Dendritic Cell Leukemia: a Review

Abstract

Purpose of review:
The purpose of this review was to summarize the clinical, diagnostic, and therapeutic features of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Recent findings:
Several case reports and series revealed new clinical, molecular, diagnostic, and therapeutic aspects of the disease. The clinical presentation diversity has been confirmed, with frequent leukemic non-cutaneous or rare atypical manifestations. The clonal evolution in the development of BPDCN has not been sufficiently elucidated. Although certain immunophenotypic markers (CD4, TCL1, CD123, CD56, CD303) are indicative of BPDCN, the diagnosis remains in certain cases challenging. Adult (ALL)-type chemotherapy followed by hematopoietic stem cell transplantation (HSCT) is related to a favorable outcome, while chemotherapy alone seems enough in children. Future studies should continue to investigate whether CD123-directed therapies could be utilized. BPDCN is a rare aggressive malignancy that needs an aggressive induction therapy. Although a diagnostic consensus is still lacking, and large retrospective studies are also needed to obtain standardized treatment guidelines, the future perspectives are encouraging, because of novel therapeutic agents that are under investigation.

Full text

LEUKEMIA (A AGUAYO, SECTION EDITOR)
Dendritic Cell Leukemia: a Review
Nikolaos J. Tsagarakis
1
&Georgios Paterakis
1
#Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract
Purpose of Review The purpose of this review was to summarize the clinical, diagnostic, and therapeutic features of blastic
plasmacytoid dendritic cell neoplasm (BPDCN).
Recent Findings Several case reports and series revealed new clinical, molecular, diagnostic, and therapeutic aspects of the
disease. The clinical presentation diversity has been confirmed, with frequent leukemic non-cutaneous or rare atypical manifes-
tations. The clonal evolution in the development of BPDCN has not been sufficiently elucidated. Although certain
immunophenotypic markers (CD4, TCL1, CD123, CD56, CD303) are indicative of BPDCN, the diagnosis remains in certain
cases challenging. Adult (ALL)-type chemotherapy followed by hematopoietic stem cell transplantation (HSCT) is related to a
favorable outcome, while chemotherapy alone seems enough in children. Future studies should continue to investigate whether
CD123-directed therapies could be utilized.
Summary BPDCN is a rare aggressive malignancy that needs an aggressive induction therapy. Although a diagnostic consensus
is still lacking, and large retrospective studies are also needed to obtain standardized treatment guidelines, the future perspectives
are encouraging, because of novel therapeutic agents that are under investigation.
Keywords Blastic plasmacytoid dendritic cell neoplasm .BPDCN review .Dendritic cell leukemia .BPDCN diagnosis .
Immunophenotype .Therapy
Introduction
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is rec-
ognized in the WHO 2016 classification of hematopoietic
neoplasms as a distinct acute leukemia entity [1]. Described
for the first time in 1994 as CD4+ cutaneous lymphoma with
high expression of CD56, BPDCN has been known previous-
ly with various names such as blastic natural killer (NK) leu-
kemia/lymphoma, agranular CD4+/CD56+ hematodermic
neoplasm, and agranular CD4+ NK cell leukemia [2]. It is a
rare disease presenting across all ages with either skin or both
skin and bone marrow involvement often conferring a poor
prognosis [3]. BPDCN is often associated with a complex
karyotype, frequent deletions of tumor suppressor genes, and
mutations affecting either the DNA methylation or chromatin
remodeling pathways [4].
Origin of the Neoplastic Cell
The potential of the transformed (leukemic) multipotential hema-
topoietic cell to differentiate and mature along any myeloid lineage
forms the basis for the phenotypic classification of acute and
chronic myelogenous leukemia [5]. BPDCN was once believed
to be derived from natural killer cells and is now recognized as
originating from precursors of plasmacytoid dendritic cells (DCs).
DCs comprise two functionally distinct subsets: plasmacytoid DCs
(pDCs) and myeloid DCs (mDCs). PDCs have been considered as
Th2-type dendritic cell precursors characterized by its capacities to
produce large amount of alpha interferon and to differentiate into
dendritic cells [6]. PDCs, which are defined as lineage marker
(Lin) (−)HLA-DR(+)CD56(−)CD123(+)CD11c(−) cells, are con-
sidered to be the normal counterpart of BPDCNs [7]. In BPDCN,
which is characterized by a distinctive cutaneous and bone marrow
tropism, proliferating cells have been proposed to derive from
immediate CD4(+)CD56(+) precursors of pDCs, probably a
This article is part of the Topical Collection on Leukemia
*Nikolaos J. Tsagarakis
nikolaostsagarakis@gmail.com
1
Department of Immunology, “G. Gennimatas”General Hospital,
Mesogion Avenue 154, 11527 Athens, Greece
Current Oncology Reports (2020) 22:55
https://doi.org/10.1007/s11912-020-00921-y

minor subpopulation of Lin(−)DR(+)CD56(+)CD123(+
)CD11c(−) cells, which express BDCA2, BDCA4, and myeloid
antigens, which are frequently expressed by BPDCN [7]. Thus,
BPDCN has been proposed to originate from the myeloid lineage
and, in particular, from resting pDCs [8]. However, it seems to be
more complicated, if we take into account another report, which
characterized a CD56(+) DC population that express typical pDC
markers including CD123 and BDCA2, but produce much less
IFN-I comparing with pDCs [9•]. According to this report,
BPDCN is closer to CD56(+) DCs, a novel mDC subset mixed
with some pDC features, and not to pDCs, by global gene expres-
sion profiling [9•]. Thus, it was proposed that the CD4(+)CD56(+)
neoplasm may be a tumor counterpart of CD56(+) mDCs but not
pDCs [9•]. Additionally, it should be noted that the majority of
published cases are de novo, although a rare case of BPDCN with
deletion 7q.31, in the setting of heavy pre-treatment with alkylating
chemotherapy, has been reported [10].
