Review

Blastic Plasmacytoid Dendritic Cell

NeoplasmeCurrent Insights
Sangeetha Venugopal,1 Selena Zhou,2 Siraj M. El Jamal,3 Andrew A. Lane,4
John Mascarenhas1
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare clonal hematologic malignancy of plasmacytoid
dendritic cell precursors. The presentation and clinical course of BPDCN is widely heterogeneous and was most
recently categorized as a distinct clinical entity by the World Health Organization in 2016. The expanded under-
standing of the pathobiology of BPDCN has improved diagnostic accuracy and informed novel targeted therapeutic
options. The United States Food and Drug Administration-approval of tagraxofusp (SL-401) in December 2018 has
focused attention on this leukemia frequently associated with skin involvement. Herein, we aim to: (1) review etiology;
(2) summarize diagnostic criteria; and (3) discuss historic treatments and novel therapies for BPDCN.

Clinical Lymphoma, Myeloma & Leukemia, Vol. -, No. -, --- ª 2019 Elsevier Inc. All rights reserved.
Keywords: Acute leukemia, CD123, Myeloid neoplasms, SL-401, Tagraxofusp

Introduction
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a
hematopoietic clonal neoplasm originating from plasmacytoid
dendritic cell (pDC) precursors. BPDCN was first proposed as a
distinct entity in 1998 when Kameoka et al described 2 cases of
cutaneous agranular CD2-/CD4þ/CD56þ “lymphoma.”1 Since
that time, its rarity has led to a rich history of misdiagnosis and
irregular nomenclature, including CD56þ/TdTþ blastic NK cell
tumor and CD4þ/CD56þ hematodermic neoplasm.2,3 Lucio et al
were the first to note a shared pattern of high CD123 expression
and propose pDCs as the origin of BPDCN,4 which was validated
by a subsequent study that demonstrated immune function in
leukemic cells similar to pDCs.5 This understanding of the biology
and origin of this rare neoplasm led the World Health Organization
to establish the term BPDCN in 2008 and classify it as a distinct
entity in 2016.6,7
1
Tisch Cancer Institute, Division of Hematology/Oncology
2
3
Icahn School of Medicine at Mount Sinai, New York, NY
Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
4
Dana-Farber Cancer Institute, Department of Medical Oncology, Harvard Medical
School, Boston, MA
Submitted: Apr 9, 2019; Revised: May 14, 2019; Accepted: Jun 4, 2019
Address for correspondence: John Mascarenhas, MD, Director, Adult Leukemia Pro-
gram, Leader, Myeloproliferative Disorders Clinical Research Program, Associate Pro-
fessor of Medicine, Tisch Cancer Institute, Division of Hematology/Oncology, Icahn
School of Medicine at Mount Sinai, One Gustave L. Levy P, Box 1079, New York, NY
10029
E-mail contact: john.mascarenhas@mssm.edu
Epidemiology
BPDCN is a rare disease, with an overall incidence rate of 0.04
cases per 100,000 people.8 It is generally a disease of older males,
with a median age of 53 to 68 years and a 2.0 to 3.3:1 male to
female ratio.8-10 Recently, it was found to have a bimodal incidence
pattern, with higher incidences at younger than 20 years and older
than 60 years of age.8,10,11 Ethnic predilection is not clear, with
conflicting published reports.8
The Genesis of BPDCN
BPDCN evolves from a progenitor pDC, and normal pDCs known
for their senescence comprise less than 0.5% of circulating mono-
nuclear cells. pDCs are commonly found in lymph nodes and tonsils.
They are rare in the thymus, bone marrow, spleen, and mucosa-
associated lymphoid tissue. pDCs accumulate in lymph nodes12 on
exposure to antigenic stimuli, may it be viral infection or autoimmune
disease, such as systemic lupus erythematosus and psoriasis.13,14 In
response to foreign viral nucleic acids, pDCs secrete massive amounts of
type I interferons (IFNa and IFNb) and other proinflammatory cy-
tokines (interleukin [IL]-6, IL-8, IL-12, and tumor necrosis factor)
through activation of toll-like receptor 7/9-MyD88-IRF7 pathway.
Coupled with their antigen presentation capacity, pDCs orchestrate
innate and adaptive immune responses, thus cementing their role as an
arbitrator of innate and adaptive immune system.12 Additionally,
mature pDC proliferation (MPDCP) have been associated with
myeloid neoplasms, although data does not support MPDCP as a
precursor lesion to BPDCN.15,16 Detailed evaluation failed to detect
any viral markers (Epstein-Barr virus or human herpesvirus-6) in

2152-2650/$ - see frontmatter ª 2019 Elsevier Inc. All rights reserved.

https://doi.org/10.1016/j.clml.2019.06.002 Clinical Lymphoma, Myeloma & Leukemia Month 2019 -1
 BPDCNeCurrent Insights
BPDCN,3 thus vetoing the role of latent viral infection in the patho-
genesis of this disease. Elucidation of the pathogenesis of BPDCN is still
a work in progress, and ongoing endeavors hope to shed light on the
precise biology of this rare hematologic neoplasm.
