful, depending on the specific treatment protocol or regimen used. MRD is an essential component of patient evaluation during sequential therapy.54   

European LeukemiaNet
The European LeukemiaNet management recommendations for CML are similar to those of NCCN.31,38 The U.S. Association for Molecular Pathology6 and European LeukemiaNet recommendations for KD mutation analysis39 both provide very similar guidelines.  

Other
In 2010, technical recommendations for MRD assessment and definitions for response based on MRD results were made in an effort to standardize MRD measurements and MRD data reporting in European ALL trials.55 

U.S. Preventive Services Task Force Recommendations
Not applicable. 

References    

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  9. Mughal TI, Goldman JM. Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia. Clin Lymphoma Myeloma. Mar 2007;7 Suppl 2:S81-84. PMID 17382017
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  19. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. Aug 16 2012;120(7):1390-1397. PMID 22613793
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  21. Radich JP. Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia. Cancer. Jan 15 2012;118(2):300-311. PMID 21717440
  22. Druker BJ, Guilhot F, O'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. Dec 7 2006;355(23):2408-2417. PMID 17151364
  23. Press RD, Love Z, Tronnes AA, et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood. Jun 1 2006;107(11):4250-4256. PMID 16467199
  24. Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia. Dec 2003;17(12):2401-2409. PMID 14523461
  25. Wang L, Pearson K, Ferguson JE, et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukaemia. Br J Haematol. Mar 2003;120(6):990-999. PMID 12648069
  26. Quintas-Cardama A, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood. Jun 18 2009;113(25):6315-6321. PMID 19369233
  27. Müller MC, Hanfstein B, Erben P, et al. Molecular Response to First Line Imatinib Therapy Is Predictive for Long Term Event Free Survival in Patients with Chronic Phase Chronic Myelogenous Leukemia – An Interim Analysis of the Randomized German CML Study IV. Blood 2008;112:129. Abstract 333.
  28. Hehlmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-alpha in newly diagnosed chronic myeloid leukemia. J Clin Oncol. Apr 20 2011;29(12):1634-1642. PMID 21422420
  29. de Lavallade H, Apperley JF, Khorashad JS, et al. Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol. Jul 10 2008;26(20):3358-3363. PMID 18519952
  30. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. Dec 1 2008;112(12):4437-4444. PMID 18716134
  31. Baccarani M, Castagnetti F, Gugliotta G, et al. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol. Apr 2015;94 Suppl 2:S141-147. PMID 25814080
  32. Press RD, Galderisi C, Yang R, et al. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res. Oct 15 2007;13(20):6136-6143. PMID 17947479
  33. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR analysis can be used as a primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood. Nov 1 2004;104(9):2926-2932. PMID 15256429 
  34. Wang L, Knight K, Lucas C, et al. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica. Feb 2006;91(2):235-239. PMID 16461309
  35. Press RD, Willis SG, Laudadio J, et al. Determining the rise in BCR-ABL RNA that optimally predicts a kinase domain mutation in patients with chronic myeloid leukemia on imatinib. Blood. Sep 24 2009;114(13):2598-2605. PMID 19625707
  36. Marin D, Khorashad JS, Foroni L, et al. Does a rise in the BCR-ABL1 transcript level identify chronic phase CML patients responding to imatinib who have a high risk of cytogenetic relapse? Br J Haematol. May 2009;145(3):373-375. PMID 19344397
  37. Kantarjian HM, Shan J, Jones D, et al. Significance of increasing levels of minimal residual disease in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in complete cytogenetic response. J Clin Oncol. Aug 1 2009;27(22):3659-3663. PMID 19487383
  38. Baccarani M, Cortes J, Pane F, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. Dec 10 2009;27(35):6041-6051. PMID 19884523
  39. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. Aug 4 2011;118(5):1208-1215. PMID 21562040
  40. Hughes T, Deininger M, Hochhaus A, et al. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results. Blood. Jul 1 2006;108(1):28-37. PMID 16522812
  41. Hughes TP, Kaeda J, Branford S, et al. Frequency of major molecular responses to imatinib or interferon alfa plus cytarabine in newly diagnosed chronic myeloid leukemia. N Engl J Med. Oct 9 2003;349(15):1423-1432. PMID 14534335
  42. Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol. Sep 2009;22(3):355-365. PMID 19959086
  43. Hughes T, Branford S. Molecular monitoring of BCR-ABL as a guide to clinical management in chronic myeloid leukaemia. Blood Rev. Jan 2006;20(1):29-41. PMID 16426942
  44. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2010;2010:7-12. PMID 21239764
  45. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. Apr 22 2010;115(16):3206-3214. PMID 20154213
  46. Terasawa T, Dahabreh I, Castaldi PJ, et al. Systematic reviews on selected pharmacogenetic tests for cancer treatment: CYP2D6 for Tamoxifen in breast cancer, KRAS for anti-EGFR antibodies in colorectal cancer, and BCR-ABL1 for tyrosine kinase inhibitors in chronic myeloid leukemia. Rockville: Agency for Healthcare Research and Quality (AHRQ). Technology Assessment. 2010.
  47. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. Dec 24 2009;114(27):5426-5435. PMID 19880502
  48. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial. American Society of Hematology 54th Annual Meeting, December 2012. 2012:Abstract 163.
  49. Alikian M, Gerrard G, Subramanian PG, et al. BCR-ABL1 kinase domain mutations: methodology and clinical evaluation. Am J Hematol. Mar 2012;87(3):298-304. PMID 22231203
  50. Cortes JE, Kantarjian H, Shah NP, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. Nov 29 2012;367(22):2075-2088. PMID 23190221
  51. Khoury HJ, Cortes JE, Kantarjian HM, et al. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. Apr 12 2012;119(15):3403-3412. PMID 22371878
  52. Cortes JE, Kantarjian HM, Brummendorf TH, et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. Oct 27 2011;118(17):4567-4576. PMID 21865346
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Coding Section