Clinical Presentation
BPDCN usually presents with cutaneous involvement as the first
manifestation, with subsequent or simultaneous spread to bone
marrow and peripheral blood. Patients with BPDCN usually
present with solitary or multiple skin lesions. Cutaneous lesions
can present as isolated nodules, macules, and disseminated mac-
ules and nodules [11]. A nodular pattern is a more common
feature than the originally reported “bruise-like”pattern [12].
Localized or disseminated lymphadenopathy at presentation is
common. Leukemia as the first presenting symptom without
any cutaneous involvement is a rare finding and can masquerade
as acute undifferentiated leukemia. The neoplasm presents with
an aggressive behavior, and the clinical findings include cytope-
nia, particularly thrombocytopenia [13]. BPDCN with “leuke-
mic”presentation otherwise presents no major distinguishing
features and is at least as aggressive as its cutaneous-involved
BPDCN counterpart [14].
The clinical presentation diversity of BPDCN has been
highlighted through several case reports. Thus, BPDCN has
previously appeared as a renal mass [15] and as complete
monocular vision loss due to optic nerve involvement [16],
while it has been identified in the nasal cavity [17], on the
trunk, or even on the scalp [18]. Lung involvement at initial
presentation lacking cutaneous lesion [19], colon involvement
[20], leukemic presentation with massive splenomegaly [21],
and atraumatic splenic ruptures that triggered both remission
and death in a single case [22], have been previously reported.
Epidemiology
The precise incidence of BPDCN is difficult to estimate due to
constantly changing nomenclature and lack of precise defin-
ing criteria prior to the 2008 WHO classification system [23].
A male predominance (male/female ratio = 3.3/1) and an
incidence 0.000045% have been reported [24•] . In any case,
the dismal course and prognosis of BPDCN have been
underlined through the publication of a patient with
BPDCN, who did not accept further therapy, and survived
3 months only [13]. Clinical characteristics at diagnosis that
have been associated with poorer outcomes include age >
60 years, abnormal karyotype, and terminal deoxynucleotidyl
transferase (TdT) negativity in the BPDCN cells [25••]. In the
absence of reliable parameters for predicting prognosis in
BPDCN other than age, tumor stage, and/or clinical presenta-
tion, simple methods, such as FISH for CDKN2A/CDKN2B,
could help to identify the most aggressive cases (with biallelic
loss of locus 9p21.3) [26].
Morphology
Common morphological features of BPDCN include a
monotonous appearance of medium-sized tumor cells or
large atypical monocytoid cells, resembling lymphoblasts
or myeloblasts. BPDCN with immunoblastoid morpholo-
gy and MYC rearrangement and overexpression has also
been reported [27]. In BPDCN, the nuclei have a slightly
irregular contour, finely dispersed chromatin, and a con-
spicuous nucleolus [28]. The nuclei can be irregular,
folded, or flowerlike, and the cytoplasmic membrane
might appear with dendritic-like protrusions and pseudo-
podia. Some tumor cells have intracytoplasmic
microvacuoles [29], while necklace-like microvacuoles
of tumor cells have also been described [30]. In the lymph
nodes, hypercellularity with a monotonous population of
intermediate-sized cells, dispersed singly or arranged in
loose aggregates, can be observed. The cells have round
to oval nuclei, with fine chromatin and prominent nucle-
oli; the cytoplasm is generally scant, without visible gran-
ules [31]. Histopathological examination of skin lesions
reveals tumor infiltration, extended from the dermis to
the cutaneous adipose tissue, but with no invasion of the
epidermis [32]. The tumor cells may be plasmacytoid,
ranging in size from small to intermediate, with a high
nuclear-cytoplasmic ratio, probably without nucleoli
[32]. In bone marrow smears, dysplastic changes can be
observed [33], especially in megakaryocytes, [24•]while
immunohistochemistry (IHC) might be the only method to
detect minimal bone marrow infiltration [24•,34,35].
Immunophenotype
Diagnosis of BPDCN is mainly based on immunophenotypical
characterization of leukemic cells in skin lesions, blood, or bone
marrow samples. Neoplastic cells express CD4, CD43 (also
termed SPN), CD45RA, and CD56 (also termed NCAM1), as
well as the plasmacytoid dendritic cell-associated antigens
CD123 (also termed IL3RA), BDCA-2 (also termed CD303,
55 Page 2 of 13 Curr Oncol Rep (2020) 22:55

CLEC4E), proto-oncogene T cell leukemia 1 (TCL1), and
CTLA1 (also termed GZMB) [36]. On a series of 91 well-
documented cases collected by the French Study Group on
Cutaneous Lymphomas, the five most characteristic markers
of this entity (CD4, CD56, CD123, CD303, and TCL1) were
expressed simultaneously in only 46% of patients [37].
However, when 4 markers were expressed, the diagnosis could
still be reliably made without resorting to any additional stains
[37]. In a cohort of patients with bone marrow involvement,
cells were positive for CD4, CD123, TCL1, and HLA-DR and
negative for CD3, CD8, CD13, CD19, CD34, and
myeloperoxidase (MPO) [33]. Other antigens expressed by
subsets of BPDCN cases included the following: CD56
(81%), CD33 (70%), CD7 (69%), TdT (33%), CD2 (31%),
CD117 (22%), and CD5 (15%) [33]. In our cohort of patients
published 9 years ago, CD4, CD56, HLA-DR, and CD123
(bright) expression, in the absence of major B-, T- and
myeloid-associated markers, represented the core of the
immunophenotypic profile of our BPDCN cases. However, it
should be noted that TCL1 expression had not been thoroughly
investigated [28].