Molecular Pathogenesis
Although 50% to 66% of patients with BPDCN exhibit karyotypic
abnormalities, none is inherent to BPDCN.9,17 Cytogenetic abnor-
malities seen in patients with BPDCN predominantly involve
genomic losses rather than gene-specific rearrangements; the 6 key
recurrent chromosomal abnormalities include 5q, 12p, 17p, 13q, 6q,
15q, and 9 (monosomy).17,18 Furthermore, genome wide array-based
comparative genomic hybridization analysis (n ¼ 21) identified
commonly deleted chromosome regions, namely 9p21.3 (CDKN2A/
CDKN2B), 13q13.1-q14.3 (RB1), 12p13.2-p13.1 (CDKN1B),
13q11-q12 (LATS2), and 7p12.2 (IKZF1).19 It is interesting to note
that most of the deleted regions represent tumor suppressor genes
involved in cell cycle regulation. Additionally, a molecular cytogenetic
analytic series (n ¼ 47) identified a monoallelic deletion of NR3C1
(5q31), encoding the glucocorticoid receptor (a ligand-dependent
transcription factor of the nuclear hormone receptor family tumor
suppressor) in 13 (28%) of 47 patients with BPDCN. Subsequent
elaborate analysis of the t(3;5)(q21;q31) region unveiled the fusion of
NR3C1 to a long noncoding RNA gene (lincRNA-3q) that encodes a
novel, nuclear, noncoding RNA involved in G1/S cell cycle transition
via E2F.20 Moreover, MYC rearrangements on 8q24 with resultant
MYC protein overexpression was reported in 38% of BPDCN cases.
Given that MYC targets the transcription factor E2F1, it is suggested
that MYC overexpression may potentially reinforce G1/S progres-
sion.21,22 Taken together, loss of multiple cell cycle checkpoints
leading to altered G1/S transition appears to be substantial in the
molecular pathogenesis of BPDCN.
Apart from the loss of tumor suppressor genes owing to various
chromosomal deletions, patients with BPDCN share a mutational
profile comparable to other myeloid malignancies, including myelo-
dysplastic syndrome. Stenzinger et al used targeted deep sequencing
(n ¼ 33 BPDCNs) to delineate recurrent mutations in 4 genes, NRAS,
IDH2, APC, and ATM, that implicates the predominance of activated
RAS signaling in BPDCN.23 Menezes et al employed a combined
approach of whole exome sequencing (WES) in 3 cases and targeted
resequencing (n ¼ 25 BPDCNs) to elucidate mutations involving
DNA methylation (TET2),24 transcriptional regulation (ASXL1), and
transcription factors (IKZF1-3, ZEB2). NPM1 and FLT3 ITD muta-
tions, although common in acute myeloid leukemia (AML), were
infrequently identified in this series. Furthermore, it was observed that
the mutations involved in aberrant methylation patterns were associ-
ated with poor overall survival (OS) (median, 11 months vs. 79 months;
P ¼ .047).25 Additionally, a gene expression analysis identified high
expression of BCL2 in neoplastic pDCs compared with normal
pDCs.26 Collectively, the shared genetic profile between BPDCN and
related myeloid malignancies resolutely endorse a genetic link between
the 2 entities and the potential for comparable therapeutic options.
Proposed Clonal Evolution Model of
BPDCN
Given that most patients present with skin-only disease without
conspicuous bone marrow involvement and that the majority of
2 - Clinical Lymphoma, Myeloma & Leukemia Month 2019
these patients progress to a leukemic phase eventually, a clonal
evolution model was recently proposed. In this model, the initial
malignant transformation of a pDC occurs in the skin followed by
dissemination to the bone marrow.27 Griffin et al studied the
developmental ontogeny of BPDCN through serial DNA
sequencing of bone marrow and skin biopsies in 10 patients. All
patients with “skin-only” disease and negative bone marrow
assessment at diagnosis harbored known pathogenic gene variants
recurrently mutated in BPDCN and related myeloid malignancies
in the bone marrow, including ASXL1, TET2, SF3B1, ZRSR2,
CUX1, and EZH2, all consistent with clonal hematopoiesis. Post-
therapy analysis in patients with minimal to extensive marrow
involvement also showed persistent pathogenic mutations. Addi-
tionally, most mutations within bone marrow cells were also
detected in paired skin biopsies, suggesting clonal evolution from a
common pre-malignant hematopoietic precursor clone. Evidence of
clonality was further substantiated (through WES) in a patient with
“skin-only” disease who showed identical ASXL1 and TET2 mu-
tations in high variant allele frequency in the skin and bone marrow
at time of diagnosis. Interestingly, WES demonstrated that 87% of
all somatic single nucleotide variants (SNVs) were skin-specific and
11% of SNVs were bone marrow-specific, with only 2% common
SNVs, thus proposing a model of branching pre-malignant clonal
evolution in the bone marrow, with a sub-clone seeding the skin
and then acquiring additional mutations during neoplastic
evolution.27
Prognosis
BPDCN is a rare and aggressive hematopoietic neoplasm with a
median survival of less than 2 years (95% confidence interval [CI],
17-34 months).28 A population-based analysis from the Surveil-
lance, Epidemiology, and End Results database identified that
young age (age less than 60 years) and early hematopoietic stem cell
transplantation (HSCT) were predictive of superior outcomes.28
Several small studies have also shown that the presence of isolated
skin involvement and a high proliferative index are associated with
better outcomes.17,19 Moreover, TdT expression appears to corre-
late with longer survival, suggesting that differentiation state may
correlate with sensitivity to therapy.29 Furthermore, biallelic loss of
the 9p21.3 locus and NR3C1 haploinsufficiency was associated with
poor outcome, as were mutations involving the DNA methylation
machinery.19,25 Prognostication using clinical and molecular data in
BPDCN remains a challenge owing to its rarity and the lack of a
characteristic clinical/molecular profile.
