Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia – implications for the European LeukemiaNet risk classification

In 2022, the European LeukemiaNet (ELN) risk classification for Acute Myeloid Leukemia (AML) was updated for the second time 1. Since the first edition in 2010 (ref. 2), it has become one of the most commonly used systems to assess the prognosis of AML patients and to guide therapeutic decisions. A major novelty of ELN2022 is that “secondary-type” mutations (STM, also called myelodysplasia-related gene mutations), i.e., mutations in the genes, SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2, were deemed adverse risk. The importance of STMs is further emphasized by the novel 5th edition of the World Health Organization (WHO) classification of myeloid neoplasms 3 and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias 4. Patients harboring STMs are categorized as “AML, myelodysplasia-related” (AML-MR, WHO) and “AML with myelodysplasia-related gene mutations” (ICC), respectively, regardless of additional cytogenetic aberrations or a medical history of hematological malignancies. The decision to include STMs as prognostic markers was based on studies showing poor prognosis also in de novo AML patients 5, 6. However, a pertinent question also raised by the ELN is whether STMs abrogate the positive prognostic value of co-occurring favorable markers, especially NPM1 mutations. For the time being, these patients are classified as favorable in ELN2022 with STMs not being considered adverse risk in that context. To address the question if this assumption is valid, we investigated a pooled cohort of 936 NPM1-mutated AML patients who were treated in previously reported multicenter trials of the Study Alliance Leukemia (SAL; AML96 NCT00180115, AML2003 NCT00180102, AML60+ NCT00180167, SORAML NCT00893373) and the AML Cooperative Group (AMLCG-1999 NCT00266136, AMLCG2008 NCT01382147)... from the article