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Acute leukemia classification has progressed from early reliance on morphology and cytochemistry to today’s integrated approach. The WHO classification (now in its 5th edition)1 and the International Consensus Classification2 both emphasize combining morphology, immunohistochemistry, immunophenotyping, cytogenetics, genomic biomarkers and clinical context to achieve accurate diagnosis, inform prognosis, and guide treatment access.
“What has remained the same through all classification updates is the international collaboration and multidisciplinary approach, we need hematopathologists, clinicians, and geneticists integrating clinical context, morphology, phenotyping, and genomic information.”
— Dr. Hubert Tsui
Head, Division of Hematological Pathology, Precision Diagnostics and Therapeutics Program, Sunnybrook Health Science Centre
Across healthcare systems, ensuring equitable and timely access to advanced testing remains a challenge. Variability in laboratory capabilities, bioinformatics pipelines, and reimbursement policies can affect the consistency and timelines of genomic results. Coordinated testing strategies, national guidelines, and advocacy remain essential to ensure every patient benefits from precision diagnostics.
For most patients, the journey toward an acute leukemia diagnosis often begins in the outpatient clinic followed by refereral to an emergency department. The first sign is typically an abnormality in the blood, which may be quantitative (cell counts) or qualitative (cell morphology).
Because acute leukemia care is highly specialized, patients are usually referred to tertiary centers (specialized referral hospitals or cancer centers) for diagnosis and treatment. Many health systems have developed referral frameworks to make this process more consistent.
For example, in Ontario (Canada), the Acute Leukemia Referral Package helps clinicians assess3,4:
One ongoing challenge is deciding where the diagnostic “gold standard” bone marrow aspirate and biopsy should take place: in a community setting, or at a leukemia center. For many community hospitals and even some tertiary leukemia centres, a comprehensive suite of acute leukemia tests may not be available. Given the possibility of additional referred out testing, these logistical elements can impact not only the speed of diagnosis but also the quality and consistency of downstream initial (and reflex) testing, including the most appropriate cytogenetic and molecular investigations.
Bone marrow aspiration (BMA) combined with bone marrow biopsy (BMB) remain the gold standard for diagnosing myeloid neoplasms. Although invasive, it is a bedside procedure that does not require specialized facilities. Multiple tubes are typically drawn at first diagnosis: the initial tube is for morphology, followed by flow cytometry, cytogenetics, and finally one or more tubes for molecular testing.
Historically, this sequence of testing reflected both priority and speed. The diagnosis of acute leukemias relied heavily on morphology and enzyme cytochemistry, as outlined in the French–American–British (FAB) classification system. While foundational, these methods often lacked the precision needed to distinguish biologically and clinically relevant subclasses1,2.
In addition, the conventional tube order can complicate genomic testing, since samples drawn later may be more hemodilute, reducing the analytical sensitivity of downstream molecular analyses (as well as interpretation of variant allele fractions/frequencies).
“By the time you get to tube four or five, is it still bone marrow, or is it blood? What is the actual tumor content that we’re now trying to work up from a genomic perspective?”
— Dr. Hubert Tsui
When acute leukemia is suspected, the need for rapid testing adds further complexity. Not all centers have a full acute leukemia test menu, so samples may need to be distributed across different laboratories, often with extensive paperwork and incomplete electronic health record integration. In some cases, requisitions even arrive with every possible test checked off, creating uncertainty about what to prioritize.
“For some patients, we can’t get a quality aspirate. And there are no or very few circulating leukemia cells. Wow what do we do? ”
— Dr. Hubert Tsui
These practical realities highlight the challenges of ensuring consistent and timely genomic characterization across the spectrum of hematological neoplasms but this is especially important in the context of acute leukemias.
Accurate classification of AML is not only essential for diagnosis but also for access to targeted therapies. Simply labeling a case as acute myeloid leukemia (AML) is no longer sufficient.
Certain biomarkers, such as FLT3-ITD, do not define an AML subtype but act as actionable markers that directly influence treatment. In patients carrying this high-risk mutation, FLT3 inhibitors, such as midostaurin, quizartinib or gilteritinib, are used to improve outcomes5.
Other markers define favorable-risk subtypes, such as t(8;21) or inversion 16. In these cases, the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate6 , to chemotherapy has been shown to improve survival, particularly in patients with core binding factor AML.
These examples underscore how genomic characterization informs both prognosis and therapy selection.
To be clinically actionable, however, results must be delivered quickly. Guidelines recommend turnaround times of 3–5 days for key biomarkers and 5–7 days for cytogenetics, ensuring treatment decisions can be made without delay.
"Just labeling something as acute myeloid leukemia really doesn't suffice anymore"
— Dr. Hubert Tsui
As the AML patient journey becomes increasingly complex, the role of genomic analysis is expanding. Beyond initial diagnosis, classification, and risk stratification, NGS can also inform follow-up, treatment management, and measurable residual disease (MRD) monitoring. Integrating these tools more seamlessly into the clinical workflow will be key to improving outcomes.
This article adapts the presentation of Dr. Hubert Tsui (Sunnybrook Health Centre, Ontario, Canada) during the webinar “Evaluating Next-Generation Sequencing Solutions for Real-World Clinical Needs in Myeloid Malignancy,” with permission from the author.
Hubert Tsui, BSc, MD, PhD, FRCPC
Head, Division of Hematological Pathology, Precision Diagnostics and Therapeutics Program, Sunnybrook Health Science Centre, Associate Scientist, Sunnybrook Research Institute
Dr. Tsui is the division head of hematological pathology at Sunnybrook Health Sciences Centre and an assistant professor in the Departments of Laboratory Medicine and Pathobiology and Immunology at the University of Toronto. He completed his bachelor’s degree, medical degree, doctorate, and residency at the University of Toronto, with a clinical subspecialty in hematological pathology and a research focus on immunology. Tsui leads the Complex Malignant Hematology (CMH) program at Sunnybrook and is the medical-scientific lead of the Sunnybrook Hematology Biobank. He holds leadership roles with the Royal College of Physicians and Surgeons of Canada, Ontario Health – Cancer Care Ontario, and the Canadian Leukemia Study Group. His work focuses on integrating personalized biomarkers into clinical hematopathology and advancing translational research in acute leukemia, MDS, and MPN.
Interested in learning more? Watch the full webinar on demand:
References
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