Medical policy: BCR ABL1 Testing in Chronic Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Policy number: MP 2.317

Effective date: 4/1/2026

Policy

Chronic Myeloid Leukemia (CML)

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

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

Evaluation of ABL kinase domain point mutations to evaluate imatinib resistance may be considered medically necessary when there is inadequate initial response to treatment or any sign of loss of response (see Policy Guidelines), and/or when there is progression of the disease to accelerated or blast phase.

Evaluation of ABL kinase domain point mutations is considered investigational for monitoring in advance of signs of treatment failure or disease progression. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Acute Lymphoblastic Leukemia (ALL)

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

Evaluation of ABL kinase domain point mutations to evaluate imatinib resistance may be considered medically necessary when there is inadequate initial response to treatment or any sign of loss of response (see Policy Guidelines).

Evaluation of ABL kinase domain point mutations is considered investigational for monitoring in advance of signs of treatment failure or disease progression. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Policy guidelines

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.

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

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

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

More frequent monitoring is indicated for patients 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 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 patients with ALL receiving a TKI, a rise in BCR-ABL1 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.

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO - Refer to FEP Medical Policy Manual.

Description/Background

Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a clonal disorder of myeloid hematopoietic cells, accounting for 15% of adult leukemias. The t(9;22) reciprocal translocation is the basis of pathology, diagnosis, and monitoring in CML. The disease occurs in chronic, accelerated, and blast phases, but is most often diagnosed in the chronic phase.

If left untreated, chronic phase disease will progress within 3 to 5 years to the accelerated phase, characterized by any of several specific criteria such as 10% to 19% blasts in blood or bone marrow, basophils comprising 20% or more of the white blood cell count, or very high or very low platelet counts.

From the accelerated phase, the disease progresses into the final phase of blast crisis, in which the disease behaves like an acute leukemia, with rapid progression and short survival. Blast crisis is diagnosed by the presence of either more than 20% myeloblasts or lymphoblasts in blood or bone marrow, large clusters of blasts in the bone marrow biopsy, or development of a solid focus of leukemia outside the bone marrow.

Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood, and other organs. ALL is the most common childhood tumor and represents 75% to 80% of acute leukemias in children. ALL represents only 20% of all leukemias in the adult population.

The median age at diagnosis is 14 years; 60% of patients are diagnosed at before 20 years of age. Current survival rates for patients with ALL have improved dramatically over the past, primarily in children, largely due to therapy understanding of the molecular genetics of the disease, incorporation of risk-adapted therapy, and new targeted agents.

Current treatment regimens have a cure rate among children of about 80%. Long-term prognosis among adults is poor, with cure rates of 30% to 40%. Prognosis variation is explained, in part, by different subtypes among age groups, including the BCR-ABL fusion gene, which has a poor prognosis and is much less common in childhood ALL.

Disease Genetics

Chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias (ALL) are collectively termed “Philadelphia chromosome-positive (Ph+)” leukemias because they share a common pathogenic lesion, the Philadelphia (Ph) chromosome.

This chromosome results from a reciprocal translocation between chromosomes 9 and 22. On the Ph chromosome, a BCR-ABL1 fusion gene is formed that encodes a tyrosine kinase whose deregulated activity may be therapeutically targeted. Since 2003, the incorporation of tyrosine kinase inhibitors (TKIs) in the frontline treatment protocols has significantly improved the prognosis of both diseases and has shifted treatment endpoints from hematologic and cytogenetic responses to molecular responses.

The Philadelphia chromosome characterizes CML. In ALL, with increasing age, the frequency of genetic alterations associated with favorable outcomes declines and alterations associated with poor outcomes, such as BCR-ABL1, are more common.

In ALL, the Ph chromosome is found in 3% of children and 25% to 30% of adults. Depending on the exact location of the fusion, the molecular weight of the protein can range from 185 to 210 kDa. Two clinically important variants are p190 and p210; p190 is associated with ALL, while p210 is most often seen in CML.

The product of BCR-ABL1 is also a function tyrosine kinase, the kinase domain (KD) of the BCR-ABL protein is the same as the KD of the normal ABL protein. However, the abnormal BCR-ABL protein is resistant to normal regulation. Instead, the enzyme is constitutively activated and drives unchecked cellular signal transduction resulting in excess cellular proliferation.

Diagnosis

Although CML is diagnosed primarily by clinical and cytogenetic methods, qualitative molecular testing is needed to confirm the presence of the BCR-ABL1 fusion gene. If the Ph chromosome is not found, the type of fusion gene needs to be identified. This information is necessary for subsequent quantitative testing of fusion gene messenger RNA transcripts.

If the fusion gene is not confirmed, then the diagnosis of CML is called into question. Determining the qualitative presence of the BCR-ABL1 fusion gene is not necessary to establish a diagnosis of ALL.

Standardization of BCR-ABL1 Quantitative Transcript Testing

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.

A substantial effort has been made to standardize the BCR-ABL1 qRT-PCR testing and reporting across academic and private laboratories. In 2006, the National Institute of Health Consensus Group proposed an 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 IRIS trial, major molecular response is defined as a 3-log reduction relative to the standardized baseline, or 0.1% BCR-ABL1 on the IS.

In the assay, BCR-ABL1 transcripts are quantified relative to 1 of 3 recommended reference genes (e.g., ABL) to control for the quality and quantity of RNA and to normalize for potential differences between tests.

Treatment and Response and Minimal Residual Disease

Before initiation of therapy for CML or ALL, quantification of the BCR-ABL transcript is necessary to establish baseline levels for subsequent quantitative monitoring of response during treatment.

Quantitative determination of BCR-ABL1 transcript levels during treatment allows for a very sensitive determination of the degree of patient response to treatment. Evaluation of trial samples has consistently shown the degree of molecular response correlates with risk of progression.

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.

Three generations of tyrosine kinase inhibitors (TKIs) are now available for the treatment of CML patients. Thanks to their remarkable efficacy, most CML patients face a near-normal life expectancy and a non-negligible proportion of them may discontinue the treatment, achieving so-called “treatment-free remission” (TFR).

Imatinib (Gleevec; Novartis), a tyrosine kinase inhibitor (TKI), was originally developed specifically to target and inactivate the Abl tyrosine kinase portion of the BCR-ABL 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 continuation treatment of chronic phase CML results in durable responses in a large proportion of the patients with a decreasing rate of relapse.

As a result, imatinib became the primary therapy for most patients with newly diagnosed chronic phase CML.

With the established poor prognosis of Ph-positive ALL, standard ALL chemotherapy alone has long been recognized as a suboptimal therapeutic option, with 60% to 80% of patients achieving a complete response, significantly lower than that achieved in Ph-negative ALL. The inclusion of TKIs to frontline induction chemotherapy has improved complete response rates, exceeding 90%.

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

It is well established that most “good responders” who are considered to be in morphologic remission, but still have detectable levels of leukemia cells, referred to as minimal residual disease (MRD). Among children with ALL who achieve a complete response by morphologic evaluation after induction therapy, 25% to 50% may still have detectable MRD based on sensitive assays.

Current methods used for MRD detection include flow cytometry (sensitivity of MRD detection, 0.01%), or polymerase chain reaction–based analyses (Ig and T-cell receptor gene rearrangements or analysis of BCR-ABL transcripts), which are the most sensitive methods of monitoring treatment response (sensitivity, 0.001%).

Most ALL patients can be tested with Ig and T-cell receptor gene rearrangement analysis, whereas only Ph-positive patients can be tested with polymerase chain reaction analysis of BCR-ABL transcripts.

Treatment resistance

Imatinib treatment usually does not completely 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 is inadequate or there is a loss of response, resistance variant analysis is recommended to support a diagnosis of resistance (based on hematologic or cytogenetic relapse) and to guide choice of alternative doses or treatments.

Structural studies of the Abl–imatinib complex have resulted in the design of second-generation Abl inhibitors, including dasatinib (Sprycel; 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 both agents in newly diagnosed chronic phase patients have shown that both are superior to imatinib for all outcomes measured after 1 year of treatment, including complete cytogenetic response (primary outcome), time to remission, and rates of progression to accelerated phase or blast crisis.

Although initial follow-up was short, early and sustained complete cytogenetic response was considered a validated marker for survival in CML.