Intracellular expression of TCL1 is highly expressed in all
pDCL samples, while at a statistically lower level in all B-
ALL and 34% of AML [38]. The high intracellular intensity of
TCL1 expression has been considered the best marker for
pDC lineage assignment by flow cytometry (FC), being par-
ticularly useful to distinguish pDCL from CD4+/CD56 ± un-
differentiated or monoblastic acute leukemia [38]. In a com-
parison of myeloid sarcoma (MS) cases with BPDCN cases,
BPDCN was associated with positive staining for CD56, TdT
or TCL1, or negative staining for lysozyme, while neither
CD162 nor CD303 had good predictive value in
distinguishing MS from BPDCN [39].
Special consideration should be given to the expression of
CD56, CD13 and transcription factor 4 (TCF4). Myeloid antigen
expression involving CD13 may not exclude a diagnosis of
BPDCN [40]. Also, the absence of CD56 should not exclude
BPDCN diagnosis, while loss of CD56 expression can also occur
as a secondary event after chemotherapy and bone marrow trans-
plantation (BMT), probably through the contribution of
chemotherapy-induced mutations [41]. It is worth noting that a
CD56 negative BPDCN case in young age has been published
and presented as acute leukemia without skin lesion, with involve-
ment of the central nervous system (CNS) [42]. Regarding TCF4,
it is a highly sensitive marker for BPDCN and augments diagnos-
tic specificity alongside CD4, CD56, CD123, and TCL1 [43].
Immunohistochemical analyses are highly recommended
for CD123, CD56, and CD4 in BPDCN patients, particularly
in cases where the initial BM study indicates normal morphol-
ogy [34]. In a comparative study of biopsies between AML
and BPDCN cases, all BPDCN cases lacked myeloid cell
nuclear differentiation antigen (MNDA) expression,
supporting the inclusion of MNDA IHC in the diagnostic
evaluation of blastic hematopoietic infiltrates, particularly
when the differential diagnosis is between myeloid leukemia
and BPDCN [44]. Distinct findings of potential usefulness can
also be met in the literature, such as the expression of thymic
stromal lymphopoietin (TSLP) and its receptor in BPDCN
cells [35], the immunohistochemical expression of
CD31/PECAM-1 (platelet endothelial cell adhesion molecule
1) by BPDCN cells [45], and the presence of CXCL12-
positive cells in the skin, which may be associated with leu-
kemic change and a poor prognosis [46].
Taken into account all the above, but also the proposal of
Garnache-Ottou et al. [47], our team recommends a three-stage
immunophenotypical panel for BPDCN diagnosis, consisted of
a panel of “indispensable criteria,”a panel of “major criteria,”
and a panel of “minor criteria”(Fig. 1). The indispensable
criteria panel includes a low CD45/side scatter (SS) blast pat-
tern (homogeneous), MPO−, CD3−, cCD3dim/−, cCD79−,
CD19−, CD20−, CD10−, CD11c−, CD14−, CD64−, lyso-
zyme−, and HLA-DR+, which should all apply. The major
criteria panel includes CD4+, CD56+, CD123++, TCL1+,
CD43+, CD34−, and CD36+, where at least 6 out of 7 should
apply, while the minor criteria panel includes BDCA-2+,
BDCA-4+, NG2+, ILT3+, CD117−,CD13−, CD15−,and
CD5−, where at least 5 out of 8 should apply (Fig. 1).
Moreover, FC analysis permits the identification of cases with
composite immunophenotype that could be considered as
BPDCN. The ability of discrimination of coexistent or overlap-
ping, normal, or abnormal cell populations confirms the deter-
minant role of FC in the identification of “mixed-type”leuke-
mias. The combined assessment of morphology and FC analy-
sis can identify cases of leukemias of ambiguous lineage
(LAL), always implicating a significant CD56- pDC population
and a distinct leukemia component of different
immunophenotype (myeloid, monocytic, myelomonocytic,
even lymphoid). The qualitative assessment of blasts supports
the existence of > 1 blast population, and the same is true in the
FC assessment (Fig. 2). Also, the morphological blast count
and the cytogenetic quantitative evaluation (in cases with ab-
normal findings) correspond to the quantitative sum of the two
populations, as estimated with FC analysis, further supporting a
clonal origin (data not shown). Similar clonal relations of DCs
with myeloid malignancies have been previously described in
AML and myelodysplastic syndromes [47–49].
Molecular and Cytogenetic Features
Clonal evolution in the development of BPDCN remains to be
elucidated. Simple and complex recurrent cytogenetic abnor-
malities have been reported, which demonstrate predominant-
ly genomic losses, of which deletions of 5q are the most fre-
quent aberrations in BPDCN with or without cutaneous man-
ifestation; however, the gene responsible for the disease re-
mains unknown [50].
Curr Oncol Rep (2020) 22:55 Page 3 of 13 55

In a molecular cytogenetic analysis of 46 BPDCN cases,
monoallelic deletion of NR3C1 (5q31), encoding the glucocor-
ticoid receptor (GCR), was identified in 13 of 47 (28%)
BPDCN cases [51]. A retrospective analysis of 46 BPDCN
cases with abnormal karyotype has also showed that 12p- is
one of the most common structural aberrations in BPDCN
[52]. The ETV6 and CDKN1B on 12p were suggested to de-
serve further investigation as potential markers of BPDCN [52].
