RARE DISEASE
Blastic plasmacytoid dendritic cell neoplasm
Blastic plasmacytoid dendritic cell neoplasm
Blastic plasmacytoid dendritic cell neoplasm
Synonyms: BPDCN
Synonyms: BPDCN
Synonyms: BPDCN
Drug discovery
7
drugs
With orphan designations
Overview
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive myeloid malignancy derived from plasmacytoid dendritic cell precursors. It typically presents with cutaneous lesions (60–90% of cases), bone marrow involvement, and leukemic dissemination, often progressing rapidly to involve lymph nodes, CNS, and viscera [1][4][10]. Diagnosis relies on immunophenotyping (CD123, CD4, CD56) and biopsy [12]. Prognosis is poor, with a median survival of 8–14 months [4][9], though CD123-targeted therapy (tagraxofusp) and stem cell transplantation improve outcomes in eligible patients [7][11].
Therapies
First-line: Tagraxofusp (CD123-directed therapy) [9], acute leukemia-type chemotherapy (e.g., hyper-CVAD, AML protocols) [3][11], or lymphoma regimens (e.g., CHOP) [4].
Consolidation: Allogeneic hematopoietic stem cell transplantation in first remission for durable responses [3][7][9].
Emerging: CD123-targeted CAR-T cells, bispecific antibodies, and venetoclax combinations [7][11].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
341 drug discovery papers about Blastic plasmacytoid dendritic cell neoplasm, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
341 drug discovery papers about Blastic plasmacytoid dendritic cell neoplasm, with 1 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-15 | Anti-CD123 CAR-T therapy combined with autologous SCT and venetoclax maintenance in refractory BPDCN ineligible for allogeneic transplantation: a case report and review of the literature.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with limited therapeutic options for patients ineligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT). While CD123-targeted therapies and CAR T-cell infusion have shown promise, achieving durable remission without consolidative transplantation remains challenging. We report a pioneering "triple-integrated" consolidation strategy in a 55-year-old male with relapsed/refractory BPDCN and central nervous system involvement who lacked a suitable HLA-matched donor. After achieving a complete metabolic response with persistent bone marrow minimal residual disease (MRD) following Hyper-CVAD chemotherapy, the patient underwent high-dose conditioning and autologous stem cell transplantation (ASCT) sequentially followed by autologous CD123 CAR T-cell infusion (1.74×106/kg). The clinical course was complicated by Grade 3 cytokine release syndrome and suspected immune effector cell-associated HLH-like syndrome (IEC-HS), which were successfully managed with glucocorticoid and emapalumab. Notably, ASCT served as a "hematopoietic rescue" for CAR-T-induced prolonged cytopenia. To prevent late clonal escape, maintenance therapy with the BCL-2 inhibitor venetoclax was initiated post-transplant. The patient achieved sustained MRD-negative CR with a disease-free survival exceeding 13 months. This multimodal paradigm-combining intensive cytoreduction, targeted immunotherapy with marrow rescue, and molecular maintenance-provides a feasible and potentially curative alternative for BPDCN patients in the "no-donor" setting.
2026-07-07 | Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.
Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.
2026-06-22 | Metformin dual-targets metabolism and survival pathways in BPDCN.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with limited therapeutic options. Metformin, a commonly prescribed antidiabetic drug, has recently gained attention for its anticancer potential, but its effects on BPDCN remain unknown. Here, we show that metformin reduces cell viability and induces caspase-dependent apoptosis in both established (CAL-1, GEN2.2) and primary BPDCN cells, partly through activation of the intrinsic apoptotic pathway. Mechanistically, metformin activates AMPK and disrupts mitochondrial respiration and glycolysis, while inhibiting key oncogenic signaling pathways including Akt/mTOR, NF-κB, STAT3, and STAT5. In vivo, metformin reduces tumor cell infiltration in the spleen and modulates NF-κB and STAT5 signaling, although its effect on overall disease progression is limited. These results identify metformin as a multifaceted agent targeting both metabolic and survival pathways in BPDCN, supporting its potential as a therapeutic strategy in this rare malignancy.
2026-05-27 | A phase II trial of tagraxofusp, hyper-CVAD, and venetoclax for patients with newly diagnosed or relapsed/refractory BPDCN.