The Food and Drug Administration (FDA) has approved third-generation TKIs, ponatinib and bosutinib. Ponatinib is indicated for the treatment of patients with T315I-positive CML or Ph-positive ALL, or for whom no other TKI is indicated. Bosutinib is indicated for Ph-positive CML with resistance or intolerance to prior therapy.

For patients with increasing levels of BCR-ABL transcripts, there is no strong evidence to recommend specific treatment; possibilities include continuation of therapy with dasatinib or nilotinib at the same dose, or imatinib dose escalation from 400 to 800 mg daily, as tolerated, or therapy change to an alternative second- generation TKI.

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 ABL gene KD that affects protein kinase–TKI binding.

BCR-ABL1 single nucleotide variants (SNVs) account for 30% to 50% of secondary resistance. (Note that new BCR-ABL SNVs also occur in 80% to 90% of cases of ALL in relapse after TKI treatment and in CML blast transformation.)

The degree of resistance depends on the position of the variant within the KD (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 persistently associated with resistance.

The presence of ABL SNVs is associated with treatment failure. A large number of variants have been detected, but extensive analysis of trial data with low-sensitivity variant detection methods has identified a small number of variants consistently associated with treatment failure with specific TKIs.

Guidelines recommend testing for information on these specific variants to aid in subsequent treatment decisions. The recommended method is sequencing with or without denaturing high-performance liquid chromatography screening to reduce the number of samples to be sequenced.

Targeted methods that detect variants of interest for management decisions are also acceptable if designed for low sensitivity. High-sensitivity assays are not recommended.

Unlike imatinib, fewer variants are associated with resistance to dasatinib or nilotinib. For example, Guilhot et al (2007) and Cortes et al (2007) studied the use of dasatinib in imatinib-resistant CML patients in the accelerated phase and 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 dasatinib nor nilotinib is effective against resistant clones with the T315I variant. Other treatment strategies are under development for patients with this mutation.

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 variant in hematologic complete response or clinical relapse warrants variant analysis.

Regulatory status

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

On February 2019, the QXDx BCR-ABL IS Kit (Bio-Rad Laboratories) was approved by the FDA through the 510(k) pathway (K181661). This droplet digital PCR (ddPCR) test may be used in patients with diagnosed t(9;22) positive CML, during monitoring of treatment with TKIs, to measure BCR-ABL1 to ABL 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 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 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, FDA has chosen not to require any regulatory review of this test.

Rationale

Summary of evidence

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 RT-PCR is high compared with conventional cytogenetics. The evidence is sufficient to determine that the technology results in a meaningful 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 randomized trial and case series. Relevant outcomes are disease-specific survival, test validity, and change in disease status.

Studies have shown a 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 a meaningful improvement in the net health outcome.

For individuals who have a diagnosis of CML with inadequate initial response, loss of response, and/or disease progression who receive an evaluation for ABL KD SNVs to assess for TKI resistance, the evidence includes validation studies, systematic review, and case series.

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 SNVs 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 a meaningful improvement in the net health outcome.

For individuals who have a diagnosis of Philadelphia chromosome-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 a prospective cohort study and case series.

Relevant outcomes are disease-specific survival, test validity, and change in disease status. As with CML, studies have shown a 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 a meaningful improvement in the net health outcome.

For individuals who have Philadelphia chromosome-positive ALL and signs of treatment failure or disease progression who receive an evaluation for ABL KD SNVs 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 one or both of the second-generation TKIs; these variants are used to guide medication selection. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Definitions

N/A

Disclaimer

Capital Blue Cross’ medical policies are used to determine coverage for specific medical technologies, procedures, equipment, and services. These medical policies do not constitute medical advice and are subject to change as permitted by law or applicable clinical evidence from independent treatment guidelines. Treating providers are solely responsible for medical advice and treatment of members. These policies are not a guarantee of coverage or payment. Payment of claims is subject to a determination regarding the member’s benefit program and eligibility on the date of service, and a determination that the services are medically necessary and appropriate. Final processing of a claim is based upon the terms of contract that applies to the member’s benefit program, including benefit limitations and exclusions. If a provider or a member has a question concerning this medical policy, please contact Capital Blue Cross’ Provider Services or Member Services.

