Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Genetic Test: Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia (BCR-ABL)

Description:

In the treatment of Philadelphia chromosome-positive leukemias, various nucleic acid-based laboratory methods are 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 (KD) single nucleotide variants related to drug resistance when there is inadequate response or loss of response to tyrosine kinase inhibitors (TKIs), or disease progression.

Background

Myelogenous Leukemia and Lymphoblastic Leukemia

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 10-19% 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 (Vardiman, 2002). 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 (Karbasian, 2006).

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 before 20 years of age. Current survival rates for patients with ALL have improved dramatically over the past, primarily in children, largely due to a 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 a 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 (Mullighan, 2012). 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 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.

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.

Standardization of BCR-ABL1 Quantitative Transcript Testing

A substantial effort has been made to standardize the BCR-ABL1 quantitative reverse transcription-polymerase chain reaction testing and reporting across academic and private laboratories. In 2006, the National Institute of Health Consensus Group proposed an International Scale (IS) for BCR-ABL1 measurement (Hughes, 2006). The IS defines 100% as the median pretreatment baseline level of BCR-ABL1 RNA in early chronic phase CML; as determined in the pivotal International Randomized Study of Interferon versus STI571 trial, major molecular response is defined as a 3-log reduction relative to the standardized baseline, or 0.1% BCR-ABL1 on the IS. 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 (Cross, 2009; Hughes, 2006).

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 the risk of progression. Also, 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-based methods and international standards for reporting have been recommended and adopted for treatment monitoring.

Imatinib (Gleevec®; Novartis), a tyrosine kinase inhibitor (TKI), was originally developed specifically to 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” (NCCN, 2013). 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% (Jones, 2009).

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 (0% Ph-positive metaphases) is expected by 6-12 months after initial treatment with the TKI imatinib (NCCN, 2013). It is well established that most “good responders” who are considered to be in morphologic remission but have relapsed 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 polymerase chain reaction-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%) (Campana, 2012). Most ALL patients can be tested with Ig and T-cell receptor gene arrangement analysis, whereas only Ph-positive patients can be tested with polymerase chain reaction analysis of BCR-ABL transcripts.

Treatment Resistance

Imatinib treatment usually does not completely eradication 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 variant 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 (NCCN, 2013; Jones, 2009).

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. 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 (Saglio, 2010; Kantarjian, 2010). Although initial follow-up was short, early and sustained complete cytogenetic response was considered a validated marker for survival in CML (Sawyers, 2010). The FDA has approved third-generation TKIs, ponatinib, and bosutinib. Ponatinib is indicated for the treatment of patients with T315I-positive CML or Ph-positive ALL, or for whom no other TKI is indicated. Bosutinib is indicated for Ph-positive CML with resistance or intolerance to prior therapy.

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 (NCCN, 2013).

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 that affects protein kinase-TKI binding. BCR-ABL1 single nucleotide variants (SNVs) account for 30-50% of secondary resistance (Jones, 2009). (Note that new BCR-ABL SNVs also occur in 80% to 90% of cases of ALL in relapse after TKI treatment and in CML blast transformation) (Mughal, 2007). The degree of resistance depends on the position of the variant 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 presence of ABL SNVs is associated with treatment failure. A large number of variants have been detected, but extensive analysis of trial data with low-sensitivity variant detection methods has identified a small number of variants consistently associated with treatment failure with specific TKIs; guidelines recommend testing for information on these specific variants to aid 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 variants of interest for management decisions are also acceptable if designed for low sensitivity. High-sensitivity assays are not recommended.

Unlike imatinib, fewer variants are associated with resistance to dasatinib or nilotinib (von Bubnoff, 2006; Piccaluga, 2006). 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 variants (Guilhot, 2007; Cortes, 2007). However, neither dasatinib nor nilotinib are effective against resistant clones with the T315I variant (Mughal, 2007; Guilhot, 2007). Other treatment strategies are in development for patients with drug resistance.

Other acquired cytogenetic abnormalities such as BCR-ABL gene amplification and protein overexpression have also been reported (Walz, 2006). 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 (Jones, 2009). 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 variant analysis.

