Medical Policy

Policy Num:      11.003.063
Policy Name:     BCR-ABL1 Testing in Chronic Myelogenous Leukjemia and Acute Lymphoblastic Leukemia
Policy ID:          [11.003.063]  [Ac / B / M+ / P+]  [2.04.85]

Last Review:      December 03, 2024
Next Review:      November 20, 2025
 

Related Policies:

08.001.036 - Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia
08.001.043 - Hematopoietic Cell Transplantation as a Treatment of Acute Lymphoblastic Leukemia

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

Summary

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 (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.

Summary of Evidence

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

For individuals who have a diagnosis of CML who receive BCR-ABL1 fusion gene quantitative testing at appropriate intervals for monitoring treatment response and remission, the evidence includes a systematic review and nonrandomized trials. Relevant outcomes are disease-specific survival, test validity, and change in disease status. Studies have shown high sensitivity of this type of testing and a strong correlation with outcomes, including the risk of disease progression and survival, which may stratify patients to different options for disease management. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a diagnosis of CML with an inadequate initial response, loss of response, and/or disease progression who receive an evaluation for ABL kinase domain (KD) single nucleotide variants to assess for tyrosine kinase inhibitor (TKI) resistance, the evidence includes a systematic review and retrospective cohort study. Relevant outcomes are disease-specific survival, test validity, and medication use. The systematic review and case series evaluated pharmacogenetics testing for TKIs and reported the presence of KD single nucleotide variants detected at imatinib failure. These studies have shown a correlation between certain types of variants, treatment response, and the selection of subsequent treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have a diagnosis of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) who receive BCR-ABL1 fusion gene quantitative testing at baseline before and during treatment to monitor treatment response and remission, the evidence includes prospective and retrospective cohort studies and case series. Relevant outcomes are disease-specific survival, test validity, and change in disease status. As with CML, studies have shown high sensitivity for this type of testing and a strong correlation with outcomes, including the risk of disease progression, which may stratify patients to different treatment options. Also, evidence of treatment resistance or disease recurrence directs a change in medication. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have Ph-positive ALL and signs of treatment failure or disease progression who receive an evaluation for ABL1 KD single nucleotide variants to assess for TKI resistance, the evidence includes case series. Relevant outcomes are test validity and medication use. Studies have shown that specific imatinib-resistant variants are insensitive to 1 or more of the second-generation TKIs; these variants are used to guide medication selection. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable.

Objective

The objective of this evidence review is to evaluate whether testing for the BCR-ABL1 fusion gene improves the net health outcome in individuals with chronic myelogenous leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia.

Policy statements

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 section).

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 section) may be considered medically necessary for monitoring of chronic myeloid leukemia treatment response and remission.

Evaluation of ABL kinase domain (KD) 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 section); and/or when there is a progression of the disease to the accelerated or blast phase.

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

Policy Guidelines

Diagnosis of Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Qualitative molecular confirmation of the cytogenetic diagnosis (ie, 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 subsection).

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, 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 (see Rationale section).

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 on the chemotherapy regimen used.

Tyrosine Kinase Inhibitor Resistance

For CML, inadequate initial response to 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.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

Some Plans may have contract or benefit exclusions for genetic testing. 

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered.   Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

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.^1, 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 or blast phase.^2, 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. ^3,4,5,6, 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.^7, ALL is the most common childhood tumor and represents 75% to 80% of acute leukemias in children.^8, ALL represents only 20% of all leukemias in the adult population.^9, The median age at diagnosis is 17 years; more than 50% of patients are diagnosed before 20 years of age.^10, 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.^11, 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 ALL, while p210 is most often seen in CML. The product of BCR-ABL1 is also a functional tyrosine kinase; the kinase domain (KD) of the BCR-ABL protein is the same as the KD 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 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.^12, 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.^13,14,

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 with 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 patients. ^15, 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%.^16,

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.^15, 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%).^7,

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.^15,16,

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 (FDA) 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.^17,18,19, 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.^20,

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 KD that affects protein kinase-TKI binding. BCR-ABL1 single nucleotide variants (SNVs) account for 30% to 50% of secondary resistance.^16, New BCR-ABL SNVs also occur in 80% to 90% of cases of ALL in relapse after TKI treatment and in CML blast transformation. ^21, The degree of resistance depends on the position of the variant within the KD (ie, 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.^20, The consensus-recommended method is sequencing with or without denaturing high-performance liquid chromatography screening to reduce the number of samples to be sequenced.^12, 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.^22,23, For example, Guilhot et al (2007)^24, and Cortes et al (2007)^25, 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 are effective against resistant clones with the T315I variant.^21,24, 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.^26, 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.^16, 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 reverse transcription (RT)-quantitative polymerase chain reaction (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.

