Dr Issa on Testing for NPM1 or KMT2A Alterations in AML

"Even before menin inhibitors, NPM1 was guideline-recommended for testing because it informs prognosis and may influence treatment decisions as far as transplant. KMT2A [testing has become] more relevant with menin inhibitors, and knowing about the KMT2A status [absolutely] informs prognosis."

Ghayas C. Issa, MD, MS, a clinical and translational researcher in the Departments of Leukemia and Genomic Medicine at The University of Texas MD Anderson Cancer Center, discussed strategies for genetic testing in acute myeloid leukemia (AML), specifically focusing on NPM1 and KMT2A alterations.

Issa began by emphasizing the critical importance of these tests for informing prognosis and guiding treatment decisions. Regarding NPM1 mutations, guidelines have recommended testing for this alteration even prior to the development of menin inhibitors, Issa stated. Testing for NPM1 mutations can provide crucial prognostic information and can influence treatment decisions, such as the need for transplant, he added.

The standard approach for identifying this mutation is through next-generation sequencing (NGS), Issa noted. It is particularly important to retest for NPM1 at the time of relapse, as approximately 5% of cases may lose the NPM1 mutation, indicating that other mutations are driving the leukemia, Issa explained.

Testing for KMT2A alterations has become even more relevant with the emergence of menin inhibitors, Issa continued. Knowing a patient's KMT2A status provides important prognostic information and is now crucial for determining eligibility for menin inhibitors, he added. The most widely available test for identifying KMT2A rearrangement is fluorescence in situ hybridization (FISH), Issa said. Unlike NPM1, KMT2A alterations are typically founding events, meaning they are likely to persist at relapse, he explained. However, there is a chance a KMT2A rearrangement might have been missed at diagnosis, especially if not immediately clear on baseline cytogenetics, Issa cautioned. Therefore, repeating FISH at relapse is important if it was not thoroughly conducted at diagnosis, Issa concluded.