Indication - Cancer
Basic flow cytometry panel of antibodies for leukaemia
Flow cytometry (CD10, CD19, CD45, CD34, CD7, CD33, CD117, myeloperoxidase, CD79a, cytoplasmic CD3, HLA-DR, CD5, CD23, CD43)
First added in 2019
Changed in 2020
Aid to diagnosis
To aid in the diagnosis of acute leukaemias
Bone Marrow, Peripheral blood, Body fluids, Tissue, Lymph node aspirate
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 ; WHO list of priority medical devices for cancer management https://apps.who.int/iris/handle/10665/255262; WHO Guide for establishing a pathology laboratory in the context of cancer control https://www.who.int/publications/i/item/guide-for-establishing-a-pathology-laboratory-in-the-context-of-cancer-control
ICD11 code: 2B33.0
Summary of evidence evaluation
No evidence was provided on the accuracy of flow cytometry for the purposes listed, and no direct evidence was shown of its benefits. The disease classes that they cause are the basis for choosing therapy, and it is anticipated that there are RCTs that show the benefits of various treatments for different subtypes of disease, thus providing evidence for the usefulness of this test.
Summary of SAGE IVD deliberations
A diagnosis of acute leukaemia requires immunophenotyping, and this panel will simplify diagnosis in countries with minimal skilled staff and pathologists. For the diagnosis and management of acute leukaemia in LMICs, where limited treatment is available, it is essential to make the basic distinction between acute myeloid leukaemia and ALL, and ALL must be further classified into B or T cell, as the management differs. Although this is a basic panel, it will be invaluable for LMICs.
SAGE IVD recommendation
The SAGE IVD recommended conditional inclusion on the EDL of the proposed essential panel of antibodies for flow cytometry for differentiation of leukaemia subtypes, pending submission of additional evidence of use in LMICs that lack highly skilled laboratory staff. The Group requested submission within 1 year of more evidence on clinical use of the test and use of the panel in a wider range of countries and regions.
Details of submission from 2020
Disease condition and impact on patients: Acute leukaemia is fatal if not diagnosed and treated rapidly. It represents a heterogeneous group of malignancies, with different clinical, morphological, immunophenotypic and genetic features. Does the test meet a medical need? Differentiation of acute and chronic leukaemia, the myeloid and lymphoid lineages and specific subtypes is essential for choosing the correct treatment, as is exclusion of non-neoplastic haematological disease (e.g. leukaemoid reaction in systemic inflammatory processes). In ALL, classification of aggressiveness allows risk-adapted curative treatment. Immunophenotyping by flow cytometry is a rapid, reliable method for diagnosing, assessing prognosis and deciding on targeted therapy and follow-up for leukaemia (1–4). According to the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (5), diagnosis of leukaemia requires a precise morphological evaluation, with appropriate flow cytometry immunophenotyping and cytogenetic and molecular genetic testing (6). Another application of cytometry in the management of patients with leukaemia is in follow-up and monitoring of minimal residual disease, i.e. the leukaemic population that is undetectable morphologically. How the test is used: The panel is intended for laboratory use in qualitative identification of antigens by flow cytometry. It contains the minimum number of markers necessary to classify leukaemia at diagnosis and for follow-up, as reviewed by experts (5, 6). The markers should be considered a starting-point for diagnosis of leukaemia, upon which future applications could be built to monitor the response to therapy and diagnosis of haematological cancers other than acute leukaemias.
Public health relevance
According to IARC, about 440 000 new cases of leukaemia were diagnosed in 2018, with a mortality of more than 300 000. The prevalence of leukaemia was 1 174 433 globally, suggesting that many patients survive this disease. Socioeconomic impact: Childhood leukaemia accounts for 25% of all childhood malignancies. It is curable with inexpensive essential antineoplastic medicines. In certain LMICs, the prognosis of leukaemia may be as poor as 20% at 5 years, far lower than that in higher-income settings, where > 95% of affected children survive (7, 8).
WHO or other clinical guidelines relevant to the test
IARC guidelines on diagnostic criteria for myeloproliferative neoplasms (9) and the WHO priority list of medical devices for cancer management (10).
Evidence for clinical usefulness and impact
Flow cytometry is widely used for immunophenotyping blood and leukaemia cells, as it allows quantification of antigen expression, rapid analysis of large numbers of cells and determination of DNA content (7, 8). Flow cytometry can be used to detect one leukaemic cell among 10 000 normal cells and to differentiate between neoplastic and non-neoplastic regenerating blasts (for example as an effect of antineoplastic chemotherapy or other toxic myelosuppression) in assessment of the risk of relapse (11, 12). Use of flow cytometry for characterizing the immunophenotype of leukaemia cells is recommended by the principal scientific societies for adult and paediatric haematological malignancies (the European Society for Medical Oncology, the European Leukaemia Net, the International Society of Paediatric Oncology, the American Society of Hematology and the US National Comprehensive Cancer Network). According to the WHO Classification of tumours of haematopoietic and lymphoid tissues (9), diagnosis of leukaemia requires a precise morphological evaluation, with appropriate use of flow cytometry immunophenotyping and cytogenetic and molecular genetic testing (13).
Evidence for economic impact and/or cost–effectiveness
Stratification of patients by risk according to characterization of the leukaemia subtype and prognostic class ensures cost–effective treatment (14). In particular, patients with ALL who have a favourable prognosis might be spared treatment intensification or bone-marrow transplantation. Flow cytometry with a simplified panel as proposed in this application is also cost–effective when used locally or in a centralized site in resource-limited settings (9). Flow cytometry requires laboratory technicians trained in incubation and staining and a pathologist and/or a laboratory scientist trained to interpret the results.
Ethical issues, equity and human rights issues
Consent is required to obtain a sample. Flow cytometry is often not available in countries with limited resources, although it is commonly available for diagnosis of HIV infection. Cancers are therefore not diagnosed, or patients are not stratified according to risk of relapse, which ensures safe, cost–effective use of treatment (2, 5). Since chemotherapy became available, about 98% of children with ALL go into remission within weeks of starting treatment, and 90% are in remission after 10 years. In LMICs, however, survival may be only 20–50% at 10 years because of late referral to care and lack of diagnostics, cytotoxic treatment and supportive care.
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