REVIEW
Blastic Plasmacytoid Dendritic
Cell Neoplasm
Akriti Jain, MD,1 and Kendra Sweet, MD2
ABSTRACT
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hemato-
logic malignancy with an aggressive clinical course and poor prognosis.
BPDCN is most often characterized by its presentation with distinct cu-
taneous lesions. Bone marrow involvement, lymphadenopathy, spleno-
megaly, and/or cytopenias are also seen to varying degrees. BPDCN
presents with diffuse, monomorphous blasts with irregular nuclei, fine
chromatin, and scant, agranular cytoplasm. Expression of CD4, CD56,
and CD123 is the hallmark of BPDCN. The presence of $4 of CD4,
CD56, CD123, TCL1, TCF4, and CD303 is necessary for the diagnosis
of BPDCN. Prior to December 2018, management of BPDCN revolved
around intensive chemotherapy using acute myeloid leukemia or acute
lymphoblastic leukemia regimens. However, responses were transient
with poor overall survival (OS). Allogeneic stem cell transplantation
(alloSCT) is the only potentially curative treatment for BPDCN. Even so,
only a minority of patients are candidates for alloSCT given the prepon-
derance of disease in older individuals. For the few fit patients who are
candidates for alloSCT, the aim is to achieve complete remission prior
to alloSCT. Tagraxofusp (SL-401), a recombinant fusion protein con-
taining interleukin-3 fused to truncated diphtheria toxin, was the first
approved CD123-targeted therapy for BPDCN based on a phase I/II
clinical trial showing a 90% overall response rate. It was approved by
the FDA on December 21, 2018. Capillary leak syndrome is an impor-
tant adverse effect of tagraxofusp that requires close monitoring. Several
clinical trials are underway to study other regimens for the treatment of
BPDCN, including IMGN632 (pivekimab sunirine), venetoclax (alone and
in combination with hypomethylating agents), CAR-T cells, and bispecific
monoclonal antibodies.
J Natl Compr Canc Netw 2023;21(5):515–521
doi: 10.6004/jnccn.2023.7026
1
University of South Florida, Morsani College of Medicine, Tampa, Florida; and
2
Moffitt Cancer Center and Research Institute, Tampa, Florida.
JNCCN.org | Volume 21 Issue 5 | May 2023
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is
a rare hematologic malignancy with an aggressive clini-
cal course and poor prognosis.1 BPDCN is most often
characterized by its presentation with cutaneous lesions
(Figure 1). The cutaneous lesions are often asymptomatic,
can be solitary or multiple lesions, can be distributed
widely, and may range from bruise-like lesions to plaques
or nodules.2 Bone marrow involvement, central nervous
system (CNS) infiltration, lymphadenopathy, splenomeg-
aly, and/or cytopenias are also seen to varying degrees.
The nomenclature has changed many times over the
years, making descriptions of the epidemiology more
challenging. It was first described in 1995 as acute agra-
nular CD41 natural killer (NK) cell leukemia by Brody
et al.3 Since that time, understanding of the disease bi-
ology and pathophysiology has significantly improved.
Plasmacytoid dendritic cells (type 2), characterized by
expression of CD4, CD56, and CD123, are thought to be
precursors leading to the development of BPDCN.4 The
term plasmacytoid dendritic cells was coined by Grouard
et al5 in 1997. As noted, the nomenclature has evolved
from agranular CD41 NK cell leukemia to blastic NK cell
lymphoma and later to CD41 CD561 NK hematodermic
neoplasm.3,6,7 Finally, in 2008, the term BPDCN was es-
tablished by the WHO and it was categorized under AML
and related precursor neoplasms.8 In 2016, the WHO re-
vision led to classification of BPDCN as its own distinct
entity, reflecting a better understanding of its distinctive
disease biology.9 In the most recent WHO 2022 classifica-
tion, BPDCN is classified under dendritic cell and histio-
cytic neoplasms along with plasmacytoid dendritic cell
proliferation associated with myeloid neoplasm, which is
now recognized as a separate disease entity.10
BPDCN is more common in older men, with a sex
ratio of 3:1 to 5:1 and a median age of diagnosis be-
tween 60 and 70 years.2 A bimodal age distribution was
recently described, with higher incidence in patients
aged ,20 and .60 years.11 Due to the change in nomen-
clature, the accurate incidence of BPDCN is difficult to
define. It is has been reported to affect approximately
0.04 cases per 100,000 people.11 In addition, white indi-
viduals tend to have higher incidence of this disease
compared with other races.11
515
 REVIEW
Pathophysiology Clinical presentation
- Violaceous skin nodules or
- Plasmacytoid
plaques
dendritic cells
- Bone marrow, lymph node,
- Release of cytokines
visceral organ involvement
- BET protein
- CNS disease
BPDCN
Diagnosis Treatment
Diffuse, monomorphous blasts Tagraxofusp (SL-401)
in dermis and subcutaneous fat ALL-based regimens
CD4, CD56, CD123, TCL1, and
CD303 - positivity
AlloSCT
Clinical trials
Figure 1. Salient features of blastic plasmacytoid dendritic cell
neoplasm.