Diagnosis
Clinical Presentation
BDPCN is an aggressive hematologic malignancy typified by its
proclivity for cutaneous tropism and/or a leukemic phase30,31
(Figure 1). Ninety percent of patients initially present with cuta-
neous lesions (Figure 2A and 2B) and 10% with overt acute leu-
kemia.34 The cutaneous presentation of BPDCN is heterogeneous,
ranging between maculo-nodular lesions and dystropic xanthoma-
tosis.10,35,36 However, bruise-like patches in the upper body appear
to be the most common presenting sign in BPDCN limited to
skin.37 Bone marrow involvement resulting in cytopenias (particu-
larly thrombocytopenia, 78% of patients), hepatosplenomegaly, and

Figure 1 Patterns of BPDCN Involvement
Abbreviation: BPDCN ¼ blastic plasmacytoid dendritic cell neoplasm.
(Adapted From10,11,32,33)
Figure 2 A, Photograph Showing a Central Violaceous Plaque
Surrounded by Numerous Erythematous Papules on
the Shoulder. B, Violaceous Tumor With Surrounding
Petechiae on the Lower Back
Sangeetha Venugopal et al
lymphadenopathy were also noted in varying frequencies.38,39
Given that central nervous system (CNS) involvement occurs in
up to 30% of cases, flow cytometry evaluation of cerebrospinal fluid
is suggested in newly suspected cases of BPDCN.9,40 Other re-
ported sites of involvement include lung, breast, tongue, gall-
bladder, and the paranasal sinuses.9,35,41,42 Given the heterogeneity
of affected organs, computed tomography or positron emission to-
mography should be included in the initial evaluation of a patient
with suspected BPDCN.
A diagnosis of BPDCN is established by histopathologic assess-
ment of the involved tissue coupled with germane immunopheno-
typic markers (Figure 3).
Histopathology
BPDCN lesions demonstrate similar microscopic morphology
across all sites of involvement, may it be skin, lymph nodes, or bone
marrow. The neoplastic cells form dense monomorphous atypical
blastic cells resembling myeloid sarcoma. The neoplastic cells are
medium- to large-sized with scant cytoplasm, prominent single or
multiple nucleoli with irregular nuclear contours, and immature,
fine chromatin. Mitotic figures are common.2,31 The skin lesions in
BPDCN exhibit a nodular-diffuse growth pattern in the dermis,
with a predilection for perivascular/periadnexal distribution and
intra-tumoral hemorrhage. Additionally, there is a well-demarcated
dermal grenz zone, a narrow uninvolved zone of papillary dermis
between the epidermis and the underlying dendritic neoplastic cell
infiltrate.32 The epidermis and adnexa are usually spared. Further-
more, the evident absence of coagulation necrosis and angioinvasion
represent a distinctive diagnostic feature of BPDCN.30 Hematologic
involvement is remarkable for cytopenias owing to bone marrow
infiltration by the neoplastic dendritic cells.2,24,38 In aspirate smears,
Clinical Lymphoma, Myeloma & Leukemia Month 2019 -3
 BPDCNeCurrent Insights
Figure 3 Skin Biopsy Shows Blastic Plasmacytoid Dendritic Cell Neoplasm. Atypical Immature Blastic Cell Infiltration Extends Deep in
the Dermis (A; 3100). The Cells are Medium-Sized With Irregular Contours, Prominent Nucleoli, and Fine Chromatic. Mitotic
figures are Readily Found (B; 3400). The Cells are Positive for CD4, CD56, and CD123; and Negative for Other Lineage
Specific Markers Like CD3, CD19, and MPO
these cells display a distinctive cytoplasmic vacuolation pattern akin
to a “pearl necklace” and cytoplasmic pseudopod extensions.10,32,38
Immunophenotyping
Immunophenotyping is indispensable in establishing the diag-
nosis of BPDCN. The immunophenotype of BPDCN resembles
that of pDC subsets; however, with atypical CD56 expression.
BPDCN is characterized by the expression of CD4 and CD56 in
the absence of lineage-specific markers for either myeloid, T-lym-
phocytes, B-lymphocytes, or NK cells. CD5, CD7, CD68, and
CD33 may be expressed in some cases.3,10,32,43,44 The expression of
CD56 in BPDCN, but not in normal pDC, is an important feature
and likely indicates the neoplastic transformation of these cells.