6502 Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with (w/) historically dismal outcomes, including median (med) overall survival (OS) of 8 – 12 months (mos) and frequent central nervous system (CNS) involvement (Martin-Martin Oncotarget 2016, Pemmaraju Blood 2021). Tagraxofusp (TAG; first CD123-targeted therapy approved for BPDCN) improves responses (Pemmaraju JCO 2022), but relapse remains common. Venetoclax (VEN) demonstrates activity in BPDCN (Montero Cancer Disc 2017), and intensified chemotherapy may improve outcomes. We report the results of a phase II investigator-initiated trial (NCT04216524) of TAG, Hyper-CVAD, and VEN in newly diagnosed (ND) or relapsed/refractory (R/R) BPDCN. Methods: Adults (≥18 years [yrs]) w/ ND or R/R BPDCN received: Cycle [C] 1: TAG days [d] 1-5; C2, 4, 6, 8: TAG d1 – 5 w/ VEN d2 – 14 (C2) and d1 – 7 (C4, 6, 8); C3, 7: VEN d1 – 7 w/ Hyper-CVAD or mini-hyper-CVD; C5: VEN d1 – 7 w/ high-dose methotrexate/cytarabine or mini-methotrexate/cytarabine. Cycles were 28 days for up to 8 cycles, followed by POMP, VEN, and TAG maintenance. Pts received ≥8 intrathecals. Results: Nineteen pts were enrolled (14 ND; 5 R/R). Med age was 61 yrs (range, 20 – 79); 79% male. Disease sites included 84% skin, 63% bone marrow, 16% CNS, 16% extramedullary. Co-occurring mutations were TET2 (60%), ASXL1 (33%), DNMT3A (20%), NRAS (13%), KRAS (13%). Two pts had prior/concomitant MDS. For ND, overall response rate (ORR; complete remission [CR] plus CR w/ incomplete count recovery [CRi] plus partial response [PR]) was 93% (13/14, all CR/CRi). Pts received a med of 2 (1 – 6) cycles w/ 2 (1 – 3) cycles to best response. The 30- and 60-day mortality was 0%. After a 55-mos med follow-up, (19.5 – NR), med OS was 15 mos w/ 24-month OS of 42%. Med EFS was 14.6 mos w/ 24-month EFS of 42%. Nine pts (65%) went to stem cell transplant (SCT) (2 died in CR, 6 remain alive in CR; of these, 3 remain alive in CR almost 5 yrs; with only 1 post-SCT relapse). In the 4 responding pts who did not go to SCT, 3 relapsed, 1 died in CR. For R/R, ORR was 100%; CR/CRi of 50%. Pts received a med of 2 (2 – 4) prior lines; 3 (60%) had prior SCT. Pts received a med of 3 (1 – 7) cycles w/ 3 (1 – 3) to best response. Two pts went to SCT (1 auto, 1 allo); 1 pt is alive on active treatment. The 30- and 60-day mortality was 0% and 20%. With f/u ranging 1.4 – 21.8 mos, med OS and EFS is 8.9 mos; 12-month OS and EFS was 30%. In responding pts, causes of death were progression n = 4; died in CR n = 5 (3 ND, 2 R/R, 1 post SCT, 1 unknown, 3 sepsis). The most common any grade adverse events (AE) were edema (n = 13) and fatigue (n = 11). There were 2 grade 5 AE (progression, respiratory failure). Two grade 3 capillary leak events were observed. Conclusions: As frontline therapy, TAG with Hyper-CVAD, and VEN shows promising safety with no early mortality or high-grade CLS, with high response rates enabling frequent SCT consolidation and no CNS relapse. Clinical trial information: NCT04216524 .
2026-05-18 | Case Report: Tumor-related hemorrhage determined treatment sequencing in blastic plasmacytoid dendritic cell neoplasm coexisting with gastric cardia adenocarcinoma.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy that commonly presents with skin involvement and may also involve the bone marrow, peripheral blood, and lymph nodes. The coexistence of BPDCN with a primary solid tumor is extremely uncommon and poses substantial diagnostic and therapeutic challenges. We report a 70-year-old man who was first diagnosed with BPDCN after excision of a left forearm lesion and later developed recurrent hematemesis during chemotherapy. Subsequent endoscopic evaluation revealed a bleeding cardia lesion, and repeat biopsy confirmed poorly differentiated gastric cardia adenocarcinoma. After multidisciplinary evaluation, radical gastrectomy was performed first to control tumor-related bleeding, after which systemic chemotherapy for BPDCN was resumed. This case suggests that, in BPDCN patients who develop hematemesis, progressive anemia, or weight loss during treatment, prompt evaluation for a second primary gastrointestinal malignancy is warranted, and control of active tumor-related bleeding may need to precede hematologic therapy.
