Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with rising visibility due to its unique clinical presentation and distinct organ compartment involvement; emerging, disease-specific, targeted therapies; and, more recently, a markedly increased pathobiologic understanding.1 A previously elusive diagnosis, this rare entity was estimated to represent approximately 0.44% of all hematologic malignancies, with an incidence largely unknown but estimated at approximately 500 to 1,000 cases per year in the U.S.2-5
BPDCN is generally considered a disease of older patients, with a median age of 65 to 70. It has a male predominance (up to 5:1 in some series),6 may occur in any organ compartment, and is unique for its frequent extramedullary manifestations. BPDCN most commonly affects the skin, causing what is often clinically described in the hematology/oncology clinic as “purple-colored or violaceous skin lesions”7 (Figure). This is followed by bone marrow/blood/lymph node involvement and a high incidence of central nervous system involvement, with central spinal fluid (CSF) positivity frequently occurring in asymptomatic patients, therefore leading to the addition of lumbar puncture intrathecal chemotherapy as prophylaxis as a mainstay of modern BPDCN therapy.8
Typical presentation of a cutaneous blastic plasmacytoid dendritic cell neoplasm lesion
Typical presentation of a cutaneous blastic plasmacytoid dendritic cell neoplasm lesion
Nomenclature and Classification
In addition to its rarity, BPDCN has experienced numerous name and classification changes over the years, including blastic natural killer cell lymphoma (2001); agranular CD4+CD56+ hematodermic neoplasm (2005); BPDCN as a subset of acute myeloid leukemia (AML) and related family of neoplasms (2008); BPDCN as its own unique myeloid neoplasm (2016); and, most recently, BPDCN as part of dendritic cell and histiocytic neoplasms in the fifth edition of the World Health Organization’s WHO Classification of Tumours: Haematolymphoid Tumours9 and BPDCN under major categories of myeloid neoplasms and acute leukemias in the International Consensus Classification (2022).10
Differential Diagnosis
In a patient with skin and hematologic abnormalities, it is vital to consider a broad differential diagnosis. A suggested list of disease states may include AML with skin involvement (leukemia cutis), chronic myelomonocytic leukemia with skin involvement, cutaneous T-cell lymphoma, Sweet syndrome, paraneoplastic or autoimmune skin manifestations in solid tumor or hematologic malignancies, infectious/fungal etiologies, and more common skin cancers with or without BPDCN concomitantly. The key clinical pearl here is that a skin biopsy is always needed to confirm the diagnosis of cutaneous BPDCN.
Confirming and Staging Diagnosis
Because BPDCN involves so many extramedullary compartments and has myriad possible disease-mimicking states, it is important to properly confirm the diagnosis and understand its extent and areas of involvement at disease outset. The North American BPDCN Consortium put together a helpful diagnostic workup, including skin biopsy, baseline photos of all skin lesions, use of the Modified Severity-Weighted Assessment Tool scoring system, bone marrow aspirate/biopsy, cytogenetics, molecular testing, flow cytometry, immunohistochemistry specific for BPDCN, and baseline imaging (either positron emission tomography/computed tomography [PET-CT] or CT). Importantly, it has also been demonstrated that BPDCN has a higher than previously appreciated incidence of CSF involvement (~20-30%), even in the targeted therapy era.11 As a result, it is imperative that baseline lumbar puncture (LP) with delivery of intrathecal (IT) chemotherapy be rendered for all patients with BPDCN, as well as serial LP with IT chemotherapy for all patients.12
Treatment Considerations
Among some of the larger historical European series, a median overall survival rate of less than one year was commonly reported, with high early death rates during induction, as well as mortality from infection/sepsis, multi-organ failure, or rapid transformation to an acute leukemic state.13-15 Prior to the modern targeted-therapy era, academic groups used and have published on a wide range of multiagent chemotherapy regimens, generally borrowing from multiple myeloma/lymphoma-inspired, acute lymphoblastic leukemia-based, or AML-based treatments.16,17 Despite these intensive therapies, however, the majority of patients had poor outcomes and many were considered poor candidates for intensive chemotherapy given their advanced age.
Modern Era of Targeted Therapy
In this emerging era of disease awareness for BPDCN, one of the major findings has been the expression of CD123 (interleukin-3 [IL-3] alpha chain receptor) on the surface of all BPDCN cells. This breakthrough has led to the pharmacologic targeting of CD123 by novel agents, The first-in-class drug tagraxofusp, a modified diphtheria toxin payload fused to recombinant IL-3, was approved by the U.S. Food and Drug Administration in December 2018 for patients with BPDCN ages 2 years and older. In long-term follow-up, tagraxofusp was shown to have a 75% overall response rate and a 57% complete response (CR) and composite CR rate, with median duration of follow-up of 34 months and median overall survival of 15.8 months.18 A notable and potentially life-threatening side effect of tagraxofusp is capillary leak syndrome, which can possibly occur in approximately 18% to 20% of patients, almost always restricted to the first cycle of treatment.19
Another CD123-targeted agent that has recently entered later stages of clinical trial development — pivekimab sunirine — is an antibody-drug-conjugate featuring a high-affinity CD123 antibody with a cleavable linker and a unique indolinobenzodiazepine dimer payload. This promising new agent is an intravenous drug given every three weeks, has been shown to have activity in the relapsed/recurrent BPDCN setting, and is now in active clinical investigation, including in the frontline setting for BPDCN.20 A number of other CD123-directed agents are also now in active clinical trials.21 Moving beyond targeting CD123, the most well-developed targeted therapy in BPDCN is the BCL2 inhibitor venetoclax as monotherapy or in combination with anti-CD123 approaches.16,22 Stem cell transplantation also remains a curative component for patients who qualify, particularly fit patients who have achieved maximal response with first-line therapy.23,24
Conclusion and Future Directions
While BPDCN remains an ultra-rare hematologic neoplasm, focused study of this clinical entity has also yielded opportunities to study therapeutic targeting of CD123 within the rest of the hematology/oncology field. Outcomes for BPDCN are improving with incorporation of novel targeted agents such as venetoclax, and future progress will hinge on further investigation of CD123-combination therapies/triplets such as CD123/BCL2/hypomethylating agent (NCT03113643) and CD123/BCL2/chemotherapy (NCT04216524), as well as continued identification and development of possible agents beyond anti-CD123 therapeutics.12,20,24,25
Disclosure Statement
Dr. Pemmaraju reports research funding from the SagerStrong Foundation and the U.S. Department of Defense, as well as consulting or advisory activity for AbbVie, Bristol Myers Squib, CTI BioPharma, GSK, ImmunoGen, Incyte, Johnson & Johnson, Neopharm, Novartis, Pacylex, Protagonist Therapeutics, Stemline/Menarini Group, and Takeda. Dr. Phan indicated no relevant conflicts of interest. Dr. Patel is a paid consultant for Menarini-Stemline.
Acknowledgment
This research was supported in part by the University of Texas MD Anderson Cancer Center and a National Cancer Institute Cancer Center Support Grant from the National Institutes of Health (P30CA016672).