Regulatory Status

On September 2019, the Xpert BCR-ABL Ultra Test was approved for use on the GeneXpert® Dx System, GeneXpert® Infinity Systems (Cepheid) by the FDA through the 510(k) pathway (K190076). The test may be used in patients diagnosed with t(9;22) positive CML expressing BCR-ABL1 fusion transcripts type e13a2 and/or e14a2. The test utilizes RT-qPCR.

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.

Coding

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

Policy/
Coverage:

Effective May 2015

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Genetic testing for the BCR-ABL gene to aid in the diagnostic assessment or management of CML or ALL by qualitative RT-PCR, quantitative RT-PCR (RQ-PCR) or by fluorescence in situ hybridization (FISH) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

Evaluation of ABL kinase domain point mutations to evaluate patients with CML for tyrosine kinase inhibitor resistance meets member benefit certificate that there be scientific evidence when there is inadequate initial response to treatment or any sign of loss of response; and/or when there is progression of the disease to the accelerated or blast phase.

Evaluation of ABL kinase domain point mutations to evaluate patients with ALL for tyrosine kinase inhibitor resistance meets member benefit certificate that there be scientific evidence when there is inadequate initial response to treatment or any sign of loss of response.

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Genetic testing for the BCR-ABL gene by qualitative RT-PCR, quantitative RT-PCR (RQ-PCR) or by fluorescence in situ hybridization (FISH) for any other indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, genetic testing for the BCR-ABL gene by qualitative RT-PCR, quantitative RT-PCR (RQ-PCR) or by fluorescence in situ hybridization (FISH) for any other indication is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Evaluation of ABL kinase domain point mutations for monitoring in advance of signs of treatment failure or disease progression in patients with CML or ALL does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.

For members with contracts without primary coverage criteria, evaluation of ABL kinase domain point mutations for monitoring in advance of signs of treatment failure or disease progression in patients with CML or ALL is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective September 2014 – April 2015

Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

Effective November 2012 – September 2014

For contracts without Primary Coverage Criteria, genetic testing for BCR-ABL for CML or ALL is a covered service.

Effective prior to November 2012

Genetic testing for the BCR-ABL gene in individuals suspected of having CML and monitoring response to therapy by quantitative and /or qualitative RT-PCR (RQ-PCR) or by fluorescence in situ hybridization (FISH) meets ABCBS Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes.

For contracts without Primary Coverage Criteria, genetic testing for BCR-ABL for Chronic Myelogenous Leukemia is a covered service.

Rationale:

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

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).
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.
Identification and monitoring of mutations for drug resistance at response failure/disease progression; various test technologies are in use (not standardized).

Diagnosis

While the diagnosis of CML is based on the presence of characteristic cellular abnormalities in bone marrow, the presence of the Philadelphia chromosome (Ph) and/or confirmation of the BCR-ABL1 fusion gene is essential to diagnosis. The initial evaluation of chronic phase CML should include bone marrow cytogenetics, not only to detect the Ph chromosome, but to detect other possible chromosomal abnormalities (Cortes, 2012). If bone marrow is not available, FISH analysis with dual probes for BCR and ABL genes or qualitative reverse transcriptase PCR (RT-PCR can provide qualitative confirmation of the fusion gene and its type (Cortes, 2012). 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 non-standard probes may occur), as well as a baseline for monitoring response to treatment (Cortes, 2012).

Monitoring for residual disease during treatment/disease remission

Quantitative RT-PCR measurement of BCR-ABL1 RNA transcript levels is the method of choice for measuring response to treatment because of the high sensitivity of the method and strong correlation with outcomes (NCCN, 2013). Compared to conventional cytogenetics, quantitative PCR (qRT-PCR) is more than 3 logs more sensitive (Branford, 1999) and can detect one CML cell in the background of >100,000 normal cells. Quantitative RT-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 (Radich, 2012). More often, patients achieve a major molecular response (MMR; a 3-log reduction from the standardized baseline of the International Scale (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 compared to patients who had neither (Druker, 2006). At 8 years’ follow-up, none of the patients who achieved a 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 (Saglio, 2010; Kantarjian, 2010; Radich, 2012).