BDCA-2/CD303, IL-3Ra/CD123, CD2AP, TCL1, BCL11A, and
SPIB are pDC-associated markers that may aid in the diagnosis of
BPDCN.3,10,11,45-50 Although the interleukin-3 receptor alpha
chain (IL-3Ra) CD123 is expressed in the majority of BPDCN, it is
not specific as it is seen in other hematologic malignancies including
AML.3,10,31,51 CD303 (also known as blood dendritic cell antigen 2
- BDCA2), a pDC-specific type II C-type lectin receptor involved in
antigen capture and presentation,50 considered the most specific
marker for plasmacytoid dendritic cells, may be aberrantly lost in
BPDCN, thus limiting its sensitivity.52 The CD2-associated pro-
tein, an adaptor protein involved in T-cell signaling, is present in
normal and neoplastic pDCs.48,53 Its expression in BPDCN is
heterogeneous and is also expressed in diffuse large B cell lym-
phomas.53 The T-cell leukemia/lymphoma protein 1 (TCL1),
encoded by the proto-oncogene TCL1, is also present but not
4 - Clinical Lymphoma, Myeloma & Leukemia Month 2019
specific to BPDCN,46 as it is also expressed in a wide spectrum of B
and T cell lymphomas and leukemias.54 BPDCN is also positive for
granzyme B, but not perforin and TIA-1. Additionally, BCL11A
and SPIB are transcription factors involved in pDC develop-
ment49,55; however, their expression in the case of BPDCN needs to
be interpreted in conjunction with other phenotypic markers.
Terminal deoxynucleotidyl transferase (TdT) and CD68 expression
are variably expressed in 40-50% of cases.32,44 Neither CD34
expression, nor Epstein-Barr virus-encoded RNA is observed in
BPDCN. Overall, there is a distinct lack of unique BPDCN
markers, and there is no consensus on the minimal phenotype to
establish an immunophenotypic diagnosis of BPDCN. It has been
proposed that BPDCN may be confidently diagnosed when the
blastic dendritic cells pDCs express 4 of the 5 principal markers
(CD4, CD56, CD123, TCL1, and CD303).10,24,50 Cases with
immunophenotype that is short of the 4 antigens should be classi-
fied as “acute leukemia of ambiguous lineage.”56
BPDCN Mimics
Given BPDCN’s tendency for cutaneous predilection, typical skin
lesions should primarily alert the clinician to the possibility of
BPDCN. However, given that 10% of patients initially present with
aggressive leukemia sans skin involvement,34 the diagnosis of
BPDCN should be entertained in any patient presenting with poorly
differentiated leukemia with an ambivalent immunophenotype.
MPDCP commonly occurs in the setting of other myeloid neo-
plasms like chronic myelomonocytic leukemia, AML, and myelo-
dysplastic syndrome,57,58 demonstrating mature pDC morphology

and classical myeloid immunophenotype in the absence of CD56
expression.
Myeloid sarcoma (MS), another condition that can be indistin-
guishable from BPDCN based on morphology, may show a CD4-
positive/CD56-positive immunophenotype. Additionally, a large
subset of MS is CD34-negative/MPO-negative, an imminopheno-
type that is shared with BPDCN. However, the expression of
lysozyme, CD68, or CD163 is more consistent with MS. Sangle
et al identified a 7-antibody panel (CD4, CD56, CD123, TCL1,
myxovirus A (MxA), lysozyme, and myeloperoxidase) with a pre-
dictive value of  90% and employed these markers using specific
staining criteria to reasonably distinguish between MS and
BPDCN. In summary, BPDCN was associated with positive
staining for CD56, TdT, or TCL1 or negative staining for lyso-
zyme. MS was associated with positive staining for lysozyme or
myeloperoxidase, or negative staining for CD56, CD123, myxo-
virus, or TCL1.59 Myeloid cell nuclear differentiation antigen,
which is expressed in the majority of MS but not BPDCN, is also
useful and may be included in the diagnostic evaluation of blastic
hematopoietic infiltrates.60
Given the cutaneous tropism of BPDCN, it should be differen-
tiated from other CD56þ hematopoietic neoplasms with skin
involvement. The potential diagnostic pitfalls include CD56þ
AML, extranodal NK/T cell lymphoma, and classic cutaneous T cell
lymphoma.44 These distinct entities must be carefully distinguished
utilizing morphology and immunohistochemistry, given the signif-
icant prognostic and therapeutic implications (Table 1). Ultimately,
the expression of CD303 essentially confirms the pDC origin and
excludes any non-pDC hematopoietic lesions.50
Management
BPDCN is an aggressive disease with a median OS of less than a
year if left untreated.7 Given the elusive nature of the disease, there
has been no standard of care until the most recent United States
Food and Drug Administration-approved targeted therapy tagrax-
ofusp (SL-401). When tagraxofusp is not an option, acute
lymphoblastic leukemia (ALL)-inspired intensive chemotherapy
regimen with CNS prophylaxis is an acceptable alternative to induce
remission, followed by HSCT for consolidation and potential cure.
Low-intensity therapies may be a viable option in patients ineligible
for more intensive chemotherapy or HSCT (Figure 4).
Table 1 Differential Diagnosis of CD56D Hematopoietic Neoplasms With Skin Involvement by Immunohistochemistry
Disease CD4 CD56
BPDCN þ þ
AML/myeloid sarcoma þ/ þ þ/
Extra nodal NK/T cell  þ
lymphoma
Classic primary  þ
cutaneous T cell
lymphoma
Abbreviations: AML ¼ acute myeloid leukemia; BPDCN ¼ blastic plasmacytoid dendritic cell neoplasm; EBNA ¼ Epstein Barr nuclear antigen; EBV ¼ Epstein Barr virus; MPO ¼ myeloperoxidase.
