Indication - Cancer
BCR-ABL1 and ABL1 transcripts
Facility level:
Assay formats
Status history
First added in 2019
Changed in 2020
Purpose type
Diagnosis, Monitoring, Prognosis
To diagnose and monitor therapy of chronic myelocytic leukaemia (CML) and CML variants (e.g., neutrophilic CML) and prognosis of acute lymphoblastic leukaemia (ALL)
Specimen types
Venous whole blood, Bone Marrow
WHO prequalified or recommended products
WHO supporting documents
WHO classification of tumours of haematopoietic and lymphoid tissues. WHO classification of tumours, revised 4th edition, volume 2. https://publications.iarc.fr/Book-And-Report-Series/Who-Classification-Of-Tumours/WHO-Classification-Of-Tumours-Of-Haematopoietic-And-Lymphoid-Tissues-2017; 20th essential medicines list (2017) https://apps.who.int/iris/handle/10665/273826
ICD11 code: 2A20.0Z

Summary of evidence evaluation

As PCR is the reference standard test, there are no studies of test accuracy or standard assessments of test performance. Strong evidence is available, however, of the importance of assessing BCR-ABL1 and ABL1 transcripts for diagnosis and treatment monitoring. For example, evidence of the effectiveness of treatments for acute myeloid leukaemia as documented in the EML indicates its importance for identifying who will benefit from treatment. Many studies indicate that rising levels of these transcripts after treatment predict a poor clinical outcome.

Summary of SAGE IVD deliberations

PCR for detecting BCR-ABL1 fusion transcript is the recognized reference method for assessing response to treatment and disease monitoring. Detection of the t(9;22) BCR-ABL1 translocation is recommended in the principal guidelines for the diagnosis and management of CML. The BCR-ABL onco-protein can be targeted with specific inhibitors that are on the WHO EML.

SAGE IVD recommendation

SAGE IVD recommended inclusion of nucleic acid testing for BCR-ABL1 translocation in patients with CML, noting that the test is highly cost–effective and increases the efficacy of CML therapy.

Details of submission from 2020


Disease condition and impact on patients: Reports from several European registries of CML show an annual incidence of 0.7–1.0/100 000, a median age at diagnosis of 57–60 years and a male:female ratio of 1.2–1.7 (1). The estimated median prevalence is 10/100 000, which is projected to increase because of the dramatic improvement in survival of these patients due to introduction of a life-saving medicine, imatinib. Acute leukaemia is the most common childhood cancer, accounting for up to 25% of all childhood malignancies. ALL is the most common variant of leukaemia in children; Philadelphia chromosome dictates the prognosis of ALL, requiring an intensified cure. The prognosis of leukaemia is related to the health system capacity and directly to access to care. Childhood leukaemia is curable with inexpensive essential antineoplastic medicines. In certain LMICs, the prognosis of ALL can be as poor as 20% at 5 years, far behind the prognosis in higher-income settings, where > 95% survive (2, 3). For CML, access to imatinib is one of the most critical determinants of the outcome; traditional treatments, including cytotoxic agents and hydroxyurea, did not increase survival. Disparities have been described among patients covered by different insurance schemes, mirroring the effect of disparities in access to molecular diagnostics and targeted treatments (4). Does the test meet a medical need? CML and ALL are highly curable diseases. The prognosis of leukaemia reflects the efficiency of health systems in providing timely access to high-quality, safe treatment, including supportive care. Access to molecular diagnosis is essential for the entire management of CML: BCR-ABL translocation is both pathognomonic and predictive of the benefit of imatinib and other tyrosine kinase inhibitors and defines the disease and treatment response. How the test is used: IVDs are used in diagnosis, treatment and monitoring.

Public health relevance

Prevalence: The median prevalence of CML is estimated to be 10/100 000 inhabitants, which is projected to increase because of the dramatic improvement in survival of these patients due to introduction of a life-saving medicine, imatinib, and other tyrosine kinase inhibitors. Socioeconomic impact: The economic impact of cancer is significant; in 2010, the total annual economic cost of cancer was estimated at approximately US$ 1.16 trillion, threatening economies at all income levels as well as causing financial catastrophe for individuals and families.

WHO or other clinical guidelines relevant to the test

WHO does not have treatment guidelines but a basic panel of IHC markers is on the list of Priority medical devices for cancer management (5). The role of detection of BCR- ABL1 transcripts in a diagnosis of CML and the prognostic value in ALL are acknowledged in the revised WHO classification of tumours of haematopoietic and lymphoid tissues (6).

Evidence for clinical usefulness and impact

PCR is the standard technique for the diagnosis and monitoring of minimal residual disease in order to predict response and emerging resistance to treatment with imatinib and other tyrosine kinase inhibitors. Detection of the t(9;22) BCR-ABL1 translocation is recommended in guidelines for the diagnosis and management of CML, including ESMO (7) and NCCN (8). The BCR-ABL onco-protein can be targeted with the specific tyrosine kinase inhibitors on the WHO EML (imatinib, dasatinib and nilotinib) and other approved treatments. Demonstration of pathogenetic translocation is the essential diagnostic finding for targeted treatment, with a significant impact on the natural history of the disease and longer overall survival (9). Other classes of drug (hydroxyurea, interferon) resulted in significantly smaller increases in survival. In a sample Spanish population, it was estimated that a diagnosis of CML in 1990 in a 55-year- old woman would on average have reduced her life expectancy by 24.9 years, whereas a diagnosis in 2010 with tyrosine kinase inhibitors for the same woman would reduce her life expectancy by only 2.9 years (10). Monitoring of CML and early recognition of resistant clones that would require a change in treatment are based on molecular criteria or failure of response, suggesting no further benefit of therapy with a tyrosine kinase inhibitor and a switch to another, non- cross-resistant tyrosine kinase inhibitor (11–13). The WHO EML committee recognized the requirement for monitoring CML treatment and transition to second-line therapy and included second-line tyrosine kinase inhibitors in the List in 2017.

Evidence for economic impact and/or cost–effectiveness

The cost of a PCR per patient is generally US$ 100–300 in high-income settings (14). In comparative cost–effectiveness studies, imatinib appeared to be more effective than previous standard drug treatments in terms of cytogenetic response and progression-free survival, with fewer side-effects. Imatinib, which is available as a generic drug (US$ 277 401; 3.87 quality-adjusted life years (QALYs)) offered patients a 0.10 decrement in QALYs at a saving of US$ 88 343 over 5 years as compared with other tyrosine kinase inhibitors (US$ 365 744; 3.97 QALYs). The incremental cost–effectiveness ratio was US$ 883 730 per QALY (15–17). Assessment and interpretation of molecular tests require skilled, trained pathologists or molecular biologists and a thermocycler for PCR cycling.

Ethical issues, equity and human rights issues

Consent is required to obtain a blood or bone marrow sample. CML is a rare but highly curable disease, with targeted treatments that significantly affect the natural history of the disease when it is diagnosed and treated early, in the so-called chronic phase of CML. The availability of a diagnostic test is an ethical imperative to protect vulnerable patients affected with rare curable diseases.
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