Dr Loghavi on the Expansion of Genetically-Defined Subtypes in AML

Sanam Loghavi, MD, assistant professor, Department of Hematopathology, Division of Pathology/Lab Medicine, The University of Texas MD Anderson Cancer Center, discusses the expansion of genetically-defined categories of acute myeloid leukemia (AML) in the World Health Organization (WHO) classification, and how this affects the diagnosis of patients in this space.

The 5th edition of the WHO Classification of Hematologic Tumors has introduced several new categories of AML and corresponding defining genetic abnormalities, including KMT2A, MECOM, and NUP98rearrangement, as well as NMP1 mutations. Notably, there is no minimum blast threshold for all 4 of these categories, although both AML with CEBPA mutations and the newly introduced myelodysplasia-related AML category retain a blast threshold of 20% or greater.

Prior to these changes, the diagnosis of AML primarily relied on blast count, Loghavi states. A blast threshold of 20% or greater was required to diagnose patients with most AML subtypes, excluding core binding factor leukemias or acute promyelocytic leukemias, Loghavi explains. However, improved understanding of the molecular basis of leukemia revealed that disease prognosis and responses to treatment may be linked to underlying genetic factors rather than blast percentage. Therefore, the WHO opted to eliminate blast count as a diagnostic criterion, she says.

Nonetheless, clinical and pathologic correlation remains integral in AML diagnosis, Loghavi continues. Clinicians carefully consider the complete clinical context to make diagnoses, she adds, especially in more nuanced situations. For example, patients with NPM1 mutations featuring low variant allele frequency may not meet the criteria for AML at that time. However, these patients may have a higher likelihood of developing AML, Loghavi notes.

Overall, these changes reflect a shift towards a more genetics-oriented approach, acknowledging that rigid blast thresholds do not capture the full complexity of the disease, Loghavi states. This change aims to enhance diagnostic accuracy, align treatment decisions with genetic insights, and adapt to evolving understandings of AML disease biology, she concludes.