Rationale

This evidence review was created in February 2013 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 13, 2024.

Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Laboratory tests to detect the BCR-ABL1 fusion gene are used to identify chronic myelogenous leukemia (CML) and Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) and have different clinical uses. Briefly, they are as follows:

1. Diagnosis: individuals who do not have the BCR-ABL1 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 (acceptable in the absence of sufficient sample for karyotyping).

2. Monitoring BCR-ABL1 RNA transcripts for residual disease during treatment or disease remission; relevant, standardized test technology is quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Note that a baseline measurement after confirmation of a CML diagnosis and before treatment begins is strongly recommended.

3. Identification and monitoring of variants for drug resistance at response failure or disease progression; various test technologies are in use (not standardized) including reverse transcription-polymerase chain reaction (RT-PCR) and Sanger sequencing.

Population Reference No. 1

Diagnosis and Pretreatment Workup of Chronic Myelogenous Leukemia

Clinical Context and Test Purpose

The purpose of the BCR-ABL1 fusion gene qualitative testing in individuals with suspected CML is to inform diagnosis and establish a baseline for monitoring treatment.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with suspected CML.

Interventions

The test being considered is the BCR-ABL1 fusion gene qualitative testing.

Comparators

The following practices are currently being used to diagnose CML: clinical and cytogenetic methods.

Outcomes

The general outcome of interest is test validity. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of the BCR-ABL1 fusion gene qualitative testing, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Validation Studies

While the diagnosis of CML is based on the presence of characteristic cellular abnormalities in bone marrow, the presence of the 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.^27, If bone marrow is not available, fluorescence in situ hybridization analysis with dual probes for BCR and ABL genes or qRT-PCR can provide qualitative confirmation of the fusion gene and its type.^27,

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Diagnosis and Pretreatment Workup of Chronic Myelogenous Leukemia

The evidence on diagnosis and pretreatment workup in patients with CML includes validation studies. The sensitivity of testing BCR-ABL transcript levels with RT-PCR is high compared with conventional cytogenetics. Baseline measurement of BCR-ABL transcript levels is recommended as part of the initial evaluation, confirming the fusion gene, ensuring that it is detectable (rare variants requiring nonstandard probes may occur), and providing a baseline for monitoring response to treatment.

For individuals who have suspected CML who receive BCR-ABL1 fusion gene qualitative testing to confirm the diagnosis and establish a baseline for monitoring treatment, the evidence includes validation studies. Relevant outcome is test validity. The sensitivity of testing with reverse transcription-polymerase chain reaction is high compared with conventional cytogenetics. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 2

Monitoring Treatment Response and Chronic Myelogenous Leukemia Remission

Clinical Context and Test Purpose

The purpose of BCR-ABL1 quantitative testing at appropriate intervals in individuals diagnosed with CML is to monitor treatment response and remission.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals diagnosed with CML.

Interventions

The test being considered is BCR-ABL1 quantitative testing at appropriate intervals.

The 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.^20, Compared with conventional cytogenetics, qRT-PCR is more than 3 logs more sensitive^28, and can detect 1 CML cell in the background of 100,000 or more normal cells. The qRT-PCR testing can be conducted on peripheral blood, eliminating the need for bone marrow sampling. The goal of treatment is a complete molecular response (CMR), which has variable definitions based on the assay. However, only a small minority of patients achieve CMR on imatinib.^29, More often, patients achieve a major molecular response (MMR), which may be defined as a BCR-ABL1 transcription level of 0.01% or less on the International Scale (IS) or a 3-log or more reduction in BCR-ABL1 mRNA from the standardized baseline.^20, Because of the inherent imprecision of a response defined by undetectable BCR-ABL1 transcripts, which thereby varies according to the sensitivity of the test used, CMR is no longer used in guidelines, and has instead been replaced with deep molecular response, which is defined by the sensitivity of the test (eg, BCR-ABL1 transcripts of 0.01% or less on the IS or a 4-log or greater reduction from the standardized baseline, or transcripts of 0.0032% or less or a 4.5-log or greater reduction from the standardized baseline).