Abbreviations: ALL, acute lymphoblastic leukemia; AlloSCT, allogeneic stem
cell transplantation; BET, bromodomain and extraterminal domain; CNS,
central nervous system.
Etiopathogenesis
Plasmacytoid dendritic cells (pDCs) reside in the blood
and tissues and play a vital part in immune reactions by
mediating between the innate and adaptive immune sys-
tems.12 pDCs are continuously produced in the bone
marrow and eventually emerge as mature cells in the pe-
riphery.13 A range of cytokines are secreted by pDCs due
to activation of toll-like receptors. Type 1 interferon (IFN;
mainly IFN-a) is the main cytokine, but in addition, IL-6,
IL-8, IL-12, tumor necrosis factor alpha, and some other
proinflammatory cytokines are also secreted.14 This in
turn leads to activation of T cells, NK cells, and macro-
phages, which play a role in immune reactions in infec-
tions and autoimmune diseases.15 In addition, pDCs also
include other non–type 1 IFN–producing cells and differ-
entiated cells in blood and tissue, which elucidates the
phenotypic diversity of BPDCN.16,17 Nodular pDC prolifer-
ations have been recognized to be associated with various
myeloid neoplasms, including chronic myelomonocytic
leukemia (CMML), myelodysplastic syndromes (MDS), and
acute myeloid leukemia (AML), and have also been hypoth-
esized to be clonally related to BPDCN.18–20 Mature plasma-
cytoid dendritic cell proliferation (MPDCP) associated with
myeloid neoplasm was listed as a differential diagnosis of
BPDCN in WHO 2016 and was given a separate disease cat-
egory in the WHO 2022 classification. The 2 major types of
MPDCP are CMML with pDC expansion (pDC-CMML) and
AML with pDC expansion (pDC-AML).
Multiple pathogenic mechanisms have been identified
and postulated that lead to development of BPDCN. Mono-
allelic and biallelic 12p13/ETV6 deletions are thought to
be an early pathogenic event.21 In a subset of patients,
BPDCN is thought to be a secondary malignancy due to
the presence of a background of myelodysplasia.22 The
bromodomain and extraterminal domain (BET) protein
BRD4 regulates the BPDCN-specific transcriptional network
516 © JNCCN—Journal of the National Comprehensive Cancer Network
Jain and Sweet
controlled by the E-box transcription factor (TCF4), also
known as E2-2, which controls the BPDCN cells.23 TCF4
is responsible for controlling the development of com-
mitted pDCs from common dendritic cells progenitors
through various other transcription factors.24 Decrease
in TCF4 leads to reduced CD123 and CD56 expression
on pDCs.23 The overexpression of a novel long noncod-
ing RNA (lncRNA) gene, lincRNA-3q and aberrant nu-
clear factor-kB (NF-kB) pathway activation have also
been linked to BPDCN.25,26
Clinical Presentation
The most common clinical presentation of BPDCN is
asymptomatic skin lesions, seen in approximately 90% of
patients at diagnosis. The skin lesions can appear as
bruise-like areas, patches, plaques, or nodules.2 Although
some patients can present with skin-only disease, most
also have bone marrow, lymph node, and/or visceral or-
gan involvement.27,28 Rarely, patients may present with a
leukemic phase of the disease without any skin lesions.29
CNS involvement is seen in approximately 30% of pa-
tients.30 Soft tissues, breast, gallbladder, tongue, and lung
are other less common sites of disease.31–33 Some patients
may also have other myeloid neoplasms, including
CMML, MDS, and/or AML, also termed prior or concomi-
tant hematologic malignancy (PCHM).20
Although a small percentage of patients will present
with isolated skin disease, most will also have BPDCN
identified in the bone marrow, lymph nodes, or visceral
organs as well.8,25–27
Diagnosis
The North American BPDCN Consortium recently released
recommendations to aide in a uniform diagnostic ap-
proach.34 A multidisciplinary approach is essential, in-