The degree of molecular response has been reported to correlate with risk of progression in patients treated with imatinib (Press, 2006). 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 (Branford, 2003; Wang, 2003; Quintas-Cardama, 2009; Müller, 2008). 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 (Hehlmann, 2011; de Lavallade, 2008; Marin, 2008).

Based on imatinib follow-up data, it is recommended that for patients with a complete cytogenetic response, molecular response to treatment be measured every 3 months for 3 years, then every 3-6 months thereafter (NCCN, 2013; Baccarani, 2009). Without complete cytogenetic response (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 as well, (NCCN, 2013) 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 (Press, 2007; Branford, 2004; Wang, 2006; Press, 2009; Marin, 2009; Kantarjian, 2009). However, the amount of rise that is considered clinically significant for considering mutation testing is not known. Factors affecting the clinically significant change include the variability of the specific assay used by the laboratory, as well as the level of molecular response achieved by the patient. Thresholds used include 2- to 10-fold increases, and increases of 0.5-1 log (NCCN. 2013; Baccarani, 2009; Branford, 2011). 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 (Soverini, 2011).

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 Institute of Health Consensus Group proposed an International Scale (IS) for BCR-ABL1 measurement (Hughes, 2006). 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 (Hughes, 2003). In the assay, BCR-ABL1 transcripts are quantified relative to one 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. (41, 42) Percent ratios on the IS are determined at local labs by a test-specific conversion factor (IS % ratio=local % ratio x 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: http://www.whereareyouontheis.com/Default.aspx ). In the U.S., many laboratories offer BCR-ABL quantitative testing (e.g., Quest, ARUP, LabCorp and Mayo) and most specify on their websites that results are standardized to the IS.

Identification ofABLkinase domain mutations (mutations associated with TKI-resistance)

Screening for BCR-ABL1 kinase domain point mutations (i.e., single nucleotide polymorphisms) in chronic phase CML is recommended for patients with inadequate initial response to TKI treatment, those with evidence of loss of response, and for patients who have progressed to accelerated or blast phase CML (NCCN, 2013). The purpose of testing for kinase domain point mutations is, in the setting of potential treatment failure, to help select among other possible TKI treatments or allogeneic stem-cell transplantation. The following discussion focuses only on kinase domain point mutations.

In 2010, the Agency for Healthcare Research and Quality published a systematic review on BCR-ABL1 pharmacogenetic testing for tyrosine kinase inhibitors in CML (Terasawa, 2010). 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. However, during the public comment period, the review was strongly criticized by respected pathology organizations for lack of attention to several issues that were subsequently insufficiently addressed in the final report. Importantly, the review grouped together studies that used kinase domain mutation screening methods with those that used targeted methods, and grouped together studies that used mutation detection technologies with very different sensitivities. The authors dismissed the issues as related to analytic validity and beyond the scope of the report. However, in this clinical scenario assay with different intent (screening vs. targeted) and assays of very different sensitivities may lead to different clinical conclusions and an understanding of these points is critical.

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

The particular methods to detect BCR-ABL kinase domain mutations will have great influence on the detection frequency, analytical sensitivity and the clinical impact of testing. The various mutation detection methods available have widely different analytic sensitivities, from the least sensitive direct Sanger sequencing to the highly sensitive mutation-specific quantitative polymerase chain reaction (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 also a screening method with initially higher sensitivity to detect the presence or absence of any 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).

Kinase Domain Point Mutations and Treatment Outcomes. Branford et al. (Branford, 2009) have summarized much of the available evidence regarding kinase domain mutations detected at imatinib failure, and subsequent treatment success or failure with dasatinib or nilotinib. The 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 it 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 60-66% 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 stem-cell transplantation remained the only available treatment until the advent of new agents such as ponatinib (Cortes, 2012). Most common,’ however, does not necessarily correspond to clinically significant. Based on the available clinical studies, the majority of imatinib-resistant mutations remain sensitive to dasatinib and nilotinib. However, preexisting or emerging mutations T315A, F317L/I/V/C, and V299L are associated with decreased clinical efficacy with dasatinib treatment following imatinib failure. Similarly, preexisting or emerging mutations Y253H, E255K/V, and F359V/C have been reported for decreased clinical efficacy with nilotinib treatment following imatinib failure. In the survey reported by Branford et al., a total of 42% of patients tested had T315I or one of these dasatinib- or nilotinib-resistant mutations (Branford, 2009). 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 the subsequent treatment (NCCN, 2012; Soverini, 2011). In the absence of any of these actionable mutations, various treatment options are available. Note that these data have been obtained from studies in which patients were all initially treated with imatinib. No data are available regarding mutations developing during first-line therapy with dasatinib or nilotinib (Alikian, 2012).

