Blastic Plasmacytoid Dendritic Cell Neoplasm Research Articles

Flotetuzumab as a salvage immunotherapy in advanced CD123-positive hematological malignancies, a phase 1 pilot study

CD123 “expression” is common in hematological malignancies, including acute lymphoblastic leukemia (ALL). Flotetuzumab is a novel, investigational CD3/CD123 DART®. We conducted a phase 1 study evaluating safety and efficacy of flotetuzumab in relapsed/refractory ALL (Cohort A) and other advanced CD123-positive hematological malignancies (excluding myeloid malignancies) (cohort B). Thirteen patients (9 in Cohort A and 4 in Cohort B) were treated at dose level 1 (500 ng/kg/day) before early closure due to discontinuation of drug development by sponsor. Two dose limiting toxicities (Grade 4 thrombocytopenia and neutropenia) occurred in one patient in Cohort B. Cytokine release syndrome occurred in most patients (85%), all being grade ≤2. Responses only occurred in Cohort B, with a partial response in one patient with Hodgkin’s lymphoma and morphological complete remission in the bone marrow in one patient with blastic plasmacytoid dendritic cell neoplasm. In conclusion, flotetuzumab had a manageable safety profile in advanced CD123-positive hematological malignancies.

Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature.

Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies.

Real-world evidence on tagraxofusp for blastic plasmacytoid dendritic cell neoplasm - collected cases from a single center and case reports.

Blastic plasmacytoid dendritic cell neoplasia (BPDCN) is a rare, aggressive hematologic malignancy. Until recently, the only curative treatment consisted of intensive chemotherapy, followed by hematopoietic cell transplantation (HCT) in eligible adult cases. Tagraxofusp, a CD123-targeted protein-drug conjugate and the first approved targeted treatment for BPDCN,might enhance outcomes especially in patients not eligible for intensive therapies. Here, we report real-world outcomes of five male patients with a median age of 79 years who received tagraxofusp as first-line treatment for BPDCN. Tagraxofusp was found to be well-tolerated in this elderly cohort, with only one patient requiring discontinuation. Three patients responded to the treatment (two patients achieved a CR and one patient achieved a partial response), of which two subsequently underwent allogeneic (allo) HCT. One patient is alive and well after ≥ 4 years after alloHCT, and one patient shows sustained CR after now 13 cycles of tagraxofusp. The other three patients died of progressive disease 4-11 months after initiation of treatment. In line with results from 13 published cases outside clinical trials in the literature, sustained responses were associated with CR after tagraxofusp treatment and subsequent alloHCT. Our results provide real-world evidence for safety and efficacy of tagraxofusp as first-line treatment for BPDCN.

Genome-wide DNA methylation-analysis of blastic plasmacytoid dendritic cell neoplasm identifies distinct molecular features

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.

Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

[Clinical Characteristics of CD4-CD56+ Blastic Plasmacytoid Dendritic Cell Neoplasm].

To explore the clinical manifestations, pathological features, immunophenotype, as well as diagnosis, treatment and prognosis of patients with CD4-CD56+ blastic plasmacytoid dendritic cell neoplasm (BPDCN), in order to further understand the rare disease. The clinical data, laboratory examinations and treatment regimens of two patients with CD4-CD56+ BPDCN in the First Affiliated Hospital of Wannan Medical College were retrospectively analyzed. The two patients were both elderly males with tumor involved in skin, bone marrow, lymph nodes, etc. Immunohistochemical results of skin lesions showed that both CD56 and CD123 were positive, while CD4, CD34, TdT, CD3, CD20, MPO and EBER were negative. Flow cytometry of bone marrow demonstrated that CD56, CD123, and CD304 were all positive, while specific immune markers of myeloid and lymphoid were negative. Two patients were initially very sensitive to acute lymphoblastic leukemia or lymphomatoid chemotherapy regimens, but prone to rapid relapse. The overall survival of both patients was 36 months and 4 months, respectively. CD4-CD56+ BPDCN is very rare and easily misdiagnosed as other hematological tumors with poor prognosis. Acute lymphoblastic leukemia or lymphomatoid therapy should be used first to improve the poor prognosis.