cluding a hematologist, stem cell transplant physician,
dermatologist, and expert hematopathologist. Initial workup
recommendations include laboratory evaluations such as a
CBC count, complete metabolic panel, and lactate dehydro-
genase, as well as a bone marrow biopsy with flow cytome-
try, cytogenetics, and next-generation sequencing. Imaging
with PET/CT is also recommended. The modified severity
weighted assessment tool (mSWAT) can be used for an ob-
jective assessment of skin involvement.35 The mSWAT was
initially introduced as an instrument to track tumor skin
burden in mycosis fungoides/Se
zary syndrome. The per-
centage total body surface area (TBSA, %) is measured sepa-
rately for patches, plaques, and tumors within the 12 body
regions, and each lesion type is multiplied by a number
(patch 5 1; plaque 5 2; tumor 5 4) to derive the mSWAT
score.35 A lumbar puncture with intrathecal chemotherapy
is also an essential part of the initial evaluation.
| Volume 21 Issue 5 | May 2023
Blastic Plasmacytoid Dendritic Cell Neoplasm
Histopathology and Immunohistochemistry
BPDCN presents with diffuse, monomorphous blasts with
irregular nuclei, fine chromatin, and scant, agranular cyto-
plasm. The typical cutaneous lesions comprising these
cells involve the dermis and subcutaneous fat, and spare
the epidermis. Characteristically, there is no angioinvasion
or coagulative necrosis.8
Expression of CD4, CD56, and CD123 is the hallmark
of BPDCN, and its diagnosis heavily relies on the identifi-
cation of this distinctive immunophenotype.2 In addition,
other markers specific to pDCs can help aide in diagnosis,
including CD303, TCF4, and TCL1. As per WHO 2022, the
expression of CD123 and one other pDC marker (CD123,
TCL1, TCF4, CD304, and CD303) in addition to CD4 and/
or CD56 is necessary for the diagnosis of BPDCN. The
other immunophenotypic diagnostic criteria as per WHO
2022 include the expression of any 3 pDC markers and
absent expression of all expected negative markers (MPO,
lysozyme, CD3, CD14, CD19, and CD34).10,36
Karyotype and Mutations
There is no characteristic karyotypic abnormality seen in
BPDCN. The most common cytogenetic anomalies in-
clude 5q, 6q, monosomy 9, 12p, 13q, and 15q. The short
arm of chromosome 12, the 12p13 locus which contains
ETV6, is the most frequent finding in BPDCN. In addi-
tion, approximately 75% of patients have a complex kar-
yotype.20 Rearrangement involving the MYC locus on
8q24 leading to MYC protein overexpression is seen in
approximately 38% patients.37
Next-generation sequencing has led to identification
of mutations in BPDCN. The mutational landscape seen
in BPDCN is quite similar to myeloid neoplasms, with a
high prevalence of genes including TET2, ASXL1 (epige-
netic mutations), ZRSR2, SRSF2, U2AF1 (splicing muta-
tions), NRAS, KRAS (RAS pathway), and ATM.22,38,39 Other
less common mutations include APC, BRAF, IDH1, IDH2,
KIT, KRAS, MET, MLH1, RB1, RET, TP53, CDKN1B, CDKN2A,
and VHL.39–41 Overexpression of IGLL1, LRMP, BCL11A,
BCL2, and genes involved in lymphoid proliferation, such
as BCL6, IKZF1, ETV6, and MYC, support a lymphoid-like
origin of BPDCN. Of note, IKZF1 abnormalities are highly
prevalent in BPDCN but absent in myeloid neoplasms, ex-
cept for rare cases in the very particular context of pediatric
AML.42
Management and Prognosis
Until recently, there were no consensus guidelines on
management of BPDCN.43 Prior to December 2018,
management of BPDCN revolved around intensive che-
motherapy utilizing AML (7 1 3 [7 days of cytarabine 1
3 days of either daunorubicin or idarubicin]) or ALL/
B-cell lymphoma (HCVAD [hyperfractionated cyclo-
phosphamide/vincristine/doxorubicin/dexamethasone]
JNCCN.org | Volume 21 Issue 5 | May 2023
REVIEW
or CHOP [cyclophosphamide/doxorubicin/vincristine/
prednisone]) regimens. Based on retrospective studies,
ALL-based regimens have resulted in better response