ABL kinase domain mutational analysis is recommended if there is inadequate initial response (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) 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.

Since 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 following initial treatment failure. Targeted assays use different technologies, which can be made very sensitive to 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. While some results have been positive, not all mutations detected in advance predict treatment failure and more study is recommended before these assays are used for monitoring in advance of treatment failure (Soverini, 2011; Branford, 2009). A direct correlation of low-sensitivity and high-sensitivity assays and a limited correlation with clinical outcomes supports recommendations of sequencing, with or without DHPLC screening, for identification of mutations (Ernst, 2009). Although high-sensitivity assays identified more mutations than did sequencing, the clinical impact of the additional mutations was viewed as uncertain.

Other types of mutations in addition to 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 (Jones, 2009; Alikian, 2012).

Ongoing Clinical Trials

Over 100 ongoing clinical trials resulted from a search of online site clinicaltrials.gov for ‘BCR-ABL1 and CML’; many of these trials are treatment regimen-related. (http://www.clinicaltrials.gov)

Five ongoing trials were found that have direct genetic testing/molecular testing involvement.

The Multicenter Trial Estimating the Persistence of Molecular Remission in Chronic Myeloid Leukaemia in Long Term After Stopping Imatinib (STIM 2) will measure the rate of molecular relapse defined by the rate of patients having a significant increasing of BCR-ABL transcript for 2 years after stopping treatment. Secondary outcomes include overall survival, molecular profile of patient, treatment costs, and event-free survival. http://www.clinicaltrials.gov/ct2/show/NCT01343173.
A Study of Complete Molecular Response for Chronic
Myeloid Leukemia in Chronic Phase Patients, Treated With Dasatinib (CMR-CML) will measure the rate of complete molecular response (CMR) after treatment with dasatinib. Secondary outcomes include progression-free survival, and number of participants with adverse events. http://www.clinicaltrials.gov/ct2/show/NCT01342679
Nilotinib Versus Standard Imatinib (400/600 mg QD) Comparing the Kinetics of Complete Molecular Response (CMR) for CML-CP (chronic phase) Pts With Evidence of Persistent Leukemia by RQ-PCR will measure the rate of confirmed best cumulative Complete Molecular Response within the first year of study therapy with imatinib or nilotinib. Secondary outcomes include kinetics of CMR achieved in both treatment arms, progression-free survival, EFS (event-free survival) and OS (overall survival) between the two arms, and kinetics of CMR achieved after cross-over. http://www.clinicaltrials.gov/ct2/show/NCT00760877
Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients will measure the negative predictive value ratio (rNPV) of dPCR over qRT-PCR. Secondary outcomes include rate of molecular and cytogenetic relapse, rate of dPCR (digital PCR)-positive patients, rate of dPCR negative patients, rate of patients who are maintaining dPCR negativity for 36 month, time to molecular relapse, overall survival, quality of life, and rate of patients progressing or developing resistance. http://www.clinicaltrials.gov/ct2/show/NCT01578213; http://www.clinicaltrials.gov/ct2/show/NCT01580059
Extending Molecular Responses With Nilotinib in Newly Diagnosed Chronic Myeloid Leukemia (CML) Patients in chronic phase (CP) will evaluate efficacy, using molecular response, of nilotinib 300 mg BID in the treatment of newly diagnosed CML-CP patients. No secondary outcomes were defined. http://www.clinicaltrials.gov/ct2/show/NCT01580059

Summary

Extensive clinical data have led to the development of congruent recommendations and guidelines developed both in North America and in Europe concerning the use of various types of molecular tests relevant to the diagnosis and management of chronic myelogenous leukemia (CML). These tests are also useful in the accelerated and blast phases of this malignancy. Appropriate uses are summarized as follows:

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 Philadelphia chromosome (Ph) was not found, and to identify the type of fusion gene, as 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.

