Defining 2 Biologically and Clinically Distinct Groups in Acute Leukemia with a Mixed Phenotype.

Abstract

A mixed phenotype is characteristic of de novo Mixed Phenotype Acute Leukemia (MPAL) but can also be seen in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with a mixed phenotype and define Acute Myeloid Leukemia with Mixed Phenotype (AML-MP) and MPAL as two distinct groups by characterizing the clinical, genetic, and transcriptomic features. Clinically, patients with AML-MP and MPAL were both treated with either AML- or acute lymphoblastic leukemia (ALL)-directed induction regimens. AML-MP shows inferior responses (HR, 12.5; 95% CI, 2.72-57.8; p=.001), while MPAL shows better responses to ALL-directed treatment. Genetically, AML-MP harbors more frequent RUNX1 (23/52, 44%) and TP53 (12/52, 23.1%) mutations. In contrast, RUNX1 mutations are less frequent in MPAL (8/35, 23%, p=.01 vs AML-MP) and TP53 mutations as a driver are virtually absent in MPAL. Transcriptionally, AML-MP shows enrichment for stemness signatures, and a relative deficit of transcription factors critical for myeloid and lymphoid differentiation. Furthermore, AML-MP rarely switches to a lymphoid immunophenotype after treatment, in contrast to MPAL (1/40, 2.5%, vs. 10/28, 35.7%, p=.0003). Lastly, a genomic classification framework is proposed for future studies. Together, these data support the designation of AML-MP as a diagnosis distinct from MPAL and provide novel insights into the pathogenesis and therapies of acute leukemia with a mixed phenotype.