rates compared with AML-based or CHOP-based regi-
mens.2,44 However, responses to intensive chemotherapy
are typically short-lived, with a median OS in the range
of 5 to 30 months.22,30,45 CNS prophylaxis is essential for
patients who receive conventional intensive chemother-
apy. Intrathecal chemotherapy prophylaxis has been as-
sociated with better OS.30 Some other lower-intensity
options that have been used to treat BPDCN include
gemcitabine and docetaxel, azacitidine, pralatrexate, and
bendamustine. These therapies have resulted in PRs or
CRs in small series, but OS remains poor with these op-
tions as well.46–50
Allogeneic stem cell transplantation (alloSCT) is the
only known potentially curative treatment for BPDCN.
However, a minority of patients with BPDCN are alloSCT
candidates given the preponderance of disease in older in-
dividuals. For the few young and fit patients who are con-
sidered alloSCT candidates, the aim is to achieve complete
remission (CR) prior to alloSCT. A 3-year OS ranging from
74% to 82% has been reported in retrospective studies of
patients who underwent alloSCT in first complete remis-
sion (CR1).51–53 In a report on 11 patients, autologous SCT
was assessed and a 4-year OS of 82% was described.51
BPDCN is a systemic disease, and even in patients
who present with skin-only disease, later systemic in-
volvement is common and outcomes are poor. Hence,
even though surgical excision and radiation therapy
were used in the past, they are now only used in the
palliative setting.54
Tagraxofusp-erzs
Overexpression of CD123 (IL3Ra) seen in 100% of patients
with BPDCN has been of great interest for many years.2,26
Tagraxofusp (TAG or SL-401), a recombinant fusion pro-
tein containing IL-3 fused to truncated diphtheria toxin,
was the first approved CD123-targeting agent. Tagraxo-
fusp gets internalized by receptor-mediated endocytosis,
and intracellularly the catalytic domain of the diphtheria
toxin is proteolytically cleaved. It then gets transported
into the cytoplasm, where it inhibits protein synthesis by
ADP-ribosylating elongating factor-2 and ultimately leads
to apoptotic cell death.55,56 The recommended dosage of
tagraxofusp is 12 mcg/kg once daily intravenously on
days 1 to 5 of a 21-day cycle. Treatment is continued until
disease progression or unacceptable toxicity.
In the first pilot study using this agent, of the 11
patients enrolled with BPDCN, 7 attained clinical re-
sponses (CR in 5 patients, PR in 2 patients) with a sin-
gle course of the therapy.57 The median duration of
response was 5 months (range, 1–201 months). Subse-
quently, a phase I/II open-label, multicenter clinical
517
 REVIEW
trial investigated the efficacy and safety of tagraxofusp.58
In this trial, Pemmaraju et al58 first described in detail
the clinical response criteria for BPDCN: normalization
of peripheral blood counts; bone marrow blasts (,5%);
regression of nodal, spleen, and liver masses; and 100%
clearance of all skin lesions with no new lesions. Com-
plete response (clinical) with minimal residual skin ab-
normality is a response criteria unique to BPDCN that
includes the above CR criteria with the exception of skin
lesions wherein marked clearance of all skin lesions
from baseline is observed; however, some residual hy-
perpigmentation or abnormality with BPDCN identified
on biopsy (or no biopsy performed) is allowed. Of the 29
patients with treatment-naïve BPDCN, 21 (72%) showed
combined CR and clinical CR; 13 patients (45%) were
bridged to alloSCT in CR1. A 2-year OS of 52% was re-
ported. In patients with relapsed/refractory BPDCN, an
overall response rate of 65% was reported, with a median
OS of 8.5 months. This study led to FDA approval of ta-
graxofusp on December 21, 2018.54,58
Use of tagraxofusp in BPDCN is associated with a
unique adverse effect of capillary leak syndrome (CLS).