Comparators

The following practice is currently being used to diagnose CML: cytogenetics.

Outcomes

The general outcomes of interest are disease-specific survival, test validity, and change in disease status. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of the BCR-ABL1 quantitative testing, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Clinical Studies

Systematic Reviews

Campiotti et al (2017) conducted a systematic review reporting on the safety of imatinib discontinuation in patients who had previously achieved an undetectable BCR-ABL transcript level.^30, Characteristics and results of the meta-analysis are reported in Tables 1 and 2, respectively.

Table 1. SR & M-A Characteristics

Table 2. SR & M-A Results

Nonrandomized Studies

Results from the International Randomized Study of Interferon versus STI571 trial, reported by Druker et al (2006), 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.^31, 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. The similar near absence of progression in patients who achieved an MMR has been reported in registration studies of nilotinib and dasatinib.^17,18, Impacts of MMR level monitoring via in-house assays versus PCR kits have been explored elsewhere and have reported identical molecular responses in 98% of samples.^32,18,

Several studies have used these tests to guide discontinuation of select tyrosine kinase inhibitors (TKIs) in CML patients who have achieved an appropriate molecular response and to monitor treatment-free remission.^33,34,35, The largest of these studies, the European Stop Tyrosine Kinase Inhibitor Study (EURO-SKI) trial, reported by Saussele et al (2018), evaluated discontinuation of TKIs in 755 patients with CML who had been treated with TKIs for more than 3 years and had achieved a molecular response graded as MR4 (BCR-ABL1 transcription level of 0.01% or less on the IS) for at least 1 year.^36, Molecular response was assessed monthly for the first 6 months, every 6 weeks for the remainder of the year, and then every 3 months for at least 3 years. The trigger to resume treatment with TKIs was loss of MMR. Treatment-free remission rate was 50% at 2 years (95% confidence interval [CI], 46 to 54); loss of MMR despite restarting TKIs was seen in 2 patients. Similar findings were reported by Ross et al (2019) in recent updates of the Nilotinib Treatment-free Remission Study in CML Patients (ENESTfreedom) Study, a large single-arm phase 2 study, which evaluated discontinuation of first-line treatment with nilotinib in the 190 patients with CML who had been treated with nilotinib for more than 2 years and achieved sustained deep molecular response.^37, The predictive relationship between early molecular response at 3 months and eventual achievement of deep molecular response with imatinib or nilotinib treatment was explored by Wang et al (2019) in 206 patients with chronic-phase CML.^38, The predictive value of the 3-month molecular response was further supported by Berdeja et al (2019) in the Rates of Deep Molecular Response by Digital and Conventional PCR with Frontline Nilotinib in Newly Diagnosed CML (ENESTnext) study, which demonstrated the feasibility of further treatment monitoring at BCR-ABL1 transcript levels below 0.001% on the IS via digital PCR.^39, Discontinuation of therapy with first- or subsequent-line dasatinib was investigated by Shah et al (2020) in the DASFREE trial.^40, Patients were required to have been treated for a minimum of 2 years and to have achieved dasatinib-induced MR4.5 for at least 1 year prior to study entry. The primary outcome was the rate of treatment-free remission (TFR), defined as the proportion of patients with maintained MMR without restarting treatment, at 1 year post-discontinuation of dasatinib. 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 final 5-year analysis of DASFREE was published in 2023.^41, Univariate analysis indicated patients aged ≥65 years (hazard ratio [HR] for age <65 years, 2.744; 95% CI, 1.136 to 6.626), those who had received dasatinib as first-line therapy (HR, 0.393; 95% CI, 0.168 to 0.918), or had received dasatinib for a duration equal to or longer than the median duration (HR, 0.524; 95% CI, 0.277 to 0.990) experienced favorable TFR rates.

Characteristics, results, and limitations of these studies are highlighted in Tables 3 through 6.