Monitoring during treatment with tyrosine kinase inhibitors: 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 that 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 (IS) for reporting have been recommended and adopted for treatment monitoring.

Treatment failure: the presence of ABL kinase domain point mutations are 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 that are consistently associated with treatment failure with specific tyrosine kinase inhibitors; guidelines recommend testing for, and using information regarding these specific mutations in subsequent treatment decisions. The recommended method is sequencing with or without denaturing high-performance liquid chromatography (DHPLC) screening to reduce the number of samples that need 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.

Policy Guidelines and Position Statements

The NCCN Practice Guidelines v.3.2013 Chronic Myelogenous Leukemia outline recommended methods for diagnosis and treatment management of CML, including BCR-ABL1 tests for diagnosis, monitoring, and ABL kinase domain mutations, and were referred to extensively in this document (NCCN, 2013). The European LeukemiaNet management recommendations for CML are very similar to those of NCCN and have also been cited in this document (Baccarani, 2009). The U.S. Association for Molecular Pathology (Jones, 2009) and European LeukemiaNet recommendations for kinase domain mutation analysis (Soverini, 2011) have been referenced; both provide very similar guidelines.

2015 Update

A literature search conducted through March 2015 did not reveal any new information that would prompt a change in the coverage statement.

2018 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2018. No new literature was identified that would prompt a change in the coverage statement.

2019 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2019. No new literature was identified that would prompt a change in the coverage statement.

2020 Update

A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.

2021 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Discontinuation of therapy with first- or subsequent-line dasatinib was investigated by Shah et al in the DASFREE trial (Shah, 2020). Patients were treated for a minimum of 2 years and were required to achieve dasatinib-induced MR4.5 for at least 1 year prior to study entry. At 1 year, TFR was 48% (95% CI, 37 to 59%) in all enrolled patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib therapy (≥median; P =.0051), line of therapy (first-line; p =.0138), and age (>65 years; P =.0012).

The open-label, phase 2 STop IMatinib 2 (STIM2) study utilized droplet digital PCR (ddPCR) to quantify BCR-ABL1 transcript levels for 175 patients with chronic phase CML and undetectable transcripts by RT-qPCR for at least 2 year prior to imatinib discontinuation (Nicolini, 2019). A conversion factor was calculated for ddPCR to apply positive BCR-ABL1 ratios on the international scale (IS). In a multivariate analysis, duration of imatinib therapy (≥ 74.8 months) and ddPCR (≥ 0.0023% IS) were identified as predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415 to 0.972) and P = 0.008 (HR, 0.556; 95% CI, 0.360 to 0.858), respectively. Overall treatment-free remission at 12 months (TFR) was 49% overall compared to 54% in patients negative on ddPCR and those below 0.0023% IS on ddPCR. For patients above 0.0023% IS on ddPCR, TFR was 32%. While the use of ddPCR was investigated as a more sensitive technology compared to qPCR, the authors note that standardizing ddPCR readings on the IS across labs is challenging (Yan, 2019).

2022 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Atallah et al evaluated molecular recurrence after TKI discontinuation in 171 patients with CML (Atallah, 2021). Monitoring for molecular recurrence (BCR-ABL1 >0.1%) was performed using PCR on the IS scale. Patients were classified as having undetectable (<MR4.5 with adequate ABL1 control amplification; n=143) or detectable (n=28) BCR-ABL1 IS ratio. Molecular recurrence was significantly associated with undetectable BCR-ABL1 transcripts by either ddPCR or RQ-PCR at the time of TKI discontinuation (HR, 3.60; 95% CI, 1.99-6.50) and at 3 months (HR, 5.86; 95% CI, 3.07-11.1).