The FDA has now described CLS screening criteria, in-
cluding symptoms such as hypoalbuminemia, edema,
hypotension, cytokine release syndrome, infusion-related
reaction, and “catch all” criteria (cardiac arrest, cardio-
pulmonary failure, multiorgan failure, and multiple organ
dysfunction syndrome). Patients who meet $2 of these
criteria, with at least 2 of the symptoms occurring within
7 days of each other, are defined as having CLS.59 CLS
from tagraxofusp resulted in the death of 2 patients in
the phase I/II trial.58 CLS was seen in 8 (18%) patients
treated at the recommended phase II dose on the study;
of these patients, 6 (14%) experienced grade 2 CLS, 1
(2%) had a grade 4 event, and 1 (2%) had a grade 5 event
(death). The other death was in a patient treated with a
lower dose of tagraxofusp prior to implementation of
safety measures.58 Hypoalbuminemia, hypersensitivity
reactions, and elevation of liver enzymes were some of
the other adverse effects observed. Hypoalbuminemia
is the most consistent predictor of CLS, and hence before
initiation of therapy, a serum albumin level of $3.2 g/dL
with adequate cardiac function is required.60 Guidelines
for monitoring and management of CLS and other impor-
tant toxicities are described in detail by Pemmaraju et al58
in the supplementary appendix accompanying the phase
I/II open-label, multicenter clinical trial investigating the
efficacy and safety of tagraxofusp. Briefly, recommenda-
tions include checking albumin and body weight daily
until the infusion is complete. A decline in albumin to
3.0 to 3.5 g/dL or by $0.5 g/dL, or an increase in body
weight by $1.5 kg over pretreatment weight on the previ-
ous treatment day requires withholding of tagraxofusp and
interventions, including albumin infusion (25 g intravenous
518 © JNCCN—Journal of the National Comprehensive Cancer Network
Jain and Sweet
albumin every 12 hours until serum albumin is .3.5 g/dL)
and/or fluid restriction with or without diuretics. In addi-
tion, any systolic blood pressure reading #80 mm Hg re-
quires withholding of the infusion along with normal saline
bolus.58
In a recent follow-up of the pivotal tagraxofusp trial,
for the 65 patients who received tagraxofusp as frontline
treatment for BPDCN, the overall response rate was noted
to be 75%.61 At a median follow-up of 34 months, the me-
dian time to response was 39 days and median duration
of response was 24.9 months. The median OS of the first-
line cohort was 15.8 months. In addition, the overall rate
of transplant in CR1 was 51% (6 autologous SCT and 13
alloSCT). For patients who proceeded to transplant, the
median OS was 38.4 months. Updates on follow-up of
CLS reported that 21% (n518) of patients treated at
12 mcg/kg developed CLS.61 In a recent report on CNS
disease in 100 patients with BPDCN, the incidence of
CNS involvement was 22% (n522).62 Within the short
follow-up time of the phase I/II trial, CNS relapse has not
been reported after tagraxofusp, which was common with
other intensive chemotherapy regimens used in BPDCN.