Table 3. Summary of Key Nonrandomized Trials

Table 4. Summary of Key Nonrandomized Trial Results

Table 5. Study Relevance Limitations

Table 6. Study Design and Conduct Limitations

The degree of molecular response has also been reported to correlate with the risk of progression in patients treated with imatinib.^42, 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.^43,38,39,42,

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 years prior to imatinib discontinuation.^44, A conversion factor was calculated for ddPCR to apply positive BCR-ABL1 ratios on the 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 =.0366 (HR , 0.635; 95% CI, 0.415 to 0.972) and p =.008 (HR, 0.556; 95% CI, 0.360 to 0.858), respectively. Overall TFR at 12 months 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.^45,

Atallah et al (2021) evaluated molecular recurrence after TKI discontinuation in 171 patients with CML.^46, Monitoring for molecular recurrence (BCR-ABL1 >0.1%) was performed using PCR on the IS scale. Patients were classified as having undetectable ( BCR-ABL1 IS ratio. Molecular recurrence was significantly associated with undetectable BCR-ABL1 transcripts by either ddPCR or RT -PCR at the time of TKI discontinuation (HR, 3.60; 95% CI, 1.99 to 6.50) and at 3 months (HR, 5.86; 95% CI, 3.07 to 11.1).

Haddad et al (2022) evaluated TFR after TKI discontinuation in 199 patients with CML.^47, 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 ( qRT-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).

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 (OS).^48,49,50,

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 2 years, then every 3 to 6 months thereafter.^51,52, Without a complete cytogenetic response, continued monitoring at 3-month intervals is recommended. It has been assumed that the same time points for monitoring imatinib are appropriate for dasatinib and nilotinib,^15, and would likely also be applied to bosutinib and ponatinib.

Rising BCR-ABL1 transcript levels are associated with increased risk of variants and treatment failure.^53,54,55,56,However, what constitutes a clinically significant rise to warrant variant 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.^57,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 variant testing or changes in treatment.^58,

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Monitoring Treatment Response and Chronic Myelogenous Leukemia Remission

The qRT-PCR measurement of BCR-ABL1 RNA transcript levels is the method of choice for monitoring CML during treatment and in disease remission because of the high sensitivity, strong correlation with outcomes, and ability to sample in peripheral blood.

For individuals who have a diagnosis of CML who receive BCR-ABL1 fusion gene quantitative testing at appropriate intervals for monitoring treatment response and remission, the evidence includes a systematic review and nonrandomized trials. Relevant outcomes are disease-specific survival, test validity, and change in disease status. Studies have shown high sensitivity of this type of testing and a strong correlation with outcomes, including the risk of disease progression and survival, which may stratify patients to different options for disease management. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 3

Identification of ABL Kinase Domain Single Nucleotide Variants to Assess Tyrosine Kinase Inhibitor Resistance in Chronic Myelogenous Leukemia

Clinical Context and Test Purpose

The purpose of the evaluation for ABL kinase domain (KD) single nucleotide variants (SNVs) in individuals diagnosed with CML and inadequate initial response, loss of response, and/or disease progression is to assess for TKI resistance.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals diagnosed with CML and inadequate initial response, loss of response, and/or disease progression.

Interventions

The test being considered is testing for ABL KD SNVs to assess for TKI resistance.

Screening for BCR-ABL1 KD SNVs in chronic phase CML is recommended for individuals with (1) inadequate initial response to TKI treatment, (2) evidence of loss of response, or (3) progression to accelerated or blast phase CML.^51, Testing for KD SNVs, in the setting of potential treatment failure, may help to select from among other TKI or non-TKI treatments or allogeneic cell transplantation.

Comparators

The following practice is currently being used to assess TKI resistance among individuals with an inadequate initial response, loss of response, and/or disease progression: standard workup without genetic testing.

Outcomes

The general outcomes of interest are disease-specific survival, test validity, and medication use. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

For the evaluation of clinical validity of the ABL KD SNV testing, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Clinical Studies

The Agency for Healthcare Research and Quality published a systematic review, conducted by Terasawa et al (2010), who assessed BCR-ABL1 pharmacogenetic testing for TKIs in CML.^59, Reviewers concluded that the presence of any BCR-ABL1 variant did not predict differential response to TKI therapy, although the presence of the T315I variant uniformly predicts TKI failure. Reviewers were strongly criticized by respected pathology organizations for insufficient attention to several issues. Importantly, they grouped studies that used KD SNV screening methods with those that used targeted methods, and grouped studies that used variant detection technologies with very different sensitivities.

