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

POLICY NUMBER

A.2.04.85

DESCRIPTION

In the treatment of Philadelphia 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 single nucleotide variants related to drug resistance when there is inadequate response or loss of response to tyrosine kinase inhibitors, or disease progression.

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 or blast phase. Multiple sets of criteria defining accelerated phase CML have evolved in recent decades, and may include 10% to 19% blasts in blood or bone marrow, basophils comprising 20% or more of the white blood cell count, presence of an additional clonal cytogenetic abnormality in CML cells, or very high or very low platelet counts. From the accelerated phase, the disease progresses into the final phase of blast crisis, in which the disease behaves like acute leukemia, with rapid progression and short survival. Similar to accelerated phase, multiple sets of criteria have been developed for the diagnosis of blast phase CML, and may include more than 20% myeloblasts in the blood or bone marrow, morphologically apparent lymphoblast proliferation, or development of a solid focus of leukemia outside the bone marrow.

Extensive clinical data have led to the development of congruent recommendations and guidelines developed both in North America and in Europe on the use of various types of molecular tests relevant to the diagnosis and management of CML. These tests are useful in the accelerated and blast phases of this malignancy.

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. ALL is the most common childhood tumor and represents 75% to 80% of acute leukemias in children. ALL represents only 20% of all leukemias in the adult population. The median age at diagnosis is 17 years; more than 50% of patients are diagnosed before 20 years of age. Survival rates for patients with ALL have improved dramatically, particularly 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 more than 80%. Long-term prognosis among adults is poor, with overall 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. In ALL, the Ph chromosome is found in approximately 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 associated with acute lymphoblastic leukemia, while p210 is most often seen in CML. The product of BCR-ABL1 is also a functional tyrosine kinase; the kinase domain of the BCR-ABL protein is the same as the kinase domain of the normal ABL protein. However, 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, and is instead used for risk stratification and treatment decisions in this setting.

Standardization of BCR-ABL1 Quantitative Transcript TestingA 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. 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 (eg, ABL) to control for the quality and quantity of RNA and to normalize for potential differences between tests.

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 response in a large proportion of the patients. As a result, imatinib, and, subsequently, newer-generation TKIs, became the primary therapy for most patients with newly diagnosed chronic phase CML. More recent studies have demonstrated that treatment-free remission (ie, discontinuation of certain TKIs) is safe and feasible in select patients with a stable molecular response of sufficient depth.

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 addition of TKIs to frontline induction chemotherapy has improved complete response rates, exceeding 90%.

Treatment response in Ph-positive ALL is evaluated initially by the hematologic and morphologic response (normalization of peripheral blood counts with trilineage hematopoiesis, <5% bone marrow blasts, and absence of circulating blasts and extramedullary disease), then by flow cytometry or molecular pathology. It is well established that most “good responders” who are considered to be in morphologic remission may still have considerable levels of leukemia cells, referred to as minimal (or measurable) 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 next-generation sequencing or polymerase chain reaction-based molecular analyses (eg, Ig and T-cell receptor gene rearrangements, sequencing of fusion genes, or analysis of BCR-ABL transcripts), the latter of which are the most sensitive methods of monitoring treatment response (sensitivity, 0.0001%).

Treatment Resistance

Imatinib treatment usually does not completely eradicate malignant cells. Not uncommonly, malignant clones resistant to imatinib may be acquired or selected during treatment (secondary resistance), resulting in disease relapse. Also, 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 with imatinib or another front-line TKI is inadequate or there is a loss of response, resistance variant analysis is recommended to support a diagnosis of resistance (based on hematologic, cytogenetic, and/or molecular relapse) and to guide the choice of alternative doses or treatments.