Adapted from reference.44
Sangeetha Venugopal et al
Tagraxofusp
Appreciable success of targeted therapies in related hematopoietic
neoplasms and the lack of effective therapeutic response with con-
ventional chemotherapeutic regimens in BPDCN provided the
impetus to identify an appropriate actionable target. IL3R-a
(CD123) was deemed a potential actionable therapeutic target,
given its ubiquitous expression in BPDCN and the neoplastic
dendritic blasts requirement of IL-3 supplementation for growth
and survival.5,61,62
Tagraxofusp (SL-401) is a CD123 directed recombinant fusion
protein composed of IL-3 conjugated to modified diphtheria toxin
via amide linkage. Binding of the IL-3 domain of SL-401 to its
natural receptor with subsequent internalization leads to trans-
location of the diphtheria toxin fragment to the cytosol, followed by
ADP ribosylation of elongation factor 2, with resultant cessation of
protein synthesis and cell death.63 Preclinical studies demonstrated
the exquisite cytotoxicity of SL-401 in cell lines derived from pa-
tients with BPDCN (CAL-1 and GEN2.2) and primary BPDCN
cells with femtomolar IC50 values. Additionally, SL-401 meaning-
fully expanded the median OS of a BPDCN xenograft model
following a single cycle of treatment (53 days vs. 15 days in un-
treated mice).64
Based on the encouraging preclinical enabling studies, a phase I/
II study of SL-401 was conducted in 11 patients, including those
with recurrent/refractory BPDCN or who were ineligible for stan-
dard chemotherapy. Seven (78%; n ¼ 11) of 9 evaluable patients
attained a major clinical response (complete response [CR], 5;
partial response [PR], 2) after a single course of SL-401. The me-
dian response duration was 5 months (range, 1-20þ months). Only
5 of 11 patients experienced infusion related fever and chills, all of
which resolved with supportive management. Almost all patients
had  1 adverse event, including hypoalbuminemia, edema,
hyponatremia, hypocalcemia, uremia evocative of capillary leak
syndrome, although the severity was mitigated by early adminis-
tration of parenteral albumin and diuretics. Generally, SL-401 was
well-tolerated with no treatment related mortality at the recom-
mended phase 2 dose (RP2D) of 12.5 mg/kg/day.62 The subsequent
multicenter, multicohort open label, non-randomized, single-arm
phase II clinical trial evaluated efficacy of tagraxofusp in patients
with treatment-naive or relapsed/refractory (R/R) BPDCN. The
trial consisted of 3 stages: stage 1 (lead-in, dose escalation), stage 2
Myelomonoytic
Markers (CD13, T Cell Markers
CD15, Lysozyme, Markers of EBV (CD3, CD2, CD5,
CD123 CD117, or MPO) Infection (EBNA-1) CD7, CD8)
þ   
þ  
  þ þ
   þ
Clinical Lymphoma, Myeloma & Leukemia Month 2019 -5
 BPDCNeCurrent Insights
Figure 4 Proposed Treatment Algorithm for BPDCN
Abbreviations: ALL ¼ acute lymphocytic leukemia; AML ¼ acute myeloid leukemia; BPDCN ¼ blastic plasmacytoid dendritic cell neoplasm.
(expansion), and stage 3 (pivotal, confirmatory). Stage 1 and 2
enrolled patients who were treatment-naive and patients with R/R
BPDCN, whereas the stage 3 pivotal cohort enrolled only
treatment-naive patients. Patients treated within the stage 2 and 3
cohorts received the stage 1 recommended tagraxofusp dose of 12
mg/kg/day intravenously administered daily on days 1 to 5 of a 21-
day cycle. Seven of 13 patients in the treatment-naive stage 3
BPDCN cohort achieved a sustained CR/clinical complete response
(CRc) (53.8%; 95% CI, 25.1%-80.8%). After a median follow-up
of 11.5 months, the median response duration was not reached.
Among 29 treatment-naive patients across all stages, the overall
response rate (ORR) was 90% (26/29) with a 72% (21/29) rate of
CR þ CRc þ CRi (CRi ¼ CR with incomplete hematologic re-
covery), and 45% (13/29) of these patients successfully bridged to
HSCT (10 allogeneic þ 3 autologous). The median OS was not
reached among 29 treatment-naive patients with a median follow-
up of 23.0 months (range, 0.2-41þ months). Capillary leak syn-
drome was the most serious but manageable treatment emergent
adverse event noted.65 This study led to the United States Food and
Drug Administration approval of tagraxofusp on December 21,
2018 for the treatment of both treatment-naive and previously
treated BPDCN in adults and pediatric patients 2 years and older.66
Induction Chemotherapy
The archival therapies for BPDCN include aggressive non-
Hodgkin lymphoma regimens such as CHOP (cyclophosphamide,
doxorubicin, vincristine, and prednisone) or CHOP-inspired, ALL
regimens such as hyper-CVAD (hyperfractionated cyclophospha-
mide, vincristine, doxorubicin, and dexamethasone) alternating with
methotrexate and cytarabine, or AML induction regimens (eg,
MICE [mitoxantrone, idarubicin, cytarabine, and etoposide];
cytarabine and an anthracycline [7 þ 3]; or FLAG-IDA [fludar-
abine, cytarabine, granulocyte colony stimulating factor, and
idarubicin]).