Coding information

Note: This list of codes may not be all-inclusive, and codes are subject to change at any time. The identification of a code in this section does not denote coverage as coverage is determined by the terms of member benefit information. In addition, not all covered services are eligible for separate reimbursement.

Covered when medically necessary

References

1. Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. Oct 01 2002; 100(7): 2292-302. PMID 12239137
2. Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012; 2012: 389-96. PMID 23233609
3. Hughes TP, Deininger MW, 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
4. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Chronic Myeloid Leukemia. Version 1.2026.
5. Jones D, Kamel-Reid S, Bahler D, et al. Laboratory practice guidelines for detecting and reporting BCR-ABL drug resistance mutations in chronic myelogenous leukemia and acute lymphoblastic leukemia: a report of the Association for Molecular Pathology. J Mol Diagn. Jan 2009; 11(1): 4-11. PMID 19095773
6. Campana D. Should minimal residual disease monitoring in acute lymphoblastic leukemia be standard of care?. Curr Hematol Malig Rep. Jun 2012; 7(2): 170-7. PMID 22373809
7. Mughal TI, Goldman JM. Emerging strategies for the treatment of mutant Bcr-Abl T315I myeloid leukemia. Clin Lymphoma Myeloma. Mar 2007; 7 Suppl 2: S81-4. PMID 17382017
8. von Bubnoff N, Manley PW, Mestan J, et al. Bcr-Abl resistance screening predicts a limited spectrum of point mutations to be associated with clinical resistance to the Abl kinase inhibitor nilotinib (AMN107). Blood. Aug 15 2006; 108(4): 1328-33. PMID 16614241
9. Piccaluga PP, Martinelli G, Rondoni M, et al. Advances and potential treatment for Philadelphia chromosome-positive adult acute lymphoblastic leukemia. Expert Opin Biol Ther. Oct 2006; 6(10): 1011-22. PMID 16989583
10. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in accelerated phase. Blood. May 15 2007; 109(10): 4143-50. PMID 17264298
11. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis. Blood. Apr 15 2007; 109(8): 3207-13. PMID 17185463
12. Walz C, Sattler M. Novel targeted therapies to overcome imatinib mesylate resistance in chronic myeloid leukemia (CML). Crit Rev Oncol Hematol. Feb 2006; 57(2): 145-64. PMID 16213151
13. Cortes J, Kantarjian H. How I treat newly diagnosed chronic phase CML. Blood. Aug 16 2012; 120(7): 1390-7. PMID 22613793
14. Branford S, Hughes TP, Rudzki Z. Monitoring chronic myeloid leukemia therapy by real-time quantitative PCR in blood is a reliable alternative to bone marrow cytogenetics. Br J Haematol. Dec 1999; 107(3): 587-99. PMID 10583264
15. Radich JP. Measuring response to BCR-ABL inhibitors in chronic myeloid leukemia. Cancer. Jan 15 2012; 118(2): 300-11. PMID 21717440
16. Campiotti L, Suter MB, Guasti L, et al. Imatinib discontinuation in chronic myeloid leukemia patients with undetectable BCR-ABL transcript level: A systematic review and a meta-analysis. Eur J Cancer. May 2017; 77: 48-56. PMID 28365527
17. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. Dec 07 2006; 355(23): 2408-17. PMID 17151364
18. Boeckx N, Laer CV, Roover JD, et al. Comparison of molecular responses based on BCR-ABL1% (IS) results from an in-house TaqMan-based qPCR versus Xpert(R) assay in CML patients on tyrosine kinase inhibitor therapy. Acta Clin Belg. Aug 2015; 70(4): 237-43. PMID 26166681
19. Etienne G, Guilhot J, Rea D, et al. Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia. J Clin Oncol. Jan 20 2017; 35(3): 298-305. PMID 28095277
20. Clark RE, Polydoros F, Apperley JF, et al. De-escalation of tyrosine kinase inhibitor therapy before complete treatment discontinuation in patients with chronic myeloid leukaemia (DESTINY): a non-randomised, phase 2 trial. Lancet Haematol. Jul 2019; 6(7): e375-e383. PMID 31201085