Transcriptional Landscape of CUT-Class Homeobox Genes in Blastic Plasmacytoid Dendritic Cell Neoplasm.

Homeobox genes encode developmental transcription factors regulating tissue-specific differentiation processes and drive cancerogenesis when deregulated. Dendritic cells (DCs) are myeloid immune cells occurring as two types, either conventional or plasmacytoid DCs. Recently, we showed that the expression of NKL-subclass homeobox gene VENTX is restricted to conventional DCs, regulating developmental genes. Here, we identified and investigated homeobox genes specifically expressed in plasmacytoid DCs (pDCs) and derived blastic plasmacytoid dendritic cell neoplasm (BPDCN). We analyzed gene expression data, performed RQ-PCR, protein analyses by Western blot and immuno-cytology, siRNA-mediated knockdown assays and subsequent RNA-sequencing and live-cell imaging. Screening of public gene expression data revealed restricted activity of the CUT-class homeobox gene CUX2 in pDCs. An extended analysis of this homeobox gene class in myelopoiesis showed that additional CUX2 activity was restricted to myeloid progenitors, while BPDCN patients aberrantly expressed ONECUT2, which remained silent in the complete myeloid compartment. ONECUT2 expressing BPDCN cell line CAL-1 served as a model to investigate its regulation and oncogenic activity. The ONECUT2 locus at 18q21 was duplicated and activated by IRF4, AUTS2 and TNF-signaling and repressed by BMP4-, TGFb- and IL13-signalling. Functional analyses of ONECUT2 revealed the inhibition of pDC differentiation and of CDKN1C and CASP1 expression, while SMAD3 and EPAS1 were activated. EPAS1 in turn enhanced survival under hypoxic conditions which thus may support dendritic tumor cells residing in hypoxic skin lesions. Collectively, we revealed physiological and aberrant activities of CUT-class homeobox genes in myelopoiesis including pDCs and in BPDCN, respectively. Our data may aid in the diagnosis of BPDCN patients and reveal novel therapeutic targets for this fatal malignancy.

A non-resolving bruise and the 'pearl necklace'-Blastic plasmacytoid dendritic cell neoplasm.

A non-resolving bruise and the 'pearl necklace'-Blastic plasmacytoid dendritic cell neoplasm.

A novel MYB::PAIP1 oncogenic fusion in pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is dependent on BCL2 expression and is sensitive to venetoclax.

A novel MYB::PAIP1 oncogenic fusion in pediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is dependent on BCL2 expression and is sensitive to venetoclax.

Efficacy and manageable safety of tagraxofusp in blastic plasmacytoid dendritic cell neoplasm: a case series of pediatric and adolescent/young adult patients.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) predominantly occurs in adults ≥60 years old; 10-20% of cases are pediatric or adolescent/young adult (AYA) patients. Tagraxofusp (TAG, Elzonris®) is the only approved treatment for BPDCN; in the United States it is approved for patients aged ≥2 years. Data on treating pediatric and AYA BPDCN patients are limited. We present a case series of pediatric and AYA patients with BPDCN treated with TAG. Eight patients (five newly diagnosed; three relapsed/refractory [R/R]), aged 2-21 years, received 12 mcg/kg TAG. Seven patients were female; most had skin (n = 6) and/or bone marrow (n = 4) involvement. No new safety signals were identified. Grade 3 adverse events were headache (n = 1) and transaminitis (n = 2). Three patients with newly diagnosed BPDCN achieved complete response, one achieved partial response, and one had stable disease (SD). One patient with R/R BPDCN achieved a minor response; one had SD. Seven patients (88%) were bridged to stem cell transplant: 80% of newly diagnosed patients and 100% of R/R patients. Five patients remained alive at last follow-up. These cases highlight the efficacy and safety of TAG in pediatric and AYA patients for whom there is no other approved BPDCN therapy.