Of the aggressive leukemia-inspired regimens for the treatment of
BPDCN, ALL-based regimens appear to be more successful than
6 - Clinical Lymphoma, Myeloma & Leukemia Month 2019
AML-based regimens. One study of 15 patients treated with ALL-
based regimens and 26 patients treated with AML-based regimens
found significant improvement in both CR rates (66% vs. 26%;
P ¼ .02) and OS benefit (12.3 vs. 7.1 months; P ¼ .02) with the
ALL-based therapy group. However, 35% of treated patients who
achieved complete remission subsequently relapsed, more frequently
after ALL-type chemotherapy, at a median time of 9.1 months
(range, 5.8-19.8 months) after diagnosis.9 This was further
corroborated by a study of 46 patients that found ALL-based reg-
imens and HSCT to have better outcomes than AML- and
lymphoma-based regimens.67 Regardless of the chosen induction
chemotherapy, intrathecal therapy should be included as BPDCN
has a predilection for involvement of the CNS, and intrathecal
prophylaxis has been shown to reduce incidence of CNS disease and
improve OS.40 Tagraxofusp clinical trials have not reported CNS
relapses, suggesting that novel agents may have improved activity in
the CNS. However, those trials excluded patients with active CNS
disease at the time of enrollment, which indicates that additional
studies focused on treatment of BPDCN with CNS involvement
may be required to define optimal clinical practice in this setting.
A meta-analysis of 97 patients with a purported diagnosis of
BPDCN evaluated the impact of different therapeutic approaches
on outcome. Patients were divided into groups based on the in-
tensity of therapy: A, less aggressive than CHOP; B, moderately
intensive CHOP or CHOP-like regimens; C, intensive leukemia-
inspired regimens (lymphoblastic and myeloblastic); and D, mye-
loablative therapy followed by stem cell rescue (n ¼ 10; autologous
HSCT, 4; allogeneic HSCT, 6). Myeloablative conditioning
regimen included total body irradiation and high-dose cyclophos-
phamide in this cohort. Moderately intensive CHOP or CHOP-like
regimens did not result in better survival rates or sustained CR when
compared with less aggressive therapies. However, leukemia-
inspired regimens demonstrated a CR rate of 94% with approxi-
mately 40% sustained CR. Although the entire group D cohort
enjoyed a median survival of 31.5 months, allogeneic HSCT re-
cipients had a survival benefit over autologous HSCT recipients

(38.5 vs. 16.5 months). Taken together, aggressive therapies appear
to be superior to less aggressive treatment modalities in maintaining
CR (group A, 7%; group B, 3%; group C, 35%; group D, 50%)
along with survival benefit.68
HSCT
HSCT for BPDCN is associated with improved OS and disease-
free survival (DFS) compared with chemotherapy alone.9,67,68 Aoki
et al evaluated the clinical outcomes after transplantation in patients
with BPDCN from a Japanese transplant registry (allogeneic
HSCT, n ¼ 14; autologous HSCT, n ¼ 11). All 11 patients who
underwent autologous HSCT were in CR1. Among patients who
underwent allogenic HSCT, 12 were in CR1, 2 were in CR2, and 2
were not in remission at time of HSCT. At a median follow-up of
53.5 months, patients who underwent autologous HSCT in CR1
enjoyed better OS and PFS than those that received an allogeneic
HSCT in CR1 (OS, 82% vs. 69%; P ¼ .44 and PFS, 73% vs. 60%;
P ¼ .43, respectively).69 However, a North American collaborative
multicenter study demonstrated lack of efficacy with autologous
HSCT, but this study was limited by a small sample size to evaluate
for autologous transplant (allogeneic HSCT ¼ 37 and autologous
HSCT ¼ 8). Additionally, only 5 (63%) of 8 patients were in CR1,
and the median age of the patient cohort was 10 years older than the
Japanese study.70 Taken together, autologous HSCT may have a
potential role in the management of patients with BPDCN in CR1,
especially in those deemed ineligible for allogenic HSCT.