Kinase Domain Single Nucleotide Variants and Treatment Outcomes

Xue et al (2018) reported on health outcomes in 219 patients with CML assessed for additional chromosomal abnormalities or BCR-ABL KD mutations.^60, Characteristics and results of the study are reported in Tables 7 and 8, respectively. KD mutations were found to have a significant impact on disease progression compared to additional chromosomal abnormalities. Limitations of the study are reported in Tables 9 and 10.

Table 7. Summary of Key Nonrandomized Trials

Table 8. Summary of Key Nonrandomized Trial Results

Table 9. Study Relevance Limitations

Table 10. Study Design and Conduct Limitations

Branford et al (2009) previously summarized the available evidence on KD SNVs detected after imatinib treatment failure, and subsequent treatment success or failure with dasatinib or nilotinib.^61, Studies referenced used direct Sanger sequencing, with or without denaturing high-performance liquid chromatography screening to identify variants at low sensitivity. The authors surveyed variants detected in patients at imatinib failure at their own institution and compared results with a collation of variants derived from the literature. For both, the T315I variant was most common; although about 100 variants have been reported, the 7 most common (at residues T315, Y253, E255, M351, G250, F359, and H396) accounted for 60% to 66% of all variants in both surveys. Detection of the T315I variant 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 (eg, ponatinib).^62, Most common, however, does not necessarily correspond to clinically significant. Based on the available clinical studies, most imatinib-resistant variants remain sensitive to dasatinib and nilotinib. However, preexisting or emerging variants T315A, F317L, F317I, F317V, F317C, and V299L are associated with decreased clinical efficacy with dasatinib treatment following imatinib failure. Similarly, preexisting or emerging variants Y253H, E255K, E255V, and F359V, and F359C 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 1 of the dasatinib- or nilotinib-resistant variants.^61, As a result, guidelines recommend variant analysis only at treatment failure, and use of the T315I variant and the identified dasatinib- and nilotinib-resistant variants to select a subsequent treatment.^15,58, Absent any of these actionable variants, various treatment options are available. Note that these data were obtained from studies of patients all initially treated with imatinib.

ABL KD SNV 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 MMR). Variant testing is also recommended for progression to accelerated or blast phase CML. Treatment recommendations based on the variant(s) are shown in Table 3.

Because only a small number of variants have been recommended as clinically actionable, targeted assays may also be used to screen for the presence of actionable variants at treatment failure. Quantitative, targeted assays may also be used to monitor levels of already identified clinically significant variants 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 variants that predict treatment failure well in advance of clinical indications. Some results have been positive, but not all variants detected in advance predict treatment failure; more study is recommended before these assays are used for monitoring in advance of treatment failure.^58,61, A direct correlation between low-sensitivity and high-sensitivity assays and a limited correlation with clinical outcomes support recommendations of sequencing, with or without denaturing high-performance liquid chromatography screening, for identification of variants.^63, Although high-sensitivity assays identified more variants than did sequencing, the clinical impact of identifying additional variants is uncertain.

Variants 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 variants is not recommended.^16,64,

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Identification of ABL Kinase Domain Single Nucleotide Variants to Assess Tyrosine Kinase Inhibitor Resistance in Chronic Myelogenous Leukemia

Studies have evaluated pharmacogenetics testing for TKIs and have shown a correlation between certain types of variants and treatment response. Testing for SNVs, in the setting of potential treatment failure, may help to select from among other TKI treatments or allogeneic cell transplantation.

For individuals who have a diagnosis of CML with an inadequate initial response, loss of response, and/or disease progression who receive an evaluation for ABL KD single nucleotide variants to assess for TKI resistance, the evidence includes a systematic review and retrospective cohort study. Relevant outcomes are disease-specific survival, test validity, and medication use. The systematic review and case series evaluated pharmacogenetics testing for TKIs and reported the presence of KD single nucleotide variants detected at imatinib failure. These studies have shown a correlation between certain types of variants, treatment response, and the selection of subsequent treatment options. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 4

Monitoring Ph-Positive Acute Lymphoblastic Leukemia

Clinical Context and Test Purpose

The purpose of BCR-ABL1 quantitative testing at baseline before and during treatment in individuals with a diagnosis of Ph-positive ALL is to monitor treatment response and remission.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with a diagnosis of Ph-positive ALL.