Monoallelic and biallelic 12p/ETV6 deletions have been also
suggested to be highly prevalent in BPDCN, by a different
study, and their detection is enhanced by the use of fluorescence
in situ hybridization (FISH) and array-based comparative geno-
mic hybridization (aCGH) [53]. In addition, 12p/ETV6 may be
present in the bone marrow of BPDCN patients in the absence
of detectable disease suggesting that such alterations might rep-
resent an early pathogenic event [53]. The analysis of 21 cases
with array-based comparative genomic hybridization (aCGH)
showed that complete or partial chromosomal losses largely
outnumbered the gains, with common deleted regions involv-
ing 9p21.3 (CDKN2A/CDKN2B), 13q13.1-q14.3 (RB1),
Fig. 1 Proposed criteria for
BPDCN diagnosis
Fig. 2 An example of morphological and immunophenotypical discrimination of BPDCN (homogeneous blast population) andleukemias of ambiguous
lineage (LAL) (heterogeneous blast populations)
55 Page 4 of 13 Curr Oncol Rep (2020) 22:55

12p13.2-p13.1 (CDKN1B), 13q11-q12 (LATS2), and 7p12.2
(IKZF1) regions [26]. CDKN2A/CDKN2B deletion was con-
firmed by FISH [26].
The gene expression profile (GEP) of 25 BPDCN samples
was analyzed and compared with that of pDCs, their postulated
normal counterpart [8]. It was the first speculation about the
cellular derivation of BPDCN, suggested to be originated from
the myeloid lineage and in particular, from resting pDCs. The
GEP of BPDCN is characterized by aberrant NF-kappaB path-
way activation, while its genomic landscape is dominated by
structural chromosomal alterations involving ETV6, MYC, and
NR3C1, as well as mutations in epigenetic regulators particularly
TET2 [43]. TET2 and TP53 mutations are frequently observed in
BPDCN [54]. Using targeted high-coverage massive parallel se-
quencing, 50 common cancer genes have also been investigated
in 33 BPDCN samples [55]. Point mutations were revealed in
NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2,
KIT (9.1% each), APC, and RB1 (6.1%), as well as in VHL,
BRAF,MLH1,TP53,andRET1(3%each)[55].
Whole-exome sequencing (WES) of three BPDCN cases re-
vealed 37–99 deleterious gene mutations per exome (such as
IKZF3, HOXB9, UBE2G2 and ZEB2) with no common affect-
ed genes between patients, but with clear overlap in terms of
molecular and disease pathways (hematological and dermatolog-
ical disease) [56]. Half of the tumors had mutations affecting
either the DNA methylation or chromatin remodeling pathways
[56]. In a different study, WES analysis of fourteen BPDCN
patients and the patient-derived CAL-1 cell line revealed
twenty-five epigenetic modifiers mutated (e.g., ASXL1, TET2,
SUZ12, ARID1A, PHF2, CHD8), with ASXL1 being the most
frequently affected (28.6% of cases) [57].
The E-box transcription factor TCF4 has been identified as
a master regulator of the BPDCN oncogenic program using
RNAi screening [58]. TCF4 served as a faithful diagnostic
marker of BPDCN, and its downregulation caused the loss
of the BPDCN-specific gene expression program and apopto-
sis [58]. Moreover, several additional genetic observations
have been made lately, based mainly in case reports. These
include cases with EWSR1 gene rearrangement [59], loss of
genomic DNA copy numbers in the p18, p16, p27, and RB
loci [60], AT-Rich Interaction Domain 1A (ARID1A) gene
mutation [61], and absence of MYD88 L265P mutation [62].
Alterations of the cell-cycle checkpoint controlling
proteins p27 (KIP1), encoded by CDKN1B,
p16(INK4a), encoded by CDKN2A, and RB1 may exert
a profound effect in malignant transformation in BPDCN
[63]. The investigation of clonal evolution in a case of
BPDCN, by analyzing the distribution of gene mutations
in tumor cells and non-tumor blood cells, revealed that
BPDCN originated from clonal hematopoiesis with the
p.K1005fs TET2 and p.P95H SRSF2 mutations via ac-
quisition of the additional p.D1129fs TET2 and p.L287fs
NPM1 mutations [64].
The implication of 8q24/MYC in BPDCN cases is of spe-
cial concern. 8q24/MYC rearrangements occur in 10–15% of
BPDCN, often partnered with non-immunoglobulin chromo-
somal loci, and may play a role in BPDCN pathogenesis [65].
Boddu PC et al. revealed that 5 of 41 (12%) patients with
BPDCN had 8q24/MYC rearrangements, including 2 with
t(6;8)(p21;q24), 1 with t(8;14)(q24;q32), 1 with
t(X;8)(q24;q24), and 1 with t(3;8)(p25;q24) [65]. Recently,
in a study of 118 cases, forty-one (38%) MYC(+)BPDCN
(positive for rearrangement and expression) and 59 (54%)
MYC(−)BPDCN (both negative) cases were identified, while
MYC(+)BPDCN cases showed older onset, poorer outcome,
and localized skin tumors more commonly than
MYC(−)BPDCN [66•]. In a different study of 16 cases, cyto-
genetic analysis revealed a single recurrent translocation part-
ner of MYC at 6p21 in 11 cases (69%), whereas four cases
showed different MYC translocation partners (2p12, Xq24,
3p25, and 14q32) [67]. It seems that translocations involving
the 8q24/MYC locus more frequently manifest as
t(6;8)(p21;q24), and, given its association with specific clini-
copathological features suggesting even more aggressive be-
havior, t(6;8)(p21;q24) indicate a genetically defined sub-
group within BPDCN [67]. It is remarkable that a case report
has been published with immunoblastoid morphology and
MYC rearrangement and overexpression [27], suggesting a
distinct BPDCN profile. The identification of SUPT3H as a
novel 8q24/MYC partner in BPDCN with t(6;8)(p21;q24)
translocation has also been previously made [68].
