Defining 2 biologically and clinically distinct groups in acute leukemia with a mixed phenotype
Abstract
Abstract A mixed phenotype (MP) is a characteristic of de novo MP acute leukemia (MPAL), but it can also be found in other leukemias. It poses substantial classification and management dilemmas. Herein, we report a large cohort of acute leukemia with MP and define acute myeloid leukemia with MP (AML-MP) and MPAL as 2 distinct groups by characterizing 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 has inferior responses (hazard ratio, 12.5; 95% confidence interval, 2.72-57.8; P = .001), whereas MPAL has 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). Last, 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 MP.
Article Details
Authors (21)
Pallavi Galera
9Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Deepika Dilip
1New York Medical College, Valhalla, United States
Andriy Derkach
Alexander Chan
1Hematopathology Service Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Yanming Zhang
Sonali Persaud
5Molecular Cancer Medicine Service, Human Oncogenesis and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Tanmay Mishra
5Molecular Cancer Medicine Service, Human Oncogenesis and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Kyle Kramer
5Molecular Cancer Medicine Service, Human Oncogenesis and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Mahak Kathpalia
5Molecular Cancer Medicine Service, Human Oncogenesis and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
Ying Liu
Christopher Famulare
10Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
Qi Gao
Mitsubishi Chemical Corporation
Douglas A. Mata
6Department of Pathology and Laboratory Medicine, Diagnostic Molecular Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY
Maria Arcila
4Memorial Sloan Kettering Cancer Center, Molecular Diagnostic Service, Department of Pathology, New York, United States
Mark B. Geyer
Memorial Sloan Kettering Cancer Center
Eytan Stein
3Memorial Sloan Kettering Cancer Center, Medicine, New York, United States
Ahmet Dogan
Hematopathology Service, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York
Mikhail Roshal
1Memorial Sloan Kettering Cancer Center, New York, United States
Ross L. Levine
Jacob Glass
2Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY
Wenbin Xiao