Interventions

The test being considered is BCR-ABL1 quantitative testing at baseline before and during treatment to monitor treatment response and remission.

Comparators

The following test is currently being used to monitor treatment response and remission in those diagnosed with Ph-positive ALL: cytogenetics.

Outcomes

The general outcomes of interest are disease-specific survival, test validity, and change in disease status. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of the BCR-ABL1 quantitative testing, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Diagnosis and Pretreatment Workup

The diagnosis of 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.^65,

Monitoring for Residual Disease During Treatment and Disease Remission

Despite significantly higher complete response rates with TKIs in Ph-positive ALL, the response is typically short-lived, and relapses are common.^65, The principal aim of therapy after remission is to eradicate the minimal residual disease (MRD), which is the prime cause of relapse.^65,

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 complete response with contemporary post-remission therapy.^66,

Arunachalam et al (2020) performed a retrospective cohort analysis of 94 patients with Ph-positive ALL.^67, 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; 95% CI, 1.10 to 7.84) and EFS (HR, 5.4; 95% CI, 2.23 to 13.23). Characteristics and results of the study are presented in Tables 11 and 12. Study limitations are reported in Tables 13 and 14.

A study of 3184 children with B-cell ALL by Conter et al (2000) enrolled in the The Associazione Italiana di Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia (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.^68, Characteristics and results of the study are presented in Tables 11 and 12. Study limitations are reported in Tables 13 and 14.

Table 11. Summary of Key Nonrandomized Studies

Table 12. Summary of Key Nonrandomized Studies Results

Table 13. Study Relevance Limitations

Table 14. Study Design and Conduct Limitations

Minimal residual disease is also a strong prognostic factor for children and adolescents with first-relapse ALL who achieve a second remission.^66, 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.

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Monitoring Ph-Positive Acute Lymphoblastic Leukemia

Evidence on the diagnosis, pretreatment workup, and monitoring for residual disease during treatment and disease progression in patients with Ph-positive ALL includes a prospective cohort study, retrospective study, and case series. These studies have shown high sensitivity for BCR-ABL1 quantitative testing and a strong correlation with outcomes, including the risk of disease progression. This may stratify patients to different treatment options.

For individuals who have a diagnosis of Ph-positive ALL who receive BCR-ABL1 fusion gene quantitative testing at baseline before and during treatment to monitor treatment response and remission, the evidence includes prospective and retrospective cohort studies and case series. Relevant outcomes are disease-specific survival, test validity, and change in disease status. As with CML, studies have shown high sensitivity for this type of testing and a strong correlation with outcomes, including the risk of disease progression, which may stratify patients to different treatment options. Also, evidence of treatment resistance or disease recurrence directs a change in medication. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Population Reference No. 5

Identification of ABL Kinase Domain Single Nucleotide Variants Associated With Tyrosine Kinase Inhibitor Resistance in Ph-Positive Acute Lymphoblastic Leukemia

Clinical Context and Test Purpose

The purpose of testing for ABL KD SNVs in individuals with Ph-positive ALL and signs of treatment failure or disease progression is to assess for TKI resistance.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with Ph-positive ALL and signs of treatment failure or disease progression.

Interventions

The testing being considered is an evaluation for ABL KD SNVs to assess for TKI resistance.

Comparators

The following practice is currently being used to monitor individuals with Ph-positive ALL and signs of treatment failure or disease progression: standard workup without genetic testing.

Outcomes

The general outcomes of interest are test validity and medication use. Follow-up over years is of interest to monitor outcomes.

Study Selection Criteria

For the evaluation of the clinical validity of the ABL KD SNV testing, studies that met the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)

• Included a suitable reference standard (describe the reference standard)

• Patient/sample clinical characteristics were described

• Patient/sample selection criteria were described.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Review of Evidence

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

Clinical Studies

Resistance to TKIs in ALL is less well studied. Detection of variants was used to evaluate sensitivity to second- or third-generation TKI in case series by Soverini et al (2016).^69, 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.^65, In patients with ALL receiving a TKI, a rise in the BCR-ABL1 protein level while in hematologic complete response or clinical relapse warrants variant analysis.^65,

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Section Summary: Identification of ABL Single Nucleotide Variants Associated With Tyrosine Kinase Inhibitor Resistance in Ph-Positive Acute Lymphoblastic Leukemia

Evidence on the identification of ABL SNVs associated with TKI resistance in patients with Ph-positive ALL includes case series. These studies have shown that specific imatinib-resistant variants are insensitive to 1 or more of the second-generation TKIs. These variants are used to guide medication selection.