21. Devos T, Verhoef G, Stee I, et al. Interruption or Discontinuation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia: A Retrospective Cohort Study (SPARKLE) in Belgium. Acta Haematol. 2019; 142(4): 197-207. PMID 31163431
22. Sausse L, Richter J, Guilhot J, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prospective, multicentre, non-randomised, trial. Lancet Oncol. Jun 2018; 19(6): 747-757. PMID 29735299
23. Ross DM, Masszi T, Gomez Casares MT, et al. Durable treatment-free remission in patients with chronic myeloid leukemia in chronic phase following frontline nilotinib: ENESTfreedom study update. J Cancer Res Clin Oncol. May 2018; 144(5): 945-954. PMID 29468438
24. Wang R, Cong Y, Li C, et al. Predictive value of early molecular response for deep molecular response in chronic phase of chronic myeloid leukemia. Medicine (Baltimore). Apr 2019; 98(15): e15222. PMID 30985724
25. Berdeja JG, Heinrich MC, Dakhil SR, et al. Rates of deep molecular response by digital and conventional PCR with frontline nilotinib in newly diagnosed chronic myeloid leukemia: a landmark analysis. Leuk Lymphoma. Oct 2019; 60(10): 2384-2393. PMID 30912699
26. Shan NP, Garcia-Gutierrez V, Jimenez-Velasco A, et al. Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study. Leuk Lymphoma. Mar 2020; 61(3): 650-659. PMID 31647353
27. Press RD, Love Z, Tronnes AA, et al. BCR-ABL mRNA levels at and after the time of a complete cytogenetic response (CCR) predict the duration of CCR in imatinib mesylate-treated patients with CML. Blood. Jun 01 2006; 107(11): 4250-6. PMID 16467199
28. Branford S, Rudzki Z, Harper A, et al. Imatinib produces significantly superior molecular responses compared to interferon alfa plus cytarabine in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Leukemia. Dec 2003; 17(12): 2401-9. PMID 14523461
29. Nicolini FE, Dulucq S, Boureau L, et al. Evaluation of Residual Disease and TKI Duration Are Critical Predictive Factors for Molecular Recurrence after Stopping Imatinib First-line in Chronic Phase CML Patients. Clin Cancer Res. Nov 15 2019; 25(22): 6606-6613. PMID 30921542
30. Pan D, Pomicter AD, O’Hare T, et al. Deeper Than Deep: Can ddPCR Predict Successful Imatinib Cessation?. Clin Cancer Res. Nov 15 2019; 25(22): 6561-6563. PMID 31540978
31. Hellmann R, Lauseker M, Jung-Munkwitz S, et al. Tolerability-adapted imatinib 800 mg/d versus 400 mg/d versus 400 mg/d plus interferon-α in newly diagnosed chronic myeloid leukemia. J Clin Oncol. Apr 20 2011; 29(12): 1634-42. PMID 21422420
32. Wang L, Pearson K, Ferguson JE, et al. The early molecular response to imatinib predicts cytogenetic and clinical outcome in chronic myeloid leukemia. Br J Haematol. Mar 2003; 120(6): 990-9. PMID 12648069
33. Quintas-Cardama A, Kantarjian H, Jones D, et al. Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib. Blood. Jun 18 2009; 113(25): 6315-21. PMID 19369233
34. Muller MC, Hanfstein B, Erben P, et al. Molecular response to first line imatinib therapy is predictive for long term event free survival in patients with chronic phase chronic myelogenous leukemia: an interim analysis of the randomized German CML Study IV. Blood 2008; 112:129. Abstract 333.
35. Press RD, Galderisi C, Yang R, et al. A half-log increase in BCR-ABL RNA predicts a higher risk of relapse in patients with chronic myeloid leukemia with an imatinib-induced complete cytogenetic response. Clin Cancer Res. Oct 15 2007; 13(20): 6136-43. PMID 17947479
36. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. Dec 01 2008; 112(12): 4437-44. PMID 18716134
37. Baccarani M, Castagnetti F, Gugliotta G, et al. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol. Apr 2015; 94 Suppl 2: S141-7. PMID 25814080
38. Branford S, Rudzki Z, Parkinson I, et al. Real-time quantitative PCR analysis can be used as primary screen to identify patients with CML treated with imatinib who have BCR-ABL kinase domain mutations. Blood. Nov 01 2004; 104(9): 2926-32. PMID 15256429