A recent meta-analysis of allogeneic HSCT in 128 patients with
BPDCN reported a pooled OS and PFS/DFS rates of 50% (95%
CI, 41%-59%) and 44% (95% CI, 34%-53%), regardless of the
remission status at the time of allografting, suggesting that alloge-
neic HSCT is an effective treatment option in patients with
BPDCN. These pooled rates (OS and PFS/DFS) were determined
at a time point of 2 to 4 years after allograft. As most patients in the
4 studies included in the meta-analysis underwent allogeneic HSCT
in CR1, a subgroup analysis of OS and PFS/DFS in patients who
underwent HSCT in CR1 versus those who underwent allograft
beyond CR1 were performed. Predictably, patients who underwent
HSCT in CR1 had higher pooled rates of OS (67% vs. 7%) and
PFS/DFS (53% vs. 7%), thus supplementing the recommendation
of allogeneic HSCT in CR1 for BPDCN. Additionally, it was
Table 2 Low-intensity Therapy Regimens for BPDCN Treatment Reported in the Literature
Therapy Patients Mechanism
Gemcitabine þ 1 (first-line, gemcitabine Pyrimidine antimetabolite
docetaxel monotherapy) Pyrimidine antimetabolite,
3 (all with 4þ prior microtubule inhibitor
therapies)
Azacitidine 2 (first-line) DNA Methyltransferase
3 (first-line) inhibitor
Pralatrexate 1 (progression on CHOP) Antifolate
1 (first-line)
1 (progression on CHOP)
Bendamustine 5 (all with 1þ prior therapies) Alkylating and antimetabolite 1 complete skin response with progression of disease and OS
Abbreviations: CHOP ¼ cyclophosphamide, doxorubicin, vincristine, and prednisone; OS ¼ overall survival; PFS ¼ progression-free survival.
Sangeetha Venugopal et al
shown that myeloablative conditioning resulted in lower relapse
rates when compared with reduced intensity conditioning (18% vs.
40%), suggesting a possible benefit linked to the intensity of con-
ditioning regimens in BPDCN. Given the evolving long-term
outcome data of tagraxofusp, allogenic HSCT in CR1 is currently
regarded the appropriate post-remission consolidation strategy, and
CR at the time of HSCT is predictive of better outcome.71
Low-intensity Regimens
Low-intensity treatment regimens may be a reasonable alternative
in patients ineligible for a more intensive chemotherapy or HSCT
approach. However, the data is primarily derived from small
retrospective studies, and robust prospective data is lacking. Several
case reports have demonstrated the limited efficacy of azacitidine,
gemcitabine with docetaxel, pralatrexate, and bendamustine in this
population (Table 2).
The most compelling data is with gemcitabine in combination
with docetaxel. A case series examined the outcomes of 3 patients
with BPDCN who were heavily pre-treated (median, 4.6 prior
therapies), 2 of whom had relapsed after HSCT. The median OS
was 13.3 months with combination gemcitabine therapy, with 1
patient alive at the time of publication (the other 2 experienced
progression of disease). All 3 patients attained a skin CR, and both
patients with bone marrow involvement attained bone marrow
CR.73 A case report of gemcitabine monotherapy in a patient with
BPDCN with skin involvement attained a partial response, with a
decreased number and intensity of skin lesions.72
Azacitidine has the most available data. Azacitidine first showed
rapid partial regression of cutaneous disease in 2 patients; however,
both developed neutropenia and died from sepsis at 8 and 9
months.74 The second study again showed initial partial regression
of cutaneous lesions; however, all 3 patients had eventual disease
progression with survivals of 14, 17, and 25 months.75
Pralatrexate was used as both first-line therapy (1 patient) and in
the setting of CHOP failure (2 patients). In all 3 patients, a cuta-
neous response was achieved. However, these patients experienced
disease progression.76,78
The outcomes of patients with BPDCN treated with bend-
amustine was reviewed in a 5-patient case series. One patient ach-
ieved a complete skin response for 7 months with eventual
Outcome Reference
Partial skin response, alive at time of publication 72
73
Complete skin response, median PFS was 10.6 months
(1 alive at 15 months)
74
Partial skin response, both developed neutropenia and sepsis,
75
median OS was 8 months
Partial skin response, 1 alive at time of publication, median OS
was 17 months (1 patient alive at 25 months)
76
Partial skin response, alive at 24 months
77
Complete skin response, developed acute leukemia, OS 1 month
78
Partial skin response, developed acute leukemia, OS 10 months
79
26 month, 1 developed tumor lysis syndrome at 34 months,
2 immediate progression of disease
Clinical Lymphoma, Myeloma & Leukemia Month 2019 -7
 BPDCNeCurrent Insights
progression of disease, 1 died from tumor lysis syndrome, 2 were
primary therapy failure, and 1 was unevaluable owing to fatal
complications associated with an underlying myelodysplastic
syndrome.79
Even in the face of initial treatment response, durability of
clinical remission and prolongation of survival is not reliably ob-
tained with all the lower intensity therapeutic options evaluated in
BPDCN.
Skin-only BPDCN
At least 34% of patients with BPDCN present with isolated skin
findings at the time of initial presentation.10 In a study of 14 pa-
tients with isolated cutaneous BPDCN on presentation who
received first-line radiotherapy alone, 13 of 14 attained a response
(CR, 8/13; PR, 5/13). However, the optimal dose of radiotherapy
was not determined, and most patients eventually progressed.80
Radiation therapy may be an option in patients with isolated skin
lesions or in those ineligible for chemotherapy. Other treatment
options include ALL-based regimens and DeVIC (dexamethasone,
etoposide, ifosfamide, and carboplatin) with L-asparaginase.81
Management of R/R Disease
R/R disease is associated with an extremely poor prognosis, lacking
effective treatment strategy. Clinical trial enrollment is the optimal
management option for R/R disease, and in the absence of an
appropriate clinical trial option, prior therapy dictates the treatment
choice. Patients who were previously treated with ALL-based
chemotherapy should be offered tagraxofusp and vice versa. In both
cases, the treatment goal remains HSCT. Gemcitabine and docetaxel
may be an effective treatment, given the evidence of its efficacy in a
heavily pre-treated population.72 Donor lymphocyte infusion has also
been used in patients who relapse after HSCT.34,82,83
Emerging Targeted Therapeutic
Options
Apart from tagraxofusp, there are several additional CD123-
based targeted therapies under evaluation in phase I trials.
