Acute Leukemias of Ambiguous Lineage With <i>RUNX1</i> Mutations Show Similar Prognosis Compared to Acute Myeloid Leukemia With <i>RUNX1</i> Mutations: A Study From the Bone Marrow Pathology Group

The World Health Organization (WHO) 5th Edition and International Consensus Classification (ICC) have continued to delineate more genetically defined acute leukemias. Both recognize genetic aberrations associated with myelodysplastic syndromes/neoplasms (MDS) as defining MDS-related AML (AML-MR). Mutations in RUNX1 are included in this category in the ICC, but not WHO. The current classifications are unclear on how acute leukemias with ambiguous lineage (ALAL), including those of mixed lineage (MPAL) and those without a defined lineage (AUL), should be categorized in the presence of such mutations. Our multi-institutional study aims to determine the significance of RUNX1 mutation in ALAL compared to de novo AML. Newly diagnosed MPAL, AUL, and AML with RUNX1 mutations were collected. ALAL with MDS-related cytogenetics, BCR::ABL1, KMT2A rearrangements, or ZNF384 or BCL11b abnormalities were excluded. We analyzed 17 cases of ALAL and 71 cases of AML that met inclusion criteria. ALAL-RUNX1 and AML-RUNX1 showed overlapping mutational landscapes with frequent comutations in MDS-associated genes. No ALAL-RUNX1 or AML-RUNX1 cases showed concomitant TP53 mutation. ALAL-RUNX1 had more bone marrow blasts and more karyotypic abnormalities; however, neither impacted survival, nor did RUNX1 variant allele frequency (VAF). Survival analysis revealed similarly poor outcomes between them. AML-directed therapies and allogeneic hematopoietic stem cell transplant trended toward improved survival in ALAL-RUNX1; however, it did not reach significance. Our results suggest ALAL-RUNX1 is associated with younger age, higher blasts, and more karyotypic abnormalities, but has similar clinical and genetic features and outcomes to AML-RUNX1. Our findings suggest, like other MR mutations, RUNX1-mutated ALALs should be included within AML-MR.