The registrational trial using tagraxofusp in BPDCN ex-
cluded patients with known CNS disease, although this
was not specifically tested for during screening.58 Thus,
whether tagraxofusp has CNS penetration needs to be
further investigated, especially in patients with CNS dis-
ease. Given that patients with BPDCN live longer with
better therapies, it is possible for CNS disease to drive re-
lapses, and hence it is essential to use CNS-directed ther-
apy as part of the initial management of BPDCN.43
In the frontline setting, a recent retrospective analysis
compared tagraxofusp, ALL-based HCVAD therapy, and
other regimens (CHOP, AML-based, bortezomib, HMA-
based).63 A higher CR rate was seen with HCVAD-based
therapy compared with tagraxofusp and other regimens
(80% vs 59% vs 43%, respectively; P5.01). There was no sig-
nificant difference in OS (28.3 vs 13.7 vs 22.8 months, re-
spectively; P5.41) or remission duration among treatment
groups (38.6 months vs not reached vs 10.2 months, respec-
tively; P5.24). AlloSCT was performed in 51% versus 49%
versus 38% of patients, respectively (P5.455). These results
suggest a continued important role for HCVAD-based che-
motherapy in BPDCN, even in the modern targeted-therapy
era, with high CR rates in the frontline setting. Similar re-
sults were seen in a retrospective analysis at our institution,
with no significant difference in OS between patients with
BPDCN treated with tagraxofusp versus other chemothera-
pies as their first-line treatment, and patients who received
an alloSCT had significantly longer OS.44
IMGN632 (Pivekimab Sunirine)
IMGN632 (pivekimab sunirine [PVEK]), a CD123-targeted
antibody–drug conjugate, is being studied for relapsed/
| Volume 21 Issue 5 | May 2023
Blastic Plasmacytoid Dendritic Cell Neoplasm REVIEW

refractory hematologic malignancies, including BPDCN.
PVEK is composed of a humanized anti-CD123 antibody
that is covalently linked to a novel, potent DNA alkylating
agent, indolinobenzodiazepine. It is currently being studied
as monotherapy for treatment of BPDCN in the phase II
CADENZA trial (ClinicalTrials.gov identifier: NCT03386513)
(Table 1). Initial results from this study were recently re-
ported in a press release.64 Of the 4 patients who were
treated for de novo BPDCN, 2 achieved a CR, and among
the 6 patients with PCHM, 4 experienced a CR, clinical CR,
or CR with partial hematologic recovery. One fairly com-
mon toxicity associated with PVEK is peripheral edema,
which occurs at varying degrees of severity and can gener-
ally be well managed. PVEK is also being studied in combi-
nation with azacitidine and venetoclax for the treatment of
CD123-positive AML (NCT04086264). In October 2020, the
FDA granted breakthrough designation to PVEK for the
treatment of relapsed/refractory BPDCN.64
Bcl-2
Venetoclax, a bcl-2 inhibitor has been used as monotherapy
and in combination with intensive chemotherapy (HCVAD)
and hypomethylating agents in small series. In 2 patients
with relapsed/refractory BPDCN whose disease had pro-
gressed after CD123-directed therapy, venetoclax led to a
PR.65 Of the 2 patients with BPDCN who received venetoclax
in combination with HMA, 1 achieved a cutaneous re-
sponse and the other achieved a PR.66 There are multiple
trials underway, including one studying the combination of
tagraxofusp with azacitidine/venetoclax (ClinicalTrials.gov
identifier: NCT03113643) and tagraxofusp with chemother-
apy (HCVAD) along with venetoclax (NCT04216524).
CAR-T
Targeting CD123 using CAR-T cells is under investiga-
tion. UCART123 cells are allogeneic T cells targeting
CD123 in addition to harboring a ligand that confers sus-
ceptibility to rituximab. UCART123 has been shown to
have activity against BPDCN cells in preclinical studies.67
In a patient treated with CD1231 CAR-T cells, CR was
maintained post 60 days of infusion.68 UCART123 was
being studied in a phase I clinical trial in BPDCN; how-
ever, that study was terminated (ClinicalTrials.gov iden-
tifier: NCT03203369).
MB-102 is another CD123 CAR-T therapy that is be-
ing studied in BPDCN (NCT04109482). MB-102 is comprised
of adoptively transferred T cells that are genetically modified
using a self-inactivating (SIN) lentiviral vector to express a
CD123-specific, CD28-costimulatory chimeric antigen re-
ceptor (CAR) as well as a truncated human epidermal growth
factor receptor (EGFRt) (CD123.CD28.CD3z.EGFRt1T cells)
derived from autologous leukapheresis.