IMGN632 is a novel CD123-targeting antibody-drug conjugate
composed of a humanized anti-CD123 antibody linked to a DNA
alkylating agent that has shown preclinical activity in CD123þ
malignancies, including BPDCN.84 It is currently being evaluated
in a phase I study for R/R hematologic malignancies including
BPDCN, and preliminary results did not identify a dose-limiting
toxicity.85 A novel potent bispecific antibody, XmAb14045 (also
known as SQZ622), targeting both CD123 and CD3 stimulating
focused T cell-mediated killing of CD123þ cells, is being evaluated
in a phase I study that includes BPDCN.86
Additionally, Chimeric Antigen Receptor T cell (CAR-T) ther-
apy has shown broad promise in hematopoietic neoplasms. Pre-
clinical studies have demonstrated the potent anti-leukemic activity
of CD123-CAR-T cells in an AML xenograft model.87 Subse-
quently, this concept was demonstrated in a 74-year-old man with a
bulky subcutaneous mass treated with CD123þ CAR-T cells. The
patient maintained CR at 60 days post-infusion with complete
resolution of clinical symptoms and no histopathologic evidence of
disease at the time of response evaluation. The patient tolerated the
treatment and did not experience cytokine release syndrome or
8 - Clinical Lymphoma, Myeloma & Leukemia Month 2019
neurotoxicity, thus encouraging further evaluation of this immu-
notherapeutic strategy in both transplant-eligible and -ineligible
patients with BPDCN.88
Montero et al reported BCL2 dependence of BPDCN through
dynamic BH3 profiling and demonstrated that BCL2 inhibitor
(venetoclax) treatment elicited clinical response and prolonged
survival in a xenograft model.89 Off-label use of venetoclax in 2
patients with R/R BPDCN who had progressed while receiving an
CD123 directed therapy attained a partial response at 4 weeks.
However, 1 patient died of intracranial hemorrhage secondary to
thrombocytopenia (preceding venetoclax therapy), and the other
had disease progression at 12 weeks.89 Additionally, a recently
published retrospective review of venetoclax combination therapy in
R/R myeloid malignancies, including 2 patients with BPDCN who
attained a cutaneous response with 1 patient attaining a positron
emission tomography/computed tomography response and > 50%
blast reduction in the bone marrow.90 Most recently, the clinical
activity of venetoclax was demonstrated in 3 patients (n ¼ 3) who
received hyper-CVAD in combination with venetoclax. All 3 pa-
tients achieved complete remission, and 2 patients with R/R disease
were successfully bridged to HSCT.91 Based on these encouraging
findings, a phase I study is underway to evaluate venetoclax mon-
otherapy in patients with R/R BPDCN (NCT03485547).
Additionally, Sapienza et al, employing integrated bioinformatics,
demonstrated constitutive activation of the nuclear factor-kappa B
(NF-kB) pathway in primary BPDCN cells and that the proteasome
inhibitor bortezomib was capable of inhibiting cell cycle progression
in a BPDCN cell line (CAL-1) through NF-kB inhibition.26 These
results were reinforced in 7 primary BPDCN samples where bor-
tezomib was associated with a decrease in RelA (NF-kB subunit)
expression and protracted the xenograft mouse survival.92
Bromodomain and extra-terminal domain (BET) protein inhi-
bition is of therapeutic interest in BPDCN. Through gene expres-
sion profiling, Emadali et al demonstrated haploinsufficiency for
NR3C1 and a fusion between NR3C1 and a long noncoding RNA
gene (lncRNA-3q). The overexpression of lncRNA-3q appeared to,
in part, proffer sensitivity to BET inhibitor (BETi) in vitro.20 In
another study, Ceribelli et al identified a BPDCN-specific tran-
scriptional network moderated by the E-box transcription factor
TCF4, which is in turn regulated by the BET protein BRD4.
Consequently, high-throughput drug screening demonstrated that
BET inhibition induced BPDCN apoptosis secondary to disruption
of a BPDCN-specific transcriptional network governed by TCF4-
dependent super-enhancers, denoting conceivable pre-clinical
rationale for clinical trial evaluation of BETi in BPDCN.93
Conclusion
BPDCN is a rare hematopoietic malignancy with universally
poor outcomes. Advances in pathobiological understanding of
BPDCN and the advent of novel immunotherapeutic options offer
promising therapeutic strategies to patients with this aggressive
neoplasm. As therapeutic approach to BPDCN becomes standard-
ized, a prognostic model for optimal therapeutic risk stratification
needs to be validated. Elucidating the molecular underpinnings of
BPDCN will aid in the identification of potential actionable ther-
apeutic targets to more effectively manage this rare recalcitrant
neoplasm.

Disclosure
The authors have stated that they have no conflicts of interest.
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