Rare rearrangements that have been reported in BPDCN in-
clude a case with t(11;19)(q23;p13.3), KMT2A(MLL)
rearranged [69], a pediatric case of BPDCN with a KMT2A
(MLL)-MLLT1 rearrangement confirmed by molecular study
[70], and a Philadelphia chromosome-positive BPDCN case
[71].
Treatment
There is still no consensus for the treatment of BPDCN.
Intensive therapy for acute leukemia can be useful, but allo-
geneic BMT has a greater chance of long-term survival. The
majority of patients initially respond to multi-agent chemo-
therapy, though most relapse within a year, and the prognosis
is very poor. Existing data on the clinical behavior of BPDCN
are limited because reported outcomes are from small retro-
spective series, and standardized treatment guidelines are
lacking [25••].
Intensive first-line therapy and “lymphoid-type”chemo-
therapy regimens have been associated with better outcomes
[25••]. Despite the fact that BPDCN isoften initially limited to
the skin, only an aggressive initial therapy may improve the
patients’prognosis. Local treatments, such radiation therapy,
seem useless [72].
Curr Oncol Rep (2020) 22:55 Page 5 of 13 55

Formerly, the therapeutic approach of BPDCN was based
on regimens used for acute lymphoblastic or myeloid leuke-
mia and non-Hodgkin’s lymphoma [e.g., hyperCVAD,
(hyperfractionated cyclophosphamide, vincristine, doxorubi-
cin, and dexamethasone alternating with high dose methotrex-
ate and cytarabine)] and CHOP (cyclophosphamide, doxoru-
bicin, vincristine, prednisone-based regimens) followed by
allogeneic stem cell transplantation (allo-HSCT) for eligible
patients [73]. Front-line induction chemotherapy with
HyperCVAD can yield high remission rates, but allo-HSCT
is required for long-term durable remissions [74]. Auto-HSCT
for BPDCN in CR1 (1st complete response) appeared to pro-
vide promising results and deserved further evaluation in the
setting of prospective trials [75]. In the most recent study of 59
patients with BPDCN, the median overall survival from diag-
nosis was 24 months, and outcomes were similar in patients
with “skin only”or with systemic disease at presentation
[25••]. Only 55% of patients received intensive chemotherapy,
and 42% of patients underwent stem cell transplantation.
Alternative treatment options that have been previously
used for BPDCN treatment are CD123-related therapies,
venetoclax, nuclear factor-kappa B (NF-kB) inhibitors, BET
inhibitors, demethylating agents, and other chemotherapy
agents, such as pralatrexate, enasidenib, L-asparaginase with
methotrexate and dexamethasone, gemcitabine, docetaxel,
and bendamustine.
While the current standard treatment for BPDCN is acute
leukemia-based regimen followed by HSCT for transplant-
eligible patients, there are very promising results for CD123-
directed therapies [73]. The future of BPDCN treatment may
include targeted therapies without the need for cytotoxic che-
motherapy [73]. In December 2018, tagraxofusp [Elzonris], an
intravenously administered CD123-directed cytotoxin that was
developed by Stemline Therapeutics, Inc., received its first
global approval in the USA for the treatment of BPDCN in
adults and in pediatric patients aged 2 years and older [76•].
A centralized registration application for the use of tagraxofusp
in patients with BPDCN is under review in the EU.
Tagraxofusp (SL-401) is a CD123-directed cytotoxin
consisting of human interleukin-3 fused to truncated diphthe-
ria toxin that has shown robust activity in BPDCN [77]and
considerable promise in ongoing clinical trials [78]. SL-401
was also well tolerated in pediatric patients with BPDCN, and
further testing of this agent in children is warranted [79].
While SL-401 has shown potential to provide durable re-
sponses even without transplant, we do not yet know whether
it will be effective as a means to avoid transplant in patients
who are otherwise eligible [80]. The cytotoxicity of SL-401
was assessedin patient-derived BPDCN cell lines (CAL-1 and
GEN2.2) and in primary BPDCN cells isolated from 12 pa-
tients using FC and an in vitro cytotoxicity assay [81]. SL-401
exhibited a robust cytotoxicity against BPDCN cells in a dose-
dependent manner [81]. In a separate study, seven of 9
evaluable (78%) BPDCN patients had major responses in-
cluding 5 complete responses and 2 partial responses after a
single course of SL-401 [82]. The median duration of re-
sponses was 5 months (range, 1–20+ months) [82]. In a very
recent open-label, multicohort study, 47 patients were
assigned with untreated or relapsed BPDCN to receive an
intravenous infusion of tagraxofusp at a dose of 7 mug or 12
mug per kilogram of body weight on days 1 to 5 of each 21-
day cycle [83•]. Treatment continued until disease progression
or unacceptable toxic effects. Of the 47 patients, 32 were
receiving tagraxofusp as first-line treatment, and 15 had re-
ceived previous treatment [83•]. Among the 29 previously
untreated patients who received tagraxofusp at a dose of 12
mug per kilogram, the primary outcome occurred in 21 (72%),
and the overall response rate was 90%; of these patients, 45%
went on to undergo stem-cell transplantation [83•]. Survival
rates at 18 and 24 months were 59% and 52%, respectively.