cell therapies
2026-06-01 | LY09 Disease status at haematopoietic stem cell transplantation, including skin-limited disease, and survival in blastic plasmacytoid dendritic cell neoplasm: a retrospective, multicentre cohort study of the European Organisation for Research and Treatment of Cancer, Cutaneous Lymphoma Tumour Group
Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive haematological malignancy commonly involving the skin. Haematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment, yet the prognostic relevance of skin-limited disease and disease status at HSCT remains unclear. We aimed to evaluate the association between HSCT and survival in BPDCN, and to assess whether disease status at transplantation provides prognostically relevant information. We performed a retrospective multicentre cohort study across 10 European tertiary centres. Patients diagnosed with BPDCN from 2008 onward were included. Overall survival was analysed using Kaplan–Meier methods and Cox regression, with HSCT modelled as a time-dependent covariate to account for immortal time bias. Post-transplant survival was assessed according to disease status at HSCT. Forty-seven patients were included (median age 60 years, 74% male), of whom 26 (55%) underwent HSCT. In time-dependent Cox analysis, HSCT was strongly associated with improved overall survival (adjusted hazard ratio 0.17, 95% confidence interval 0.05–0.55; P = 0.003). Among transplanted patients, those transplanted in complete remission or with skin-limited residual disease tended to have better post-transplant outcomes than those with active systemic disease. In this pan-European real-world cohort, HSCT was associated with improved survival in BPDCN when analysed using a time-dependent approach. Disease status at the time of transplantation, rather than initial disease presentation, appears to provide clinically relevant prognostic information and supports the importance of achieving deep remission before HSCT whenever feasible.
2026-03-16 | Automated manufacturing of clinical-grade BDCA2 CAR NK cells in a closed system for the treatment of blastic plasmacytoid dendritic cell neoplasm.
Recent progress in chimeric antigen receptor (CAR) natural killer (NK) cell therapy has demonstrated their promising potential in cancer immunotherapy. However, most current CAR NK cell manufacturing processes utilize open systems with multiple manual steps, making it challenging to maintain consistent therapeutic quality and regulatory compliance for clinical applications. We specifically developed blood dendritic cell antigen 2 (BDCA2)-targeting CAR NK cells for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). Here, we present an automated, current good manufacturing practice (cGMP)-compliant Natural Killer Cell Transduction (NKCT) process for producing clinical-grade CAR NK cells on the CliniMACS Prodigy® platform. This closed system integrates cell separation, activation, transduction, expansion, and harvest, thereby reducing contamination risks and ensuring cell product quality. The NKCT process achieved high transduction efficiency using baboon envelope pseudotyped lentiviral vectors (BaEV-LV) produced under cGMP conditions combined with Vectofusin®-1, yielding CAR NK cells with high viability and purity. Both in vitro and in vivo studies demonstrated the potent antitumor activity of CliniMACS Prodigy-manufactured BDCA2 CAR NK cells, highlighting a promising treatment strategy for BPDCN. In summary, this automated NKCT process enables both centralized and decentralized CAR NK manufacturing and facilitates the efficient clinical translation of CAR NK cell therapies.
2026-01-17 | Paediatric blastic plasmacytoid dendritic cell neoplasm: a single-centre case series of 18 children and review of the literature.
The incidence of paediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is extremely low, and little is known about the disease. This study aims to investigate its clinical course and optimal management. We retrospectively analysed the clinical manifestations, laboratory findings, treatment responses, and survival outcomes of 18 paediatric patients with BPDCN treated at our hospital. In this cohort, the male-to-female ratio was 2.6, and the median age of onset was 12 years. Bone marrow involvement was observed in 88.9% of patients (16/18), making it the most commonly affected site, followed by the skin (13/18) and lymph nodes (13/18). Central nervous system infiltration occurred in the youngest patient (Case 13), who experienced relapse after matched sibling donor haematopoietic stem cell transplantation (MSD-HSCT). Immunohistochemical and flow cytometry analyses revealed a distinct immunophenotype, with high expression of CD4 (94.4%), CD56 (100%), CD123 (100%), CD304 (100%), and HLA-DR (100%), and no expression of myeloperoxidase and CD19. In terms of the initial response, 14 patients received acute lymphoblastic leukaemia (ALL)-like regimens, all of whom achieved complete remission (CR) after induction chemotherapy. All 18 patients proceeded to HSCT post-chemotherapy, including 15 haploidentical and 3 MSD transplants. The 4-year overall survival (OS) and event-free survival (EFS) rates for the entire cohort were 94.4% ± 5.4% (95% CI, 83.8%-100.0%) and 87.7% ± 8.2% (95% CI, 71.6%-100.0%), respectively. Paediatric patients with BPDCN who receive allogeneic HSCT-particularly haploidentical HSCT-during CR following ALL-like induction chemotherapy appear to have favorable outcomes in this limited cohort.
2025-10-16 | Clinico-hematopathologic and Genetic Characteristics of Korean Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm: A Retrospective Single-Center Cohort Study.
Blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are rare and aggressive hematologic malignancies with poorly defined molecular characteristics. Genetic data for Korean patients with this condition are scarce. We conducted the first network-based analysis of Korean patients with BPDCN, using next-generation sequencing (NGS) alongside clinical, morphological, and cytogenetic evaluations. We included