For individuals who have Ph-positive ALL and signs of treatment failure or disease progression who receive an evaluation for ABL1 KD single nucleotide variants to assess for TKI resistance, the evidence includes case series. Relevant outcomes are test validity and medication use. Studies have shown that specific imatinib-resistant variants are insensitive to 1 or more of the second-generation TKIs; these variants are used to guide medication selection. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) practice guidelines (v. 1.2025) on chronic myeloid leukemia outline recommended methods for diagnosis and treatment management of chronic myelogenous leukemia, including BCR-ABL1 tests for diagnosis, monitoring, and ABL kinase domain single nucleotide variants (see Table 15 ).^20, Guidelines for discontinuation of tyrosine kinase inhibitor therapy are detailed; molecular monitoring is recommended every month for the first 6 months following discontinuation, bimonthly during months 7 to 12, and quarterly thereafter (indefinitely) for patients who demonstrate BCR-ABL1 ≤0.01% International Scale (IS).

Table 15. Treatment Options for CML Based on BCR-ABL1 Variant Profile^i,ii

The NCCN practice guidelines (v. 2.2024) on acute lymphoblastic leukemia state that, if minimal residual disease is being evaluated, the initial measurement should be performed on completion of initial induction therapy; additional time points for minimal residual disease evaluation may be useful, depending on the specific treatment protocol or regimen used.^15, Serial monitoring frequency may be increased in individuals with molecular relapse or persistent disease. Minimal residual disease is an essential component of patient evaluation during sequential therapy. Treatment options based on BCR-ABL Mutation Profile are shown in Table 16.

Table 16. Treatment Options for ALL Based on BCR-ABL1 Variant Profile^i,ii

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently ongoing and unpublished trials that might influence this review are listed in Table 17.

Table 17. Summary of Key Trials

1. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring. Am J Hematol. Sep 2022; 97(9): 1236-1256. PMID 35751859
2. Sawyers CL. Chronic myeloid leukemia. N Engl J Med. Apr 29 1999; 340(17): 1330-40. PMID 10219069
3. Kantarjian HM, Deisseroth A, Kurzrock R, et al. Chronic myelogenous leukemia: a concise update. Blood. Aug 01 1993; 82(3): 691-703. PMID 8338938
4. Savage DG, Szydlo RM, Chase A, et al. Bone marrow transplantation for chronic myeloid leukaemia: the effects of differing criteria for defining chronic phase on probabilities of survival and relapse. Br J Haematol. Oct 1997; 99(1): 30-5. PMID 9359498
5. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. Sep 15 2022; 140(11): 1200-1228. PMID 35767897
6. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. Jul 2022; 36(7): 1703-1719. PMID 35732831
7. Malard F, Mohty M. Acute lymphoblastic leukaemia. Lancet. Apr 04 2020; 395(10230): 1146-1162. PMID 32247396
8. Esparza SD, Sakamoto KM. Topics in pediatric leukemia--acute lymphoblastic leukemia. MedGenMed. Mar 07 2005; 7(1): 23. PMID 16369328
9. Jabbour EJ, Faderl S, Kantarjian HM. Adult acute lymphoblastic leukemia. Mayo Clin Proc. Nov 2005; 80(11): 1517-27. PMID 16295033
10. National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Leukemia - Acute Lymphocytic Leukemia (ALL). 2020. https://seer.cancer.gov/statfacts/html/alyl.html. Accessed August 13, 2024.
11. Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012; 2012: 389-96. PMID 23233609
12. 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 01 2006; 108(1): 28-37. PMID 16522812
13. Cross NC. Standardisation of molecular monitoring for chronic myeloid leukaemia. Best Pract Res Clin Haematol. Sep 2009; 22(3): 355-65. PMID 19959086
14. 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
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