 

Codes Numbers Description
CPT  

See Policy Guidelines

  81170 (effective 1/1/2016)

ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib tyrosine kinase inhibitor resistance), gene analysis, variants in the kinase domain  

 

81206 

BCR/ABL1 (t(9:22)) (eg, chronic myelogenous leukemia) translocation analysis; major breakpoint, qualitative or quantitative 

 

81207 

Minor breakpoint, qualitative or quantitative 

 

81208 

Other breakpoint, qualitative or quantitative 

 

81401 

Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) –GENES:

ABL (c-abl oncogene 1, receptor tyrosine kinase) (e.g., acquired imatinib resistance), T315I variant 

 

0016U 

Oncology (hematolymphoid neoplasia), RNA, BCR/ABL1 major and minor breakpoint fusion transcripts, quantitative PCR amplification, blood or bone marrow, report of fusion not detected or detected with quantitation
Proprietary test: QuantideX® qPCR BCR-ABL Test
Lab/Manufacturer: University of Iowa, Department of Pathology, Asuragen 

 

0040U 

BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis, major breakpoint, quantitative
Proprietary test: MRDx® BCR-ABL Test
Lab/Manufacturer: MolecularMD 

ICD-9-CM Diagnosis

204.00-204.02

Lymphoblastic leukemia, acute, code range

ICD-10-CM (effective 10/01/15) 205.10-205.12

Myeloid leukemia, chronic, code range

  C91.00-C91.02

Acute lymphoblastic leukemia (ALL), code range

  C92.10-C92.12

Chronic myeloid leukemia, BCR/ABL-positive code range

  C92.20-C92.22

Atypical chronic myeloid leukemia, BCR/ABL-negative code range

ICD-10-PCS (effective 10/01/15)  

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.

Type of Service    
Place of Service    

 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines.

"Current Procedural Terminology© American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/15/2019 

Annual review, updating policy criteria #2, bullet point #3 for specificity. Also updating coding. 

07/25/2018 

Annual review, rewriting policy verbiage to update the timing for testing in item #2, adding medical necessity for quantitative testing in relation to use of the International Scale reporting. 

08/07/2017 

Interim review, rephrasing medical necessity criteria for clarity. No change to policy intent. 

04/26/2017 

Interim review to align with Avalon quarterly schedule. Updated category to Laboratory. 

04/19/2017

Annual review, no change to policy intent.

04/27/2016 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale and references. 

12/01/2015 

Updated CPT coding with 2016 codes. No change to policy intent. 

04/23/2015 

Annual review, no change to policy intent. Updated background, description, rationale and references. Added coding.

04/16/2014

Policy verbiage updated to address use with ALL. Title name updated to include ALL.  Updated description, background, policy verbiage, policy guidelines, rationale and references.


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