Structural studies of the ABL-imatinib complex have resulted in the design of newer-generation ABL inhibitors, including bosutinib (Bosulif; Pfizer), dasatinib (Sprycel; Bristol-Myers Squibb) and nilotinib (Tasigna; Novartis), which were initially approved by the U.S. Food and Drug Administration for treatment of patients resistant or intolerant to prior imatinib therapy. Trials of these agents in newly diagnosed chronic-phase patients have demonstrated superiority to imatinib for outcomes including complete cytogenetic response, major molecular response, time to remission, and/or rates of progression to accelerated phase or blast crisis, leading to their approval for front-line chronic phase use. The FDA has also approved the third-generation TKI ponatinib and the allosteric ABL1 inhibitor asciminib. Ponatinib is indicated for the treatment of patients with T315I-positive CML or Ph-positive ALL, or for whom no other TKI is indicated, while asciminib is indicated for the treatment of chronic-phase CML in patients with T315I or who have received prior treatment with ≥2 TKIs.

There is no strong evidence to recommend specific treatment changes on the sole basis of rising BCR-ABL1 transcripts detected by quantitative polymerase chain reaction.

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 single nucleotide variants (SNVs) account for 30% to 50% of secondary resistance. New BCR-ABL SNVs also occur in 80% to 90% of cases of ALL in relapse after TKI treatment and in CML blast transformation. The degree of resistance depends on the position of the variant within the kinase domain (i.e. active site) of the protein. Some variants are associated with moderate resistance and are responsive to higher doses of TKIs, while other variants may not be clinically significant. Two variants, 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 consensus-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 bosutinib, dasatinib, or nilotinib. For example, Guilhot and colleagues and Cortes and colleagues studied the use of dasatinib in imatinib-resistant CML patients in the accelerated phase and in blast crisis, respectively, and found that dasatinib response rates did not vary by the presence or absence of baseline tumor cell BCR-ABL1 variants. However, neither bosutinib, dasatinib, nor nilotinib is effective against resistant clones with the T315I variant. 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. 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. 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.

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 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 U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Chronic Myelogenous Leukemia

BCR-ABL1 qualitative testing for the presence of the fusion gene may be considered medically necessary for the diagnosis of chronic myeloid leukemia (see Policy Guidelines).

BCR-ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction at baseline before initiation of treatment and at appropriate intervals (see Policy Guidelines) may be considered medically necessary for monitoring of chronic myeloid leukemia treatment response and remission.

Evaluation of ABL kinase domain single nucleotide variants to assess individuals for tyrosine kinase inhibitor resistance may be considered medically necessary when there is an inadequate initial response to treatment or any sign of loss of response (see Policy Guidelines); and/or when there is a progression of the disease to the accelerated or blast phase.

Evaluation of ABL kinase domain single nucleotide variants is considered investigational for monitoring in advance of signs of treatment failure or disease progression.

Acute Lymphoblastic Leukemia

BCR-ABL1 testing for messenger RNA transcript levels by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) at baseline before initiation of treatment and at appropriate intervals during therapy (see Policy Guidelines section) may be considered medically necessary for monitoring of Philadelphia chromosome-positive acute lymphoblastic leukemia treatment response and remission.

Evaluation of ABL kinase domain single nucleotide variants to assess individuals for tyrosine kinase inhibitor resistance may be considered medically necessary when there is an inadequate initial response to treatment or any sign of loss of response.

Evaluation of ABL kinase domain single nucleotide variants is considered investigational for monitoring in advance of signs of treatment failure or disease progression.

POLICY EXCEPTIONS

None

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Diagnosis of Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Qualitative molecular confirmation of the cytogenetic diagnosis (i.e., detection of the Philadelphia chromosome) is necessary for accurate diagnosis of chronic myelogenous leukemia (CML). Identification of the Philadelphia chromosome is not necessary to diagnose acute lymphoblastic leukemia (ALL); however, molecular phenotyping is usually performed at the initial assessment (See Determining baseline RNA transcript levels and Subsequent Monitoring).

Distinction between molecular variants (ie, p190 vs. p210) is necessary for accurate results in subsequent monitoring assays.

Determining Baseline RNA Transcript Levels and Subsequent Monitoring

Determination of BCR-ABL1 messenger RNA transcript levels should be done by quantitative real-time reverse transcription-polymerase chain reaction-based assays, and reported results should be standardized according to the International Scale.

For CML, testing is appropriate at baseline before the start of imatinib treatment, and testing is appropriate every 3 months when the individual is responding to treatment. After a complete cytogenetic response is achieved, testing is recommended every 3 months for 2 years, and then every 3 to 6 months thereafter during treatment.