39. Wang L, Knight K, Lucas C, et al. The role of serial BCR-ABL transcript monitoring in predicting the emergence of BCR-ABL kinase mutations in imatinib-treated patients with chronic myeloid leukemia. Haematologica. Feb 2006; 91(2): 235-9. PMID 16461309
40. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. Aug 04 2011; 118(5): 1208-15. PMID 21562040
41. Terasawa T, Dahabreh IJ, Castaldi PJ, et al. Systematic reviews on selected pharmacogenetic tests for cancer treatment: CYP2D6 for Tamoxifen in breast cancer, KRAS for anti-EGFR antibodies in colorectal cancer, and BCR-ABL1 for tyrosine kinase inhibitors in chronic myeloid leukemia. Rockville, MD: Agency for Healthcare Research and Quality; 2010.
42. Xue M, Cheng J, Zhao J, et al. Outcomes of 219 chronic myeloid leukemia patients with additional chromosomal abnormalities and/or tyrosine kinase domain mutations. Int J Lab Hematol. Feb 2019; 41(1): 94-101. PMID 30285321
43. Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter?. Blood. Dec 24 2009; 114(27): 5426-35. PMID 19880502
44. Cortes JE, Kim DW, Pinilla-Ibarz J, et al. A Pivotal Phase 2 Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL): Results of the PACE Trial. American Society of Hematology 54th Annual Meeting, December 2012. Abstract 163.
45. Ernst T, Gruber FX, Pelz-Ackermann O, et al. A co-operative evaluation of different methods of detecting BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia on second-line dasatinib or nilotinib therapy after failure of imatinib. Haematologica. Sep 2009; 94(9): 1227-35. PMID 19608684
46. Alikian M, Gerrard G, Subramanian PG, et al. BCR-ABL kinase domain mutations: methodology and clinical evaluation. Am J Hematol. Mar 2012; 87(3): 298-304. PMID 22231203
47. Fielding AK, Zakaur GA. Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia. Curr Hematol Malig Rep. Jun 2013; 8(2): 98-108. PMID 23475624
48. Campana D. Minimal residual disease in acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2010; 2010: 7-12. PMID 21239764
49. Conter V, Bartram CR, Valsecchi MG, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results of the AIEOP-BFM ALL 2000 study. Blood. Apr 22 2010; 115(16): 3206-14. PMID 20154213
50. Soverini S, De Benedittis C, Polakova KM, et al. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. Oncotarget. Apr 19 2016; 7(16): 21982-90. PMID 26980736
51. Soverini S, Bassan R, Lion T. Treatment and monitoring of Philadelphia chromosome-positive leukemia patients: recent advances and remaining challenges. J Hematol Oncol. 2019 Apr 23; 12(1): 39. doi: 10.1186/s13045-019-0729-2. PMID 31014376; PMCID: PMC6480772.
52. Radich J, Yeung C, Wu D. New approaches to molecular monitoring in CML (and other diseases). Blood. 2019 Nov 7; 134(19): 1578-1584. doi: 10.1182/blood.2019000838. PMID 31333919; PMCID: PMC9635586.
53. Soverini S, Bernardi S, Galimberti S. Molecular Testing in CML between Old and New Methods: Are We at a Turning Point?. J Clin Med. 2020 Nov 27; 9(12): 3865. doi: 10.3390/jcm9123865. PMID: 33261150; PMCID: PMC7760306.
54. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology: Acute Lymphoblastic Leukemia. Version 2.2025.
55. Cross NC, White HE, Evans PA, et al. Consensus on BCR-ABL1 reporting in chronic myeloid leukemia in the UK. Br J Haematol. 2018; 182(6): 777-788. doi: 10.1111/bjh.15542. PMID 30125955
56. Song HY, Noh H, Choi SY, et al. BCR-ABL1 transcript levels at 4 weeks have prognostic significance for time-specific responses and for predicting survival in chronic-phase chronic myeloid leukemia patients treated with various tyrosine kinase inhibitors. Cancer Med. 2018; 7(10): 5107-5117. doi: 10.1002/cam4.1753. PMID: 30176171
57. Negrin, Robert S. Chronic myeloid leukemia blast phase: Diagnosis and treatment. In UpToDate Online. Literature review current through November 2025. Last updated November 4, 2024.
58. 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