A Blastic Plasmacytoid Dendritic Cell Neoplasm-like Phenotype Identifies a Subgroup of NPM1-Mutated AML Patients with Worse Prognosis While Has Not Predictive Value in NPM1-Wt AML
Authors: Guolo Fabio , Minetto Paola , Kunkl Annalisa , Tedone Elisabetta , Clavio Marino , Miglino Maurizio , Caviglia Fabrizio , Colombo Nicoletta , Cagnetta Antonia , Cea Michele , Ballerini Filippo , Ravetti Jean Louis , Gobbi Marco , Lemoli Roberto Massimo 
Published: October 2019

Abstract
Background
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) are a very rare group of diseases included by WHO 2016 classification among the myeloid neoplasms and usually display an aggressive course with dismal outcome. BPDCN are characterized by a recurrent phenotype (CD45low/CD34-/CD56+/CD4+/CD123+), in the absence of other lineage differentiation markers. Our group recently reported that a subset of patients diagnosed with AML with NPM1-mutation carrying co-expression of CD123, CD56 and CD4, a "BPDCN-like" phenotype, showed poor prognosis.
The aim of the present study was to evaluate the incidence and the prognostic impact of BPDCN-like phenotype in a wider cohort of cytogenetically normal AML patients, irrespectively of NPM1-mutational status.
Methods
We retrospectively evaluated a cohort of 83 younger (age <60 yrs), consecutive AMLpatientswith normal karyotype, who have been intensively treated in our institution between 2006 and 2016. All patients were treated with the same fludarabine-containing induction regimen.
In all patient, 4 (until 2012) or 8 color immunophenotypic analysis was performed at diagnosis by analysing erythrocyte-lysed whole BM blasts to identify relevant antigen aberration patterns and the pathological leukemia phenotype for future minimal residual disease assessment. We defined a BPDCN-like signature the positivity of at least two among CD56/CD4/CD123 antigens and we evaluated the prognostic impact and the correlation with biological, molecular and cytogenetic features.
Results
Fifteen patients (18%) showed a BPDCN-like signature. Neither the presence of NPM1-mutation nor FLT3-ITD or biallelic CEBPA mutation showed a significant correlation with BPDCN-like signature. BPDCN-like patients had significantly higher WBC count at diagnosis (p<0.05). No clear correlation with sex or age at diagnosis was observed.
Among analyzed variables, only the presence of NPM1-mutation correlated with complete response (CR) probability.
With a median follow-up of 63 months, 3-year Overall Survival (OS) was 52% in the whole cohort (median 38 months). Patient with NPM1 mutation or biallelic CEBPA mutation had a better outcome (p<0.03). OS was not significantly influenced by the FLT3-ITD mutation or by the presence BPDCN-like features.
However, as we previously reported, in the subgroup of 30 patients with NPM-1 mut AML, the presence of BPDCN-like features conferred a poor prognosis (3-year OS 25% vs 77% for BPDCN positive and negative NPM-1 mut patients, respectively, p<0.001), irrespectively of mutational status for FLT3-ITD or other clinical features. Even if CR rate was not affected, all NPM1-mut patient with BPDCN-like phenotype failed to achieve minimal residual disease (MRD)-negative CR (p<0.05).
On the contrary in the 38 NPM-1 wt patients a trend towards better outcome was observed in BPDCN-like patient, unless not statistically significant (3-year OS 71% vs 35% for BPDCN-like positive and negative NPM-wt patients, respectively, p=0.156). No difference in MRD clearance probability was observed in this subgroup.
Conclusions
Our extended analysis confirms that a peculiar BPDCN-like immunophenotype among NPM-1 mut AML patients is associated with significantly worse outcome in this otherwise favorable subset of AML. Patient with BPDCN-like features showed high level of minimal residual disease after induction, suggesting an intrinsic chemo-resistance. Interestingly, this observation was strictly restricted to NPM-1 mutated AML, suggesting that peculiar alterations in this distinct entity contribute to the prognostic impact of BPDCN-like features in this setting.
The biological explanation of this finding is not clear and further gene-expression profiling studies are ongoing in order to explain our findings.
Figure. Figure.

Disclosures
Gobbi: Pfister: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.