Acute Erythroid Leukemia Associated With Myeloid Neoplasms: Clinicopathologic Features and Evidence of Clonal...

Acute erythroid leukemia (AEL) is a rare and aggressive variant of leukemia with erythroid differentiation. AEL can arise de novo or transform from underlying myeloid neoplasms (MNs); however, the clinicopathologic and molecular genetic features associated with AEL transformation are poorly defined. Through a multi-institutional collaboration, we characterized 116 cases of AEL transformed from MNs, predominantly myelodysplastic neoplasms (MDS; 59%, n=68) and BCR::ABL1-negative myeloproliferative neoplasms (MPN; 28%, n=33). Median age at AEL diagnosis was 66 years (range, 26-94 years) with a male-to-female ratio of 1.3:1. At initial MN diagnosis, the MDS group had a significantly higher rate of complex karyotypes (76% vs. 8%; P < 0.0001) and TP53 mutations (98% vs. 11%; P < 0.0001), and a shorter median time to transformation (7.6 vs. 82.4 months; P < 0.0001), compared with the MPN group. Conversely, the MPN group preferentially acquired complex karyotypes and co-mutations including TP53 and TET2, during progression. Consequently, at the time of AEL transformation, both groups exhibited similar frequencies of complex karyotypes (94% vs. 92%; P = 0.6574) and TP53 mutations (100% vs. 92%; P = 0.1176) and a dismal median overall survival (1.4 vs. 1.5 months; P = 0.7893). Notably, among 58 cases with longitudinal cytogenetic and molecular data, 100% shared at least one genetic aberration between the MN and AEL stages, suggesting a direct clonal relationship. Taken together, these findings show that AEL can clonally evolve from underlying MNs through distinct initial molecular genetic pathways that ultimately converge into an adverse genetic landscape with poor prognosis.