Among the 15 previously treated patients, the response rate
was 67%, and the median overall survival was 8.5 months
[83•]. Serious adverse events included capillary leak syn-
drome, while hepatic dysfunction and thrombocytopenia were
common [83•].
According to Kerr D et al., all transplant-eligible patients
should undergo allo-HSCT consolidation given the current
available data indicating this is the optimal approach to
achieve a long-term remission [80]. Once the CD123-
directed therapies are established as standard regimens, future
studies may be designed to investigate whetherthese therapies
can be utilized without the use of transplant [80]. Furthermore,
combination therapy using anti-CD123 agents with high-dose
induction chemotherapy or other low-dose regimens for
elderly/frail patients should be investigated [80]. Given its
promising results in early clinical trials, it appears that
CD123 is the most viable target for BPDCN, and future stud-
ies should continue to exploit its expression on BPDCN cells
[80]. Additional CD123-directed therapies, especially chime-
ric antigen receptor-therapy (CAR-T), may also give promis-
ing results in trials that are currently underway [80].
It has been also disclosed that venetoclax or other BCL2
inhibitors undergo expedited clinical evaluation in BPDCN,
alone, or in combination with other therapies [84]. In vivo clin-
ical activity of venetoclax in patient-derived xenografts and in 2
patients with relapsed chemotherapy-refractory disease has
been demonstrated, through primary tumor cell functional pro-
filing to predict BCL2 antagonist sensitivity [84]. A different
case report has supported the use of venetoclax in the off-label
treatment of BPDCN with Bcl-2 overexpression [85].
An aberrant activation of the NF-kB pathway and a molec-
ular shutoff of the NF-kB pathway with anti-NF-kB-treatment
have been successfully demonstrated by GEP and IHC on the
BPDCN cell line CAL-1 [8]. NF-kB inhibition in BPDCN cell
lines, achieved using either an experimental specific inhibitor
JSH23 or the clinical drug bortezomib, interferes in vitro with
55 Page 6 of 13 Curr Oncol Rep (2020) 22:55

leukemic cell proliferation and survival [86]. Bortezomib ef-
ficiently inhibited the phosphorylation of the RelA NF-kB
subunit in BPDCN cell lines and primary cells from patients
in vitro and in vivo in a mouse model [86]. Bortezomib can be
associated with other drugs used in different chemotherapy
regimens to improve its impact on leukemic cell death [86].
Moreover, high-throughput drug screening revealed that
bromodomain and extra-terminal domain inhibitors (BETis) in-
duced BPDCN apoptosis, attributable to disruption of a
BPDCN-specific transcriptional network controlled by TCF4-
dependent super enhancers [58]. BETis retarded the growth of
BPDCN xenografts, supporting their clinical evaluation in this
malignancy [58]. Also, inhibitors for bromodomain and BETis
and aurora kinases (AKis), inhibited CAL-1 (MYC(+)BPDCN)
growth more effectively than PMDC05 (MYC(−)BPDCN) cell
lines [66•], while a BCL2 inhibitor was effective in both CAL-1
and PMDC05, indicating that this inhibitor can be used to treat
MYC(−)BPDCN [66•]. Another study pointed to NR3C1 as a
haploinsufficient tumor suppressor in a subset of BPDCN and
identified BET inhibition, acting at least partially via a long
noncoding RNA (lncRNA) gene blockade, as a novel treatment
optioninBPDCN[51].
Additional reports have proposed several different potential
therapeutic alternatives. Thus, case reports of three older pa-
tients with BPDCN demonstrated that azacitidine was insuffi-
cient as monotherapy to provide durable disease control but
was a well-tolerated therapy [87]. The median survival in this
small series was 17 months, consistent with previous reports in
the literature, justifying the use of this therapy in patients who
are unfit for intensive chemotherapy and HSCT [87]. L-
asparaginase with methotrexate and dexamethasone had also
been proposed as an effective treatment combination in
BPDCN [88], while a case report suggested ABVD therapy
as useful for patients with BPDCN who cannot receive HSCT
[89]. Bendamustine hydrochloride, a well-tolerated bifunction-
al drug acting as an alkylating and antimetabolite agent, was
tested in five cases of relapsed BPDCN with moderate results
[90], and disease responses to pralatrexate [25••,91,92]and
enasidenib [25••] have been identified. Gemcitabine and doce-
taxel have also been proposed as a novel treatment combination
regimen for BPDCN [93]. Through the adoption of a preclinical
BPDCN mouse model, established by the CAL-1 cell line xe-
nografting, the efficacy of the combination of the epigenetic
drugs 5′-azacytidine and decitabine in controlling the disease
progression in vivo has also been demonstrated [57].
Liver X receptor (LXR) agonists have also been proposed
as a novel therapeutic option, as it was demonstrated that the
modified cholesterol homeostasis observed in BPDCN can be
normalized by treatment with LXR agonists and apoptosis is
triggered [94]. Finally, the efficacy of a novel chimeric mono-
clonal antibody (ch122A2 mAb) that mediates a strong cellu-
lar cytotoxicity directed against a specific human pDC marker,
CD303, has been demonstrated in humanized mice, resulting
in significant pDC depletion in bloodstream and secondary
lymphoid organs such as spleen [95]. Thus, it could represent
a promising cytotoxic mAb candidate for pathologiesin which
decreasing type I IFNs or pDCs depleting may improve pa-
tient prognosis [95].
A special comment should be made for CNS involvement.
BPDCN patients studied at diagnosis frequently display occult
CNS involvement and treatment of occult CNS disease might
lead to a dramatically improved outcome of BPDCN [96].
