Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), a rare malignancy of the hematopoietic system, is distinguished by its highly recognizable skin manifestations and complex pathophysiology, which continue to captivate the medical community's investigative spirit and challenge its resolve. Recently, Dr. Yue Lu from Lu Daopei Medical provided an in-depth analysis of BPDCN's origins, clinical presentation, diagnostic methods, and treatment advancements, shedding light on the cutting-edge developments in this field. The following article, based on his insights, has been prepared by Hematology Frontier for our readers.

Key Takeaways

• BPDCN is classified under myeloid neoplasms, specifically within the dendritic cell/histiocytic tumors category.
• Multidisciplinary collaboration is essential for BPDCN diagnosis, with immunophenotyping being the gold standard.
• BPDCN presents clinically with characteristic skin changes, with or without bone marrow involvement, and often shows extensive extramedullary involvement.
• The era of targeted drug therapy has arrived. While Tagraxofusp is not yet available in China, alternatives such as venetoclax, hypomethylating agents, and traditional chemotherapy regimens can be considered.
• CNS management should begin at the initial diagnosis and continue throughout the treatment process.
• For allo-HSCT, patients are advised to undergo myeloablative conditioning (MAC) during CR1 if possible, with post-transplant maintenance therapy using venetoclax and hypomethylating agents recommended.

Overview of BPDCN

Histiocytic and dendritic cell tumors originate from or exhibit differentiation toward cells of the mononuclear phagocyte system, including monocytes, macrophages, and dendritic cells, and are classified under myeloid neoplasms. In the 2022 fifth edition of the WHO classification of hematopoietic and lymphoid tissues, BPDCN and myeloid neoplasms associated with mature plasmacytoid dendritic cell proliferation were classified under plasmacytoid dendritic cell tumors.

In healthy individuals, plasmacytoid dendritic cells (pDCs) constitute only a tiny fraction of all nucleated cells, less than 0.5%. In acute myeloid leukemia (AML), BPDCN accounts for less than 1%, and it represents only 0.44% of newly diagnosed hematologic malignancies annually. BPDCN exhibits a bimodal age distribution, with higher incidence rates observed in individuals under 20 years old and those over 60, with a median age at diagnosis of 65 years. It is rare in children. The disease predominantly affects older male patients, with a male-to-female ratio of approximately 3:1. Currently, there is no evidence linking BPDCN to racial or geographical factors, nor have specific environmental, genetic, or acquired factors been identified that increase the risk of developing BPDCN.

The cell of origin for BPDCN is believed to be the pDC, an important subset of dendritic cells. Like other mononuclear phagocytes, pDCs originate from CD34+ primitive myeloid stem cells. pDCs are capable of secreting a variety of cytokines, including interferon-α (IFN-α), interleukin-6 (IL-6), IL-8, IL-12, and tumor necrosis factor-α (TNF-α). These cytokines play a crucial role in immune responses, activating T cells, natural killer (NK) cells, and macrophages.

Approximately 20% of BPDCN patients have a history of myeloid neoplasms, such as MDS, CMML, and CML. BPDCN shares significant genetic overlaps with chronic myelomonocytic leukemia (CMML), including mutations in genes such as TET2, ASXL1, SRSF2, and NRAS. Furthermore, about 75% of BPDCN patients present with complex chromosomal abnormalities, with the most common being abnormalities in chromosomes 5q, 6q, monosomy 9, 12p, 13q, and 15q. Gene mutations play a crucial role in the pathogenesis of BPDCN, particularly alterations in epigenetic regulation and the RAS signaling pathway, involving genes such as TET2, ASXL1, NRAS, KRAS, IDH1, ZRSR2, U2AF1, ATM, and MYC overexpression. These genetic and signaling pathway alterations may collectively contribute to BPDCN tumorigenesis, proliferation, and aggressiveness, offering potential molecular targets for diagnosis and treatment.

BPDCN’s clinical presentation is most notably characterized by skin changes. Approximately 85% to 90% of BPDCN patients exhibit skin lesions, which vary in shape, size, and color. Specifically, the lesions can appear as nodules, plaques, or bruise-like areas, ranging from 1 cm to 10 cm in size, and vary in color from brown to purple. The most commonly affected areas include the face or scalp (20%), followed by the lower limbs (11%), trunk (9%), and upper limbs (7%). The distribution of lesions is often uneven and may involve single or multiple sites. Additionally, about 6% of patients report mucosal involvement, particularly in the oral mucosa. The typical skin manifestations can be categorized into three main types: (1) solitary or a few isolated purple nodules, which is the most common type, accounting for approximately 73%; (2) solitary or a few purple bruise-like macules, about 12%; and (3) disseminated lesions, about 15%, including macules and nodules.

In addition, while some BPDCN cases progress indolently, most exhibit aggressive behavior characterized by rapid systemic dissemination. Among BPDCN patients, the median bone marrow infiltration is as high as 73%. The most common peripheral blood abnormalities include thrombocytopenia (78%), anemia (65%), and neutropenia (34%). Lymphadenopathy and splenomegaly occur in 56% and 44% of patients, respectively. Beyond hematologic manifestations, BPDCN may also present with involvement of other sites, such as the tonsils, paranasal sinuses, lungs, eyes, and central nervous system (CNS). Notably, a few BPDCN cases may present solely with bone marrow involvement without skin lesions.