Without a complete cytogenetic response, continued monitoring at 3-month intervals during treatment is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib and will likely also be applied to bosutinib and ponatinib.

More frequent monitoring is indicated for individuals diagnosed with CML who are in complete molecular remission and are not undergoing treatment with a tyrosine kinase inhibitor (TKI).

For ALL, the optimal timing remains unclear and depends upon the chemotherapy regimen used.

Tyrosine Kinase Inhibitor Resistance

For CML, inadequate initial response to tyrosine kinase inhibitors (TKIs) is defined as failure to achieve a complete hematologic response at 3 months, only minor cytogenetic response at 6 months, or major (rather than complete) cytogenetic response at 12 months.

Unlike in CML, ALL resistance to TKIs is less well studied. In individuals with ALL receiving a TKI, a rise in the BCR-ABL mRNA level while in hematologic complete response or clinical relapse warrants variant analysis.

Loss of response to TKIs is defined as hematologic relapse, cytogenetic relapse, or 1-log increase in BCR-ABL1 transcript ratio and therefore loss of major molecular response.

Kinase domain single nucleotide variant testing is usually offered as a single test to identify T315I variant or as a panel (that includes T315I) of the most common and clinically important variants.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

07/18/2013: New policy added. Approved by Medical Policy Advisory Committee.

09/16/2014: Policy title changed from "BCR-ABL1 Testing for Diagnosis, Monitoring, and Drug Resistance Mutation Detection in Chronic Myelogenous Leukemia" to "BCR-ABL1 Testing in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia." Policy description updated regarding acute lymphoblastic leukemia, disease genetics, and treatment and response and minimal residual disease. Policy statement section updated to add "Chronic Myelogenous Leukemia" and "Acute Lymphoblastic Leukemia." Added three policy statements under acute lymphoblastic leukemia heading regarding BCR/ABL1 testing and the evaluation of ABL kinase domain point mutations. Policy guidelines updated to clarify the timing of testing in patients who are responding to treatment or who have a complete cytogenetic response. Added and updated the following headings in the Policy Guidelines: Diagnosis of CML and ALL, Determining baseline RNA transcript levels and subsequent monitoring, and TKI resistance. Added ICD-9 diagnosis codes 204.00-204.02 to the Code Reference section.

04/21/2015: Policy reviewed. Policy statements unchanged. Policy guidelines updated to add medically necessary and investigational definitions.

08/21/2015: Code Reference section updated for ICD-10.

12/31/2015: Code Reference section updated to add new 2016 CPT code 81170.

06/09/2016: Policy number A.2.04.85 added. Policy description updated regarding diagnosis, treatment, and response of CML and ALL. Policy statements unchanged. Policy guidelines section updated regarding determining baseline RNA transcript levels and subsequent monitoring: For CML, after a complete cytogenetic response is achieved, recommended testing changed from "every 3 months for 3 years" to "every 3 months for 2 years."

08/01/2017: Code Reference section updated to add new CPT code 0016U.

12/06/2017: Policy description updated regarding treatment. Policy statements updated to change "point mutations" to "single nucleotide variants." Policy Guidelines updated to add genetics nomenclature update.

03/28/2018: Code Reference section updated to add new CPT code 0040U, effective 04/01/2018.

10/29/2018: Policy description updated regarding testing. Policy statements unchanged. Policy Guidelines updated regarding monitoring patients with CML.

11/18/2019: Policy description updated regarding tests. Policy statements unchanged.

11/19/2020: Policy description updated regarding tests. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature update.

01/14/2022: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/08/2022: Policy description updated. Policy statements updated with minor wording changes. Policy Guidelines updated to change "patients" to "individuals."

11/13/2023: Policy description updated. Medically necessary statement for BCR-ABL1 qualitative testing updated with minor wording change. Policy Guidelines updated.

01/08/2025: Policy description updated. Policy statements unchanged.

SOURCE(S)

Blue Cross and Blue Shield Association Policy # 2.04.85

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.