Arunachalam et al performed a retrospective cohort analysis of 94 patients with Ph-positive ALL (Arunachalam, 2020). The median age was 33 years (range, 14 to 70 years). Patients were categorized based on MRD good risk or poor risk groups based on BCR-ABL copy number ratio. In the entire cohort, the 5-year OS and event-free survival (EFS) were 45.2% and 35.2%, respectively, and median OS and EFS were 46 months and 28 months, respectively. In multivariate analysis, MRD poor risk stratification was associated with worse OS (HR, 2.9; CI, 1.10 to 7.84) and EFS (HR, 5.4; CI, 2.23 to 13.23).

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Haddad et al evaluated TFR after TKI discontinuation in 199 patients with CML (Haddad, 2022). Monitoring for MMR (BCR-ABL1/ABL1 transcript ratio ≤ 0.1% IS) was determined by quantitative real-time PCR. Failure of TFR was defined as the loss of MMR (QR-PCR >0.1% IS) on a single test and CMR was defined as undetectable transcript levels. At 36 months after TKI discontinuation, 53 patients lost MMR; the estimated 5-year TFR rate was 79%. Estimated 5-year TFR rates were higher with MR4 and MR4.5 at ≥5 years versus MR4 at <5 years (87% vs. 92% vs. 64%, respectively; p<.0001).

CPT/HCPCS:

