Acute Myeloid Leukemia with Plasmacytoid Dendritic Cell Differentiation: Predominantly Secondary AML, Enriched for RUNX1 Mutations, Frequent Cross-Lineage Antigen Expression and Poor Prognosis
Authors: Xiao Wenbin , Goldberg Aaron D , Famulare Christopher , Baik Jeeyeon , Gao Qi , Tallman Martin S. , Zhang Yanming , Arcila Maria E , Roshal Mikhail 
Published: October 2019

Abstract
Introduction
Plasmacytoid dendritic cells (PDC) are the major natural type I interferon producing dendritic cells that play critical roles in the immune response. PDC are differentiated from hematopoietic stem cells under the control of multiple transcription factors including GATA-2, IKAROS, IRF8, TCF4, ID2 and RUNX1. PDC can be easily identified by flow cytometry due to high-level expression of CD123, HLA-DR and CD303/BDCA2 in the context of lack of lineage markers. In healthy subjects, PDC are <1% of total nucleated cells in both marrow and blood, but are present in a relatively narrow range of proportions. Neoplastic proliferation of PDC leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal proliferation of PDC has also been described in chronic myelomonocytic leukemia (CMML). The association between PDC and acute myeloid leukemia (AML) has not been reported. Here we characterize the clinicopathologic features of AML patients with increased PDC. We also demonstrate the clonal relationship between leukemic blasts and PDC at the molecular levels.
Patients and Methods
AML patients were searched from the patient database at the MSKCC between 5/2014 and 12/2017. Flow cytometric data obtained on the bone marrow aspirate at the diagnosis were reviewed and cases with PDC proportion greater than 3% of WBC (defined by CD45 positive cells) were included. All the patients had genomic sequencing studies (a targeted NGS panel comprising 30 genes with mutations enriched in AML) performed at diagnosis. PDC and leukemic blasts were sorted by flow cytometry from a subset of patients (N=6) and mutational profiles were compared after sequencing studies. Histopathologic assessment was also performed.
Results
24 patients were identified (20 male and 4 female) with a median age of 69 years old (Interquartile range IQR: 56-76). The prevalence was approximately 5% among total new AML patients diagnosed during the same time period. 21 (88%) patients were secondary AML (18 AML with myelodysplasia-related changes (AML-MRC) and 3 therapy-related AML) and only 3 (12%) were de novo AML. No skin presentation was seen.
17 (71%) patients had cytogenetic abnormalities but only 1 with complex karyotype, 1 del(5p) and 3 del(7q). 14 (58%) had pathogenic RUNX1 aberrations (13 mutations and 1 rearrangement, Figure 1A). Other recurrent mutations included ASXL1 (N=7, 29%), IDH1 (N=4, 17%), SRSF2 (N=4, 17%), DNMT3A (N=3, 13%), TET2 (N=3, 13%), NRAS (N=3, 13%), and TP53 (N=3, 13%).
The median of PDC proportion was 8.1% (IQR: 4-12.7%). In contrast to BPDCN, these PDC were negative for CD56, TCL-1 and TdT (Figure 1B). The leukemic blasts from 17 (71%) patients showed cross-lineage antigen expression including CD19 (N=4), CD2 and/or CD7 (N=9), and both CD7/CD19 (N=4). The sorted leukemic blasts and PDC shared identical mutations in 6 examined patients confirming the clonal relationship. Unlike CMML with increased PDC, PDC in AML did not form aggregates, showed leukemic distribution pattern and were also increased in peripheral blood at diagnosis.
17 patients received Daunorubicin based induction therapy and 6 had hypomethylating agents. 13 achieved complete remission (5 MRD negative, 6 MRD positive, 2 unknown MRD status). 11 received allo-HSCT with 5 relapsed post transplant. With a median follow-up of 17 months, 18 patients have died. The median survival was 20 months (Figure 1C).
Conclusion
AML with plasmacytoid dendritic cell differentiation has unique clinicopathologic features including predominantly secondary AML, enriched for RUNX1 mutations, frequent cross-lineage antigen expression and poor prognosis. The PDC are clonally related to the leukemic blasts. CMML with PDC proliferation, AML with PDC differentiation and BPDCN might represent a spectrum of myeloid stem cell neoplasm with aberrant PDC differentiation. Further studies are needed to investigate the molecular mechanism of particularly the role of RUNX1 in PDC differentiation in AML.
Figure 1 Figure 1.

Disclosures
Goldberg: Celgene: Research Funding; Abbvie: Research Funding; AROG: Research Funding; Pfizer: Research Funding. Tallman:ADC Therapeutics: Research Funding; Orsenix: Other: Advisory board; AbbVie: Research Funding; BioSight: Other: Advisory board; Cellerant: Research Funding; Daiichi-Sankyo: Other: Advisory board; AROG: Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria.