Keywords
Blastic plasmacytoid dendritic cell neoplasm - CD123 - hematopoietic cell transplant
Introduction
Blastic plasmacytoid dendritic cell neoplasm(BPDCN), formerly known as primary cutaneous
natural killer/T-cell lymphoma, has now been classified as a separate entity in the
2016 World Health Organization (WHO) myeloid neoplasms classification.[1],[2] Plasmacytoid dendritic cell has been described as the cell of origin.[1] BPDCN can be observed in all age groups, but it is more common in elders.[1],[3],[4] The male-to-female ratio is 2.2:1.[4] After the first case reported in 1994, around 200 cases have been described in the
literature.[4] It constitutes 0.44% of all hematologic malignancies in a year.[4] Majority cases present with cutaneous manifestations such as plaque or nodules,
red to purple in color.[5] Its presentation is often confused with other dermatologic disease manifestations.
The disease also involves the bone marrow, spleen, and lymph nodes.[5] BPDCN may coexist with myelodysplastic syndrome, and 10%–20% cases may progress
to acute myeloid leukemia.[5],[6]
Case Report
An 18-year-old adolescent female presented with bilateral glandular neck swellings
of 15 days. No systemic symptoms were observed. On examination, the cervical lymph
nodes were firm to hard and nontender. There was a single cutaneous maculopapular
lesion, 2.5 cm × 2 cm in size over left anterior aspect of the thigh, reddish-purple
in color which resolved spontaneously. The liver and spleen were not palpable. Investigations
showed a hemoglobin level of 7.8 g/dl, white blood cell count of 29,000/cu mm, and
platelet count of 59,000/cu mm, with 68% atypical cells on peripheral blood smear
[Figure 1]. Organ functions were unremarkable. Imaging identified retroperitoneal lymphadenopathy.
Bone marrow aspirate and biopsy showed a hypercellular marrow with 87% blasts suggestive
of acute leukemia [Figure 2]. Flow cytometric analysis revealed tumor cells to be positive for CD4, CD56, CD123,
CD304 (BDCA-4), CD117, CD7, CD45, and human leukocyte antigen (HLA)-DR. The cells
were negative for CD13, CD33, CD10, CD19, CD20, cMPO, TdT, CD41, and CD61 [Figure 3]. These findings were suggestive of BPDCN, although CD303 (BDCA-2) was not done due
to unavailability. She received four cycles of hyper-CVAD chemotherapy regimen, and
bone marrow was in morphological remission after cycle IB. She underwent allogenic
hematopoietic cell transplantation (HCT) with an 8/10 HLA antigen partially mismatched
(high-resolution typing) sibling sister. Standard myeloablative conditioning with
total body irradiation (TBI) and injectable busulfan was administered, and CD34 cell
dose of 6.0 × 106 cells/kg (with a CD3 cell dose of 0.54 × 108 cells/kg) was infused. She received graft-versus-host disease (GVHD) prophylaxis
with posttransplant cyclophosphamide on day +3 and day +4 along with tacrolimus and
mycophenolate mofetil from day +5 onward. Neutrophil and platelet engraftment occurred
on day +15 and day +16, respectively. During her peritransplant period, she developed
acute gut GVHD on day +15 which responded to standard methylprednisolone therapy.
While on methylprednisolone, she had a reactivation of cytomegalovirus for which she
received ganciclovir for 2 weeks followed by valganciclovir. She was on regular follow-up
without significant symptoms or morbidity but developed asymptomatic medullary relapse
19 months posttransplant. Intensive treatment and alternative “palliative” options
were discussed. The patient and family chose to pursue decitabine monotherapy with
intent for disease control only due to financial constraints. The patient developed
febrile neutropenia after two cycles of decitabine and eventually died due to intracranial
hemorrhage thereafter, 24.5 months from the initial diagnosis.
Figure 1 Peripheral blood smear showing tumor cells (marked by arrow)
Figure 2 Bone marrow biopsy with magnified view and immunohistochemistry markers (CD3, CD4,
CD56, and MPO)
Figure 3 Flow cytometry analysis on bone marrow aspirate sample
Discussion
Management of this young patient provided three learning opportunities for the treating
team: arriving at a diagnosis in an unusual presentation of a very rare disorder,
clinical management of aggressive disease in the background of scanty literature evidence,
and treatment of relapse in such a disease setting. Our patient had peripheral blood
and bone marrow involvement with cervical and retroperitoneal lymphadenopathy at presentation.
There was a single cutaneous lesion which resolved spontaneously before treatment.
With respect to diagnosis, the 2008 WHO Classification identifies BPDCN as a neoplasm
which typically expresses CD4 and CD56 in addition to at least 1 of the pDC-associated
antigens – CD123, TCL-1, CD304, or CD303/BDCA2 – in the absence of lineage-specific
markers.[6] A diagnostic criteria with 5 point scoring system based on flow cytometry has also
been mentioned wherein a score of more than 2 favors the diagnosis of BPDCN.[6]
To date, there has been no consensus regarding the standard treatment of this disease.
Although the disease usually shows early clinical response, relapse is very common.
Various chemotherapy combinations such as acute myeloid leukemia (AML)-based induction,
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), hyper-CVAD, and
steroids have all been used.[5],[7],[8],[9] In a retrospective analysis of BPDCN patients who were treated with hyper-CVAD,
CR rate was found to be 90% and OS ranged from 23 to 29 months, which was superior
to a CHOP-like regimen.[9] A recent review recommends AML like induction therapy followed by consolidation
with allogenic HCT, owing to its myeloid lineage.[6],[10] HCT in first complete remission (CR1) has been suggested for a durable outcome.[6] As per the European Society for Blood and Marrow Transplantation, there was an increase
in overall survival and no relapse within 27 months in patients who received allogenic
HCT in CR1.[10] In a case series of HCT in ten patients (6 allogenic HCT and 4 autologous HCT) with
a median age of 28.5 years and conditioning regimen of cyclophosphamide with TBI,
overall survival was improved with the use of myeloablative conditioning followed
by HCT (31.5 months) as compared to chemotherapy alone (13 months).[3]
Management of relapsed disease is also fraught with worse outcomes using conventional
chemotherapy as well as newer reported therapeutic options such as hypomethylating
agents, bendamustine, pralatrexate, and venetoclax.[1] It is worth noting that tegraxofusp-ezrs (ELZONRIS, a Monoclonal Ab, SL-401, directed
against interleukin-3 receptor alpha chain [CD123] along with a truncated diphtheria
toxin fusion protein), an immunotoxin genre of targeted immunotherapy has been recently
approved by the USFDA (December 2018) with a reported CR rate of around 55% with a
duration of response of around 5 months.[1] Ongoing clinical trials evaluating novel therapeutic modalities strategies such
as CAR-T cells (e.g., NCT03203369 and NCT03485547) will shed more light on the management
of this aggressive malignancy.[1]
BPDCN carries a poor prognosis with a median survival of around 12–16 months, and
overall survival depends on the age and clinical characteristics of the patient.[3],[4],[8] This case report exemplifies a rare disorder presenting at an unusual age with challenges
of the diagnosis and management that are unique. It is important to initiate the treatment
early and consolidate it with HCT for longer remission.