81170	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	BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; minor breakpoint, qualitative or quantitative
81208	BCR/ABL1 (t(9;22)) (eg, chronic myelogenous leukemia) translocation analysis; other breakpoint, qualitative or quantitative
81401	Molecular pathology procedure, Level 2 (eg, 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) ABCC8 (ATP-binding cassette, sub-family C [CFTR/MRP], member 8) (eg, familial hyperinsulinism), common variants (eg, c.3898-9G>A [c.3992-9G>A], F1388del) ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase) (eg, acquired imatinib resistance), T315I variant ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H) ADRB2 (adrenergic beta-2 receptor surface) (eg, drug metabolism), common variants (eg, G16R, Q27E) APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W) APOE (apolipoprotein E) (eg, hyperlipoproteinemia type III, cardiovascular disease, Alzheimer disease), common variants (eg, 2, 3, *4) CBFB/MYH11 (inv(16)) (eg, acute myeloid leukemia), qualitative, and quantitative, if performed CBS (cystathionine-beta-synthase) (eg, homocystinuria, cystathionine beta-synthase deficiency), common variants (eg, I278T, G307S) CFH/ARMS2 (complement factor H/age-related maculopathy susceptibility 2) (eg, macular degeneration), common variants (eg, Y402H [CFH], A69S [ARMS2]) DEK/NUP214 (t(6;9)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed E2A/PBX1 (t(1;19)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EML4/ALK (inv(2)) (eg, non-small cell lung cancer), translocation or inversion analysis ETV6/RUNX1 (t(12;21)) (eg, acute lymphocytic leukemia), translocation analysis, qualitative, and quantitative, if performed EWSR1/ATF1 (t(12;22)) (eg, clear cell sarcoma), translocation analysis, qualitative, and quantitative, if performed EWSR1/ERG (t(21;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/FLI1 (t(11;22)) (eg, Ewing sarcoma/peripheral neuroectodermal tumor), translocation analysis, qualitative, and quantitative, if performed EWSR1/WT1 (t(11;22)) (eg, desmoplastic small round cell tumor), translocation analysis, qualitative, and quantitative, if performed F11 (coagulation factor XI) (eg, coagulation disorder), common variants (eg, E117X [Type II], F283L [Type III], IVS14del14, and IVS14+1G>A [Type I]) FGFR3 (fibroblast growth factor receptor 3) (eg, achondroplasia, hypochondroplasia), common variants (eg, 1138G>A, 1138G>C, 1620C>A, 1620C>G) FIP1L1/PDGFRA (del[4q12]) (eg, imatinib-sensitive chronic eosinophilic leukemia), qualitative, and quantitative, if performed FLG (filaggrin) (eg, ichthyosis vulgaris), common variants (eg, R501X, 2282del4, R2447X, S3247X, 3702delG) FOXO1/PAX3 (t(2;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FOXO1/PAX7 (t(1;13)) (eg, alveolar rhabdomyosarcoma), translocation analysis, qualitative, and quantitative, if performed FUS/DDIT3 (t(12;16)) (eg, myxoid liposarcoma), translocation analysis, qualitative, and quantitative, if performed GALC (galactosylceramidase) (eg, Krabbe disease), common variants (eg, c.857G>A, 30-kb deletion) GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D) H19 (imprinted maternally expressed transcript [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis IGH@/BCL2 (t(14;18)) (eg, follicular lymphoma), translocation analysis; single breakpoint (eg, major breakpoint region [MBR] or minor cluster region [mcr]), qualitative or quantitative (When both MBR and mcr breakpoints are performed, use 81278) KCNQ1OT1 (KCNQ1 overlapping transcript 1 [non-protein coding]) (eg, Beckwith-Wiedemann syndrome), methylation analysis LINC00518 (long intergenic non-protein coding RNA 518) (eg, melanoma), expression analysis LRRK2 (leucine-rich repeat kinase 2) (eg, Parkinson disease), common variants (eg, R1441G, G2019S, I2020T) MED12 (mediator complex subunit 12) (eg, FG syndrome type 1, Lujan syndrome), common variants (eg, R961W, N1007S) MEG3/DLK1 (maternally expressed 3 [non-protein coding]/delta-like 1 homolog [Drosophila]) (eg, intrauterine growth retardation), methylation analysis MLL/AFF1 (t(4;11)) (eg, acute lymphoblastic leukemia), translocation analysis, qualitative, and quantitative, if performed MLL/MLLT3 (t(9;11)) (eg, acute myeloid leukemia), translocation analysis, qualitative, and quantitative, if performed MT-ATP6 (mitochondrially encoded ATP synthase 6) (eg, neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (eg, m.8993T>G, m.8993T>C) MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (eg, Leber hereditary optic neuropathy [LHON]), common variants (eg, m.11778G>A, m.3460G>A, m.14484T>C) MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (eg, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (eg, m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), common variants (eg, m.1555A>G, m.1494C>T) MT-TK (mitochondrially encoded tRNA lysine) (eg, myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (eg, m.8344A>G, m.8356T>C) MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (eg, diabetes and hearing loss), common variants (eg, m.3243A>G, m.14709 T>C) MT-TL1 MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (eg, nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (eg, m.7445A>G, m.1555A>G) MUTYH (mutY homolog [E. coli]) (eg, MYH-associated polyposis), common variants (eg, Y165C, G382D) NOD2 (nucleotide-binding oligomerization domain containing 2) (eg, Crohn's disease, Blau syndrome), common variants (eg, SNP 8, SNP 12, SNP 13) NPM1/ALK (t(2;5)) (eg, anaplastic large cell lymphoma), translocation analysis PAX8/PPARG (t(2;3) (q13;p25)) (eg, follicular thyroid carcinoma), translocation analysis PRAME (preferentially expressed antigen in melanoma) (eg, melanoma), expression analysis PRSS1 (protease, serine, 1 [trypsin 1]) (eg, hereditary pancreatitis), common variants (eg, N29I, A16V, R122H) PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50X, G205S) RUNX1/RUNX1T1 (t(8;21)) (eg, acute myeloid leukemia) translocation analysis, qualitative, and quantitative, if performed SS18/SSX1 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed SS18/SSX2 (t(X;18)) (eg, synovial sarcoma), translocation analysis, qualitative, and quantitative, if performed VWF (von Willebrand factor) (eg, von Willebrand disease type 2N), common variants (eg, T791M, R816W, R854Q)
81403	Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence ARX (aristaless-related homeobox) (eg, X-linked lissencephaly with ambiguous genitalia, X-linked mental retardation), duplication/deletion analysis CEL (carboxyl ester lipase [bile salt-stimulated lipase]) (eg, maturity-onset diabetes of the young [MODY]), targeted sequence analysis of exon 11 (eg, c.1785delC, c.1686delT) CTNNB1 (catenin [cadherin-associated protein], beta 1, 88kDa) (eg, desmoid tumors), targeted sequence analysis (eg, exon 3) DAZ/SRY (deleted in azoospermia and sex determining region Y) (eg, male infertility), common deletions (eg, AZFa, AZFb, AZFc, AZFd) DNMT3A (DNA [cytosine-5-]-methyltransferase 3 alpha) (eg, acute myeloid leukemia), targeted sequence analysis (eg, exon 23) EPCAM (epithelial cell adhesion molecule) (eg, Lynch syndrome), duplication/deletion analysis F8 (coagulation factor VIII) (eg, hemophilia A), inversion analysis, intron 1 and intron 22A F12 (coagulation factor XII [Hageman factor]) (eg, angioedema, hereditary, type III; factor XII deficiency), targeted sequence analysis of exon 9 FGFR3 (fibroblast growth factor receptor 3) (eg, isolated craniosynostosis), targeted sequence analysis (eg, exon 7) (For targeted sequence analysis of multiple FGFR3 exons, use 81404) GJB1 (gap junction protein, beta 1) (eg, Charcot-Marie-Tooth X-linked), full gene sequence GNAQ (guanine nucleotide-binding protein G[q] subunit alpha) (eg, uveal melanoma), common variants (eg, R183, Q209) Human erythrocyte antigen gene analyses (eg, SLC14A1 [Kidd blood group], BCAM [Lutheran blood group], ICAM4 [Landsteiner-Wiener blood group], SLC4A1 [Diego blood group], AQP1 [Colton blood group], ERMAP [Scianna blood group], RHCE [Rh blood group, CcEe antigens], KEL [Kell blood group], DARC [Duffy blood group], GYPA, GYPB, GYPE [MNS blood group], ART4 [Dombrock blood group]) (eg, sickle-cell disease, thalassemia, hemolytic transfusion reactions, hemolytic disease of the fetus or newborn), common variants HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog) (eg, Costello syndrome), exon 2 sequence KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2) KCNJ2 (potassium inwardly-rectifying channel, subfamily J, member 2) (eg, Andersen-Tawil syndrome), full gene sequence KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) (eg, familial hyperinsulinism), full gene sequence Killer cell immunoglobulin-like receptor (KIR) gene family (eg, hematopoietic stem cell transplantation), genotyping of KIR family genes Known familial variant not otherwise specified, for gene listed in Tier 1 or Tier 2, or identified during a genomic sequencing procedure, DNA sequence analysis, each variant exon (For a known familial variant that is considered a common variant, use specific common variant Tier 1 or Tier 2 code) MC4R (melanocortin 4 receptor) (eg, obesity), full gene sequence MICA (MHC class I polypeptide-related sequence A) (eg, solid organ transplantation), common variants (eg, 001, 002) MT-RNR1 (mitochondrially encoded 12S RNA) (eg, nonsyndromic hearing loss), full gene sequence MT-TS1 (mitochondrially encoded tRNA serine 1) (eg, nonsyndromic hearing loss), full gene sequence NDP (Norrie disease [pseudoglioma]) (eg, Norrie disease), duplication/deletion analysis NHLRC1 (NHL repeat containing 1) (eg, progressive myoclonus epilepsy), full gene sequence PHOX2B (paired-like homeobox 2b) (eg, congenital central hypoventilation syndrome), duplication/deletion analysis PLN (phospholamban) (eg, dilated cardiomyopathy, hypertrophic cardiomyopathy), full gene sequence RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene) RHD (Rh blood group, D antigen) (eg, hemolytic disease of the fetus and newborn, Rh maternal/fetal compatibility), deletion analysis (eg, exons 4, 5, and 7, pseudogene), performed on cell-free fetal DNA in maternal blood (For human erythrocyte gene analysis of RHD, use a separate unit of 81403) SH2D1A (SH2 domain containing 1A) (eg, X-linked lymphoproliferative syndrome), duplication/deletion analysis TWIST1 (twist homolog 1 [Drosophila]) (eg, Saethre-Chotzen syndrome), duplication/deletion analysis UBA1 (ubiquitin-like modifier activating enzyme 1) (eg, spinal muscular atrophy, X-linked), targeted sequence analysis (eg, exon 15) VHL (von Hippel-Lindau tumor suppressor) (eg, von Hippel-Lindau familial cancer syndrome), deletion/duplication analysis VWF (von Willebrand factor) (eg, von Willebrand disease types 2A, 2B, 2M), targeted sequence analysis (eg, exon 28)

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