Immunophenotyping is the gold standard for diagnosing BPDCN. The diagnostic criteria include: 1. Expression of CD123 and at least one other pDC marker, along with CD4 and/or CD56; 2. Expected negative markers are negative, and at least three pDC markers are positive.

In differential diagnosis, BPDCN must be distinguished from other hematologic malignancies with similar clinical presentations, particularly those that can also exhibit skin changes and pDC expression markers. pDCs mature through three consecutive stages in bone marrow differentiation. The expression pattern of key markers during pDC maturation is illustrated in Figure 2A. Briefly, the earliest pDCs express CD34 and CD117, while CD4 and CD303 are negative. As pDCs mature, they rapidly lose CD117 expression; in the intermediate stage, pDCs exhibit negative CD117 and partial expression of CD34, with increased expression of CD4 and CD303. Late-stage mature pDCs are CD34-negative and express CD4, CD303, and CD304. CD45 levels gradually increase with pDC maturation. Myeloid neoplasms with plasmacytoid dendritic cell proliferation (MPDCP) are low-grade malignancies that differ from BPDCN in being CD34-CD56-, commonly seen in CMML, and frequently harboring RAS mutations. pDC-AML differs from BPDCN in being CD34+CD56- and frequently harboring RUNX1 mutations. Clinically, when a pDC-like phenotype appears in flow cytometry, differential diagnosis can proceed according to Figure 2B.

The North American BPDCN Consortium (NABC) has established a comprehensive diagnostic approach from eight aspects (Figure 3), including skin lesion color appearance, skin biopsy and photos, mSWAT scoring (a tool for assessing the severity of skin lesions), whole-body PET-CT (extramedullary sites), bone marrow aspiration and biopsy, flow cytometry, cerebrospinal fluid (CNS assessment), and cytogenetics and gene mutations.

Current Status and Advances in BPDCN Treatment

A multicenter study led by the Montreal General Hospital in France identified six global treatment approaches for BPDCN, including chemotherapy without consolidation therapy (56.3%), chemotherapy plus allo-HSCT (15.5%), chemotherapy plus auto-HSCT (4.1%), as well as radiotherapy, novel drug treatments (e.g., SL401, bortezomib), and palliative care. Among these, the chemotherapy plus allo-HSCT group showed the best efficacy, with a survival rate of over 50%, followed by the chemotherapy plus auto-HSCT group, while non-transplant treatments had the poorest outcomes. Prognostic analysis revealed that favorable factors included NHL or AL-like regimens bridging allo/auto-HSCT, while unfavorable factors were age over 60, disseminated skin lesions, and concurrent extramedullary disease.

Regarding allo-HSCT conditioning regimen selection, a study compared four regimens: MAC+TBI, MAC without TBI, reduced-intensity conditioning (RIC)+TBI, and RIC without TBI. The results showed that the MAC+TBI group had higher OS and PFS, lower cumulative relapse rate (CIR), and similar non-relapse mortality (NRM) compared to the other three groups, while the RIC+TBI group did not show any benefits.

The CIBMTR study analyzed the impact of pre-transplant status (CR1/CR2/primary induction failure/relapse), age, and conditioning regimen on transplant outcomes. The results showed that the CR1 group had higher OS and DFS; age <60 years reduced NRM and improved OS; and the MAC/TBI regimen reduced CIR and improved DFS.

Moreover, in the non-adult patient population, CNS symptoms were observed more frequently compared to adult patients, with a lower proportion of patients presenting with skin lesions. During treatment, non-adult patients had lower early-stage mortality than adult patients and a lower rate of transplantation during CR1. However, in terms of OS, non-adult patients had significantly higher survival rates than adults.

In the treatment of BPDCN, targeted therapy has become a significant area of progress, with important advances in therapies targeting key molecules such as CD123, TCF-4, and BCL-2. The 2024 NCCN guidelines recommend Tagraxofusp and myeloid chemotherapy regimens (Figure 4) as treatment options for newly diagnosed BPDCN, and suggest allo-HSCT during CR1. For relapsed/refractory patients, the guidelines emphasize repeating systemic PET-CT and skin and extramedullary lesion biopsies, with careful CNS evaluation (Figures 5 and 6).

Expert Profile

Dr. Yue Lu

• Chief Physician, Department of Transplantation, Lu Daopei Medical (Vice President level)
• Standing Committee Member, Hematology Branch, Beijing Medical Association
• Member, Hematopoietic Stem Cell Transplantation Application Group, Hematology Branch, Chinese Medical Association
• Member, Hematology Professional Committee, Cross-Strait Medical and Health Exchange Association
• Completed clinical training at the Fred Hutchinson Bone Marrow Transplantation Center in Seattle, USA, in October 2016
• By the end of 2023, completed over 1,500 allogeneic hematopoietic stem cell transplants
• Published over 10 SCI papers in journals including Frontiers in Immunology, British Journal of Haematology, Bone Marrow Transplantation, and Biology of Blood Marrow Transplantation