Table 1. Ongoing Clinical Trials for Patients With BPDCN

ClinicalTrials.gov
Target Identifier Target Patient Population Phase Investigational Therapy Status
Combination regimens NCT03599960 Newly diagnosed BPDCN II Idarubicin, methotrexate, Recruiting
L-asparaginase,
dexamethasone
NCT04216524 Newly diagnosed BPDCN II Tagraxofusp (SL-401) in Recruiting
combination with HCVAD/
mini-CVD and venetoclax
NCT03113643 R/R BPDCN I SL-401 in combination with Recruiting
azacitidine or azacitidine/
venetoclax
CAR T-cell therapy NCT03203369 R/R BPDCN, newly I Universal CAR-T cells Terminated
diagnosed BPDCN in targeting CD123
dose expansion (UCART123)
NCT04318678 R/R CD1231 disease I CD123-directed Recruiting
(AML/MDS, B-ALL, autologous T-cell therapy
T-ALL or BPDCN)
NCT04109482 R/R BPDCN I/II MB-102 Recruiting
Bcl-2 inhibition NCT03485547 R/R BPDCN, newly I Venetoclax Active,
diagnosed BPDCN in not recruiting
dose expansion
Other CD123-targeted therapy NCT03386513 Newly diagnosed and R/R I/II IMGN632 Recruiting
BPDCN
Bispecific monoclonal antibody NCT02730312 R/R CD1231 hematologic I XmAb14045 Completed
malignancies

Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; B-ALL, B-cell acute lymphocytic leukemia; BPDCN, blastic plasmacytoid
dendritic cell neoplasm; HCVAD, hyperfractionated cyclophosphamide/vincristine/doxorubicin/dexamethasone; MDS, myelodysplastic syndromes; R/R,
relapsed/refractory; T-ALL, T-cell acute lymphocytic leukemia.

JNCCN.org | Volume 21 Issue 5 | May 2023 519

 REVIEW
As discussed earlier, most patients with BPDCN are
older with multiple comorbidities and often with rapidly
progressive disease, all of which pose significant challenges
in enrolling patients on clinical trials, especially CAR-T trials.
Others
Several other combination regimens have been tried and
mentioned in case reports for the treatment of BPDCN.
In a patient with relapsed BPDCN post alloSCT, azaciti-
dine was used in combination with tagraxofusp and
showed cutaneous and hematologic response. The com-
bination was used as a bridge to donor lymphocyte infu-
sion.69 Multiple myeloma–based therapy has also been
used in the management of BPDCN. Daratumumab, le-
nalidomide, and proteasome inhibitors as single agents
or in combination have been reported to show some ac-
tivity in case reports and preclinical models.70–73
Future Directions
Better understanding of the disease biology of BPDCN
has led to development of novel targeted therapies. BET
inhibitors are another such targeted therapy that has
shown activity against BPDCN in vitro. BET inhibitors
lead to BPDCN cell apoptosis through disruption of
TCF4.23 Future studies may involve utilization of these
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520 © JNCCN—Journal of the National Comprehensive Cancer Network
Jain and Sweet
agents clinically. In addition, a bispecific monoclonal
antibody targeting CD123 and CD3, XmAb14045, is
being evaluated in CD1231 hematologic malignancies
(ClinicalTrials.gov identifier: NCT02730312). Further-
more, another area of need of the highest priority iden-
tified by the North American BPDCN Consortium is
minimal residual disease (MRD) testing in BPDCN. The
definition of MRD in BPDCN and characterizing MRD
in various compartments of the disease will be a need
of the future.43 Some other areas that need work in the
future include development of a risk stratification scale
for BPDCN, ensuring access to clinical trials, and man-
aging cost of the targeted therapy used in BPDCN.
Submitted December 22, 2022; final revision received March 25, 2023;
accepted for publication March 28, 2023.
Disclosures: Dr. Sweet has disclosed serving as a consultant for and on
advisory boards for Gilead Sciences, Bristol Myers Squibb, Astellas Pharma,
BerGenBio, AROG Pharmaceuticals, Inc., Novartis, Curis, Inc., Pfizer Inc.,
Mablytics, Inc., Daiichi Sankyo, and Jazz Pharmaceuticals; and receiving
grant/research support from Incyte and Jazz Pharmaceuticals. Dr. Jain has
disclosed not having any financial interests, arrangements, affiliations, or
commercial interests with the manufacturers of any products discussed in
this article or their competitors.
Correspondence: Kendra Sweet, MD, Moffitt Cancer Center and
Research Institute, 12902 Magnolia Drive, Tampa, FL 33612.
Email: Kendra.Sweet@moffitt.org
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