Ulcerating skin lesions from blastic plasmacytoid dendritic cell neoplasm responding to low-dose radiotherapy-acase report and literature review.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is arare hematologic malignancy that can manifest with skin nodules and erythematous plaques. In most cases BPDCN progresses rapidly, causing multiple skin lesions and also affecting internal organs and bone marrow, warranting initiation of systemic therapies or hematopoietic stem cell transplantation (HCT). Although not curative, radiotherapy for isolated lesions might be indicated in case of (imminent) ulceration and large or symptomatic lesions. To this end, doses of 27.0-51.0 Gy have been reported. Here, we present the case of an 80-year-old male with BPDCN with multiple large, nodular, and ulcerating lesions of the thorax, abdomen, and face. Low-dose radiotherapy of 2 × 4.0 Gy was administered to several lesions, which resolved completely within 1week with only light residual hyperpigmentation of the skin in affected areas and reliably prevented further ulceration. Radiotoxicity was not reported. Therefore, low-dose radiotherapy can be an effective and low-key treatment in selected cases of BPDCN, especially in apalliative setting, with afavorable toxicity profile.

Blastic Plasmacytoid Dendritic Cell Neoplasm: A Comprehensive Review of the Disease, Central Nervous System Presentations, and Treatment Strategies.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with poor outcomes. The World Health Organization (WHO) redefined BDCN as a distinct disease entity in 2016. BPDCN arises from plasmacytoid dendritic cells, manifesting primarily in the skin, bone marrow, and lymph nodes, occasionally involving the central nervous system (CNS). This presents challenges in diagnosis and treatment, with CNS involvement often overlooked in standard diagnostic workups due to BPDCN's rarity and patients often being neurologically asymptomatic at diagnosis. CNS involvement typically emerges during relapse, yet clinical trials often exclude such cases, limiting our understanding of its development and treatment. Treatment options for CNS involvement include intrathecal (IT) chemotherapies like methotrexate and cytarabine, often in combination with systemic agents. Tagraxofusp and traditional regimens for acute myeloid leukemia show limited success at preventing CNS relapse, prompting exploration of combined therapies like hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with venetoclax and adding IT chemotherapy to other backbones. Ongoing clinical trials investigating emerging therapies offer hope despite limited focus on CNS implications. Trials incorporating CNS-involved patients aim to pioneer novel treatment approaches, potentially reshaping BPDCN management. Understanding CNS involvement's complexities in BPDCN remains crucial for tailored treatments and better patient outcomes.

Breakthrough in Blastic Plasmacytoid Dendritic Cell Neoplasm Cancer Therapy Owing to Precision Targeting of CD123.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic cancer originating from the malignant transformation of plasmacytoid dendritic cell precursors. This malignancy progresses rapidly, with frequent relapses and a poor overall survival rate, underscoring the urgent need for effective treatments. However, diagnosing and treating BPDCN have historically been challenging due to its rarity and the lack of standardized approaches. The recognition of BPDCN as a distinct disease entity is recent, and standardized treatment protocols are yet to be established. Traditionally, conventional chemotherapy and stem cell transplantation have been the primary methods for treating BPDCN patients. Advances in immunophenotyping and molecular profiling have identified potential therapeutic targets, leading to a shift toward CD123-targeted immunotherapies in both clinical and research settings. Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. However, the therapeutic effectiveness of CD123-targeting treatments needs improvement through innovative approaches and combinations of treatments with other anti-leukemic drugs. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

Diagnostic management of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in close interaction with therapeutic considerations

Blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare malignancy derived from plasmacytoid dendritic cells, can mimic both acute leukemia and aggressive T-cell lymphoma. Therapy of this highly aggressive hematological disease should be initiated as soon as possible, especially in light of novel targeted therapies that have become available. However, differential diagnosis of BPDCN remains challenging. This retrospective study aimed to highlight the challenges to timely diagnoses of BPDCN. We documented the diagnostic and clinical features of 43 BPDCN patients diagnosed at five academic hospitals from 2001–2022. The frequency of BPDCN diagnosis compared to AML was 1:197 cases. The median interval from the first documented clinical manifestation to diagnosis of BPDCN was 3 months. Skin (65%) followed by bone marrow (51%) and blood (45%) involvement represented the most common sites. Immunophenotyping revealed CD4 + , CD45 + , CD56 + , CD123 + , HLA-DR + , and TCL-1 + as the most common surface markers. Overall, 86% (e.g. CD33) and 83% (e.g., CD7) showed co-expression of myeloid and T-cell markers, respectively. In the median, we detected five genomic alterations per case including mutational subtypes typically involved in AML: DNA methylation (70%), signal transduction (46%), splicing factors (38%), chromatin modification (32%), transcription factors (32%), and RAS pathway (30%), respectively. The contribution of patients (30%) proceeding to any form of upfront stem cell transplantation (SCT; autologous or allogeneic) was almost equal resulting in beneficial overall survival rates in those undergoing allogeneic SCT (p = 0.0001). BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

A blastic plasmacytoid dendritic cell neoplasm-like immunophenotype is negatively associated with CEBPA bZIP mutation and predicts unfavorable prognosis in acute myeloid leukemia.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy which characteristically expresses an atypical phenotype including CD123+, CD56+, and CD4+. We are aimed to investigate the clinical and prognostic characteristics of AML patients exhibiting BPDCN-like immunophenotype and provide additional insights for risk stratification of AML. A total of 241 newly diagnosed AML patients were enrolled in this retrospective study and categorized into BPDCN-like positive (n = 125)/negative (n = 116) groups, determined by the present with CD123+ along with either CD56+ or CD4+, or both. Subsequently, an analysis was conducted to examine the general clinical characteristics, genetic profiles, and prognosis of the two respective groups. Patients with BPDCN-like immunophenotype manifested higher frequencies of acute myelomonocytic leukemia and acute monoblastic leukemia. Surprisingly, the presence of the BPDCN-like immunophenotype exhibited an inverse relationship with CEBPA bZIP mutation. Notably, patients with BPDCN-like phenotype had both worse OS and EFS compared to those without BPDCN-like phenotype. In the CN-AML subgroups, the BPDCN-like phenotype was associated with worse EFS. Similarly, a statistically significant disparity was observed in both OS and EFS within the favorable-risk subgroup, while only OS was significant within the adverse-risk subgrouMoreover, patients possessing favorable-risk genetics without BPDCN-like phenotype had the longest survival, whereas those who had both adverse-risk genetics and BPDCN-like phenotype exhibited the worst survival. Our study indicated that BPDCN-like phenotype negatively associated with CEBPA bZIP mutation and revealed a significantly poor prognosis in AML. Moreover, the 2022 ELN classification, in combination with the BPDCN-like phenotype, may better distinguish between different risk groups.

Imaging blastic plasmacytoid dendritic cell neoplasm with 18FDG PET/CT: A rare paediatric case

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) previously called “CD4/CD56 hematodermic neoplasm” is a rare hematolymphoid neoplasm with a very poor prognosis. The disease has rarely been described in the paediatric population and is characterized by cutaneous involvement in most cases with hematological dissemination. Given the low number of cases described, the role of 18FDG PET/CT in this disease is very little known. We herein present a case of a 14-year-old girl with BPDCN to highlight the utility of 18FDG PET/CT for staging and treatment follow-up in this rare entity.

Blastic Plasmocytoid Dendritic Cell Neoplasm (BPDCN): Clinical Features and Histopathology with a Therapeutic Overview.

Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCNs) are a rare, highly aggressive hematological malignant neoplasm that primarily involve the skin, bone marrow, lymph nodes and even extra-nodal sites. The rarity and relative poor description of cases in the literature make it necessary to review and further studies that deeply investigate this entity not only in a histopathological but also molecular field. In August-September 2023, we searched MEDLINE, PubMed and Scopus for randomized controlled trials (RCTs), narrative and systematic reviews, meta-analyses, observational studies (either longitudinal or retrospective), and case series published in English in the last 25 years using the keywords BPDCN, PDCs, Blastic NK-cell lymphoma, agranular CD4+ NK leukemia/lymphoma, agranular CD4+ CD56+ hematodermic neoplasm/tumor. Despite the progress made in recent years in the diagnosis and biological understanding of the disease, until 2018 there was no clear consensus regarding its treatment and the main therapeutic schemes used were based on chemotherapy regimens already used in the treatment of lymphomas, acute lymphoblastic leukemia (ALL) and/or acute myeloid leukemia (AML). In this narrative review, we address the definition and epidemiological features of BPDCN, provide the different theories on the etiopathogenesis with particular attention to the presumed cell of origin, discuss the main clinical manifestations that provide a sign of its presence, summarize the main histopathological and immunophenotypic characteristics with special attention to the most important markers, and finally, we provide some of the most effective information on the therapeutic treatment modalities of BPDCN.

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia

AbstractCD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/−VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/− 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643.

Spatial Response to Pivekimab Sunirine (IMGN632) In Vivo in a BPDCN Model

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy, which often manifests with skin lesions in addition to lymph node, blood, and bone marrow involvement. Standard of care treatments for BPDCN patients are intense chemotherapy or tagraxofusp (Elzonris®). Although many patients initially respond to standard-of-care therapies, most will eventually relapse. Overexpression of CD123 (IL-3Rα receptor) is a hallmark of BPDCN thus making this antigen an attractive target. Pivekimab sunirine is an antibody-drug-conjugate (ADC) comprised of a humanized anti-CD123 monoclonal antibody conjugated to a potent DNA-damaging agent, FGN849 via a cleavable linker. Pivekimab sunirine was granted orphan drug and Breakthrough Therapy designation and is currently being tested for the treatment of BPDCN patients as monotherapy and, as a triplet therapy in combination with azacitidine and venetoclax for the treatment of AML patients. Preclinically, pivekimab sunirine has demonstrated potent activity against BPDCN cells (Blood 2018 132:3956) and importantly, showed a favorable safety profile and promising efficacy in BPDCN patients (Hemasphere. 2022 Jun; 6 (Suppl): 1708-1709; ASH 2021, Abstract #1284). The goal of this study was to investigate the response to pivekimab sunirine in a pre-clinical model of BPDCN and to monitor spatial response in vivo. Pivekimab sunirine efficacy was evaluated in vitro on GEN2.2, a patient-derived BPDCN cell line, for 24h, 48h, or 72h at different concentrations. We observed a concentration and time-dependent efficacy at 48h or 72h of treatment with EC50s between 4pM and 12pM and between 1.3pM and 3pM respectively. Limited cytotoxicity was observed at the 24h time point. The efficacy of pivekimab sunirine was further confirmed in vivo in the GEN2.2 BPDCN model. Pivekimab sunirine treatment with either 0.024mg/kg or 0.08mg/kg doses at QWx3 (once weekly for 3 weeks) dosing regimen was able to restrain the tumor burden and significantly enhance survival compared to the vehicle group To assess spatial response to pivekimab sunirine, we utilized a bioluminescent (BLI) GEN2.2-luc model. Briefly, NSG mice were injected with 1x10 6 GEN2.2-luc cells followed by Fc receptor blockade on Day 2 for 24h. On Day 3, mice were treated with pivekimab sunirine (0.024mg/kg; QWx3) or vehicle intravenously. Organs were harvested on day 16 for the vehicle-treated group and day 30 for the pivekimab sunirine-treated group and tumor burden was assessed using luciferin. The vehicle group showed the presence of tumor cells in the bone marrow, spleen, and lungs. These results were confirmed by HES staining. Pivekimab sunirine treated mice showed no sign of tumor cells in any of the organs in BLI evaluation. HES staining confirmed the elimination of tumor cells in the lungs and the liver while few remaining tumor cells were observed in the spleen and the bone marrow. Overall, this work enabled us to validate the efficacy of pivekimab sunirine in a BPDCN model and to monitor its spatial effect. Data showed that pivekimab sunirine treatment significantly reduced tumor burden and increased survival compared to the vehicle group. Pivekimab sunirine treatment eradicated tumor cells in the lungs and the liver, while reducing the number of tumor cells in the spleen and bone marrow. Pivekimab sunirine is a potent ADC targeting CD123 and is highly efficacious against an aggressive BPDCN cell line model. This finding reinforces the importance of its use for the treatment of BPDCN patients.

Epidemiology and Survival Outcomes in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A US Population-Based Study

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematological malignancy arising from plasmacytoid dendritic cell precursors. BPDCN remains poorly understood due to its rarity, constantly changing nomenclature, and defining criteria. This study using the Surveillance, Epidemiology, and End Results Program (SEER) database is the largest and most recent population-based study in BPDCN. We aimed to determine the incidence, clinical characteristics, overall survival, and prognostic factors in BPDCN. Methods: Patients diagnosed with BPDCN from 2000-2019 were identified from the SEER 17 database using the International Classification of Disease for Oncology, 3 rd edition (ICD-O-3) code 9727. Patient characteristics, treatment, and survival information were obtained. Age-adjusted incidence rate per 100,000 population and incidence rate ratio (IRR) were calculated using SEER stat software with the year 2000 US population as the reference standard. Overall survival and prognostic factors were evaluated based on univariate survival analysis using Kaplan-Meier plot with log-rank test, and Cox proportional hazard regression model for multivariate survival analysis. All statistical analyses were conducted with a two-sided significant p value of <0.05 using SEER stat software and STATA software version 15.1. Results: A total of 844 patients with BPDCN were included in the study. The median age at diagnosis was 40 (IQR: 15-68) with majority < 20 years (32.5%) or > 60 years (34.3%) . Majority were males (68.1%) and Caucasians (83.5%). The lymph node was the most common primary site of involvement (56.6%) followed by the bone marrow (19.1%) and skin (13%). . Eighteen percent of the cohort received radiation therapy and 83.6% received chemotherapy. The overall incidence of BPDCN was found to be 0.05 cases per 100,000 population. Incidence was significantly lower in females than males (IRR 0.62, p < 0.01) and in African Americans compared to Caucasians (IRR 0.70m, p<0.01). There was no significant change in disease incidence from 2005 to 2019. Survival rates at 1 year, 2 years and 5 years were found to be 70%, 56% and 41% respectively. On univariate analysis, age > 60 years (p <0.01) and male gender (p< 0.01) was associated with significantly worse overall survival while survival did not differ by race (p=0.10). On multivariate analysis after adjusting for age, sex, race, marital status, radiation therapy, chemotherapy and disease primary site, age > 60 years (HR 2.70; 95% CI 2.01-3.54, p<0.01) and African American race (HR 1.44; 95% CI 1.01-2.04, p<0.04) was associated with worse overall survival. Conclusion: To our knowledge, this is the largest and most recent population-based study in BPDCN. Our study revealed a population level incidence of 0.05 cases per 100,000 population. Majority are Caucasian males with bimodal age distribution (<20 years and above 60 years). The lymph nodes are the most common site of involvement. Older age and African American ethnicity are negative prognostic factors for overall survival. Racial disparities in OS warrant further prognosis. More prospective studies are needed to determine disease characteristics and optimal treatment approaches for this rare life-threatening hematological malignancy.