Also, implementation of lumbar punctures and preventive in-
trathecal chemotherapy are proposed in BPDCN patients with
leukemic manifestation during the remission stage [97].
Radiation
BPDCN is highly aggressive even without systemic dissemi-
nation, and radiotherapy appears to be ineffective in treating
this tumor [98]. According to a case report, the simultaneous
combination of low-dose DeVIC (dexamethasone, VP16,
ifosfamide, and carboplatin) therapy with local radiation ther-
apy (LRT) could be useful in the treatment of limited-stage
BPDCN even in the elderly [32].
Transplantation
Regardless of the initial extension of the disease, it has been
suggested that only BMT significantly improved the outcome
[72]. BPDCN with marrow involvement behaves like acute
myeloid leukemia (AML), and aggressive treatment followed
by stem cell transplantation may lead to long-term remission in
selected cases. A study of 45 consecutive patients who received
an allo-HSCT (n= 37) or an auto-HSCT (n= 8) regardless of
age, pre-transplant therapies, or remission status at transplanta-
tion, revealed efficacy of allo-HSCT, especially in patients in
first complete remission (CR1), and lack of efficacy of auto-
HSCT [99]. Moreover, allo-HSCT in CR1 yielded superior 3-
year OS (versus not in CR1) [99]. In a large meta-analysis of
four studies (128 patients), the pooled OS rate was 50% for all
patients [100•]. Among patients who underwent allografting
whose disease was in CR1, pooled OS, and PFS/DFS rates
were 67% and 53%, respectively [100•]. For patients who
underwent allografting in > CR1, pooled OS, and PFS/DFS
rates were 7% for both outcomes. Relapse rates were higher
when reduced-intensity regimens were used (40% vs. 18%)
[100•]. In an older study, reduced-intensity conditioning (RIC)
allo-HSCT from unrelated donors proved feasible and seemed
to be effective in elderly patients with BPDCN, suggesting that
allo-HSCT should be pursued aggressively in patients with this
otherwise fatal disease up to 70 years of age [101]. RIC/
nonmyeloablative (RIC/NMA) conditioning regimens were
found equivalent to myeloablative conditioning (MAC) in
terms of outcome, confirming that long-lasting remissions can
be achieved in this disease, even in patients aged 60 or older
Curr Oncol Rep (2020) 22:55 Page 7 of 13 55

[102]. RIC/NMA should thus be proposed to patients not eligi-
ble for MAC, because of their age or co-morbidities, while
representing the majority of patients suffering from BPDCN
[102]. Moreover, a case report has been presented, where the
addition of IL-2 and IFN-a to the donor leukocyte infusions
resulted in a strong graft-versus-leukemia (GVL) effect, proba-
bly by enhancing T- and NK-alloreactivity, activating pDC-
blasts and augmenting their Ag-presenting properties [103].
The usefulness of allo-HSCT in CR1 for pediatric BPDCN with
skin involvement has also been suggested in a case report [104].
The Experience from Children
In a systematic literature review published in 2017, 74 chil-
dren and 283 adults aged 19 or over were reviewed and com-
pared [105••]. Age was shown to be an independent prognos-
tic factor predictive of more favorable outcomes across mea-
sures including initial response to therapy, likelihood of re-
lapse, and overall survival at follow-up [105••]. The distribu-
tion of affected organs at diagnosis was similar, and the type of
clinical presentation did not affect prognosis [105••]. Acute
lymphoblastic leukemia (ALL)-type chemotherapy regimens
were shown to be superior to other chemotherapy regimens
(AML, lymphoma, ALL/lymphoma, other, or none) in induc-
ing complete remission, and allo-HSCT was shown to in-
crease mean survival time [105••]. HSCT may be reserved
for children who relapse and achieve a second remission
[106]. Besides, not all pediatric BPDCN patients may be able
to achieve complete remission following chemotherapy with
the high-risk ALL regimen, and other treatment options must
be investigated in the future [107]. However, efficacy of AML
therapy without stem-cell transplantation in a child with
BPDCN has also been reported [108].
Remarkable are some unusual clinical presentations that
have been previously published, such as an asymptomatic 8-
year-old boy who noticed a painless mass within the subcuta-
neous tissues below the left calf [109], a solitary skin lesion
mimicking traumatic purpura [110], and a case resembling
acute rheumatic fever at presentation [111]. Skin lesions have
been proposed as possible clues to relapse of pediatric
BPDCN [112].
Differential Diagnosis
BPDCN was earlier called as blastic NK-cell lymphoma,
agranular CD4 NK-cell leukemia, agranular CD4, and 56 pos-
itive hematodermic neoplasm [106]. The differential diagnosis
includes myeloid sarcoma/AML, T cell lymphoblastic leuke-
mia/lymphoma, NK-cell lymphoma/leukemia, myeloid/NK
cell precursor acute leukemia, and some mature T cell
lymphomas/leukemias [113,114]. AML with MLL rearrange-
ment and CD4+/CD56+ expression can be misdiagnosed as
BPDCN [115]. BPDCN should be considered in differential
diagnosis of blastic leukemia with an undifferentiated and
ambiguous immunophenotype despite the absence of skin le-
sions [17], while an exhaustive immunohistochemical workup
is required to differentiate it from myeloid sarcoma and
extranodal NK/T cell lymphoma [116]. A case of myeloid
leukemia cutis with MPO, CD4, CD56, CD123, and TCL1,
has been previously published [117], and a case initially diag-
nosed and treated as non-Hodgkin CD4+ T cell lymphoma,
which evolved with early CNS relapse after an initial remis-
sion, and died 2 months later, after a second failed attempt of
chemotherapy [118]. Moreover, a rare case of BPDCN that
was initially misinterpreted as cutaneous lupus erythematosus
[119], and a histopathologically proven BPDCN initially
misdiagnosed as breast infiltrating ductal carcinoma in a 39-
year-old woman [120], have also been previously reported. It
is worth noting that a case report was referred to the existence
of BPDCN with a concomitant CD5-/CD10- B cell lympho-
proliferative disorder [121].
A high degree of suspicion and bone marrow examination
in patients with a new diagnosis of BPDCN is required to
avoid diagnostic pitfalls [121]. FC seems to represent the most
valuable approach to avoid misinterpretation and obtain a use-
ful pattern for measurable residual disease evaluation. The
evaluation of CD4 and CD56 expression for BPDCN diagno-
sis should always be considered in a low CD45/SS blast pat-
tern and different from the typical pattern of monocytic leu-
kemia, which has increased CD45 intensity and high SS. The
absence of CD19, cytoplasmic CD3 and MPO positivity, and
the identification of TCL1/CD56 co-expression, should al-
ways be confirmed for a definitive typical BPDCN diagnosis.
The Relation of BPDCN with the Myeloid Component
BPDCN is a rare, aggressive entity that frequently presents in
extramedullary sites and can show morphologic and
immunophenotypic overlap with myeloid neoplasms. Until
recently, neoplasms derived from plasmacytoid dendritic cells
(pDCs) were currently divided into two broad categories: ma-
ture pDC proliferations associated with myeloid neoplasms
(MPDMN) and BPDCN, while only BPDCN has been recog-
nized in the WHO 2016 classification of hematopoietic neo-
plasms. Recently, it was suggested that AML can exhibit pDC
differentiation, with or without monocytic differentiation, in a
manner distinct from MPDMN or BPDCN [122]. This was
based on the identification of cases, having increased myelo-
blasts and prominent CD56-negative pDC proliferations com-
prising 5–26% of bone marrow or blood cellularity as mea-
sured by FC. Thus, the existence of myeloid neoplasms with
immature pDC proliferations suggested the existence of a
broader spectrum of pDC-associated neoplasms than currently
recognized [122]. This was firstly described by Tsagarakis
et al. through the presentation of four cases diagnosed as
LAL [28]. These LAL cases revealed two significant distinct
55 Page 8 of 13 Curr Oncol Rep (2020) 22:55

populations in the CD45/RT-SC defined “blast pattern”of FC,
one of pDC origin, with a BPDCN phenotype although
CD56-, and another of monoblastic or precursor myeloid or-
igin [28]. Extended bone marrow infiltration and blastoid cell
detection in peripheral blood, and no skin involvement, were
documented in all four patients, supporting the absence of
cells with mature morphology and the close association of
pDCs with leukemic cells [28]. Similar observations were
later made by Martin-Martin L et al., who suggested that the
maturational profile of pDC blasts in BPDCN is highly het-
erogeneous, where blasts from cases with an immature pDC
phenotype exhibit an uncommon CD56-phenotype,
coexisting with CD34+ non-pDC tumor cells, typically in
the absence of extramedullary (e.g., skin) disease at presenta-
tion [123]. Besides, in an older study, it was noticed that both
mDC and pDC subsets in circulation exhibited the original
leukemic chromosomal abnormality in AML cases, providing
evidence that DC subsets in vivo may be affected by leuke-
mogenesis and may contribute to leukemia escape from im-
mune control [49].
The complicated correlation of BPDCN with myeloid neo-
plasms can be easily concluded by the proposal of a shared
clonal origin of BPDCN and chronic myelomonocytic leuke-
mia (CMML) [124], the reports of BPDCN cases associated
with CMML [125,126], the report of BPDCN with AML
[127], and the report of cutaneous BPDCN occurring after
spontaneous remission of AML [128] and of spontaneous re-
gression of cutaneous BPDCN followed by acute monocytic
leukemia evolving from MDS [129]. Maybe it is not accidental
that a BPDCN-like phenotype has been proposed as a subgroup
of npm1-mutated AML with worse prognosis [130], and
nucleophosmin is nucleus-restricted (predictive of a germline
NPM1 gene) in BPDCN, contrary to the cytoplasmic-mutated
nucleophosmin (NPMc(+) AML) in AML [131], probably in-
dicating a common progenitor of similar phenotype.
Nevertheless, it seems that the status of CD56 is closely related
to the maturational level of the initial leukemic clone.
Conclusions
BPDCN (BPDCN) is a rare, highly aggressive hematopoietic
malignancy, characterized by cutaneous and bone marrow in-
volvement and leukemic spread. Molecular data support the
current WHO classification of the disease as a myeloid disor-
der and provide a biological rationale for the incorporation of
epigenetic therapies for its treatment [56]. Chromosomal ab-
errations are frequent, and the mutational landscape of
BPDCN is being rapidly characterized, although no obvious
molecular target for chemoimmunotherapy has been identified
[78]. At present, the diagnosis and management of BPDCN
are still challenging. (ALL)-type chemotherapy followed by
HSCT is commonly thought to be related to a favorable
outcome in adults with BPDCN [132]. (ALL)-type chemo-
therapy alone seems enough in children with BPDCN with
or without cutaneous lesions [132]. HSCT increases the mean
survival time and should be performed for children who re-
lapse and achieve a second remission [132]. A disease-
specific Twitter community: #BPDCN = “BPDCN on social
media”has been created, which has led to higher levels of
engagement and discussion in the field [133].
Compliance with Ethical Standards
Conflict of Interest Nikolaos J. Tsagarakis and Georgios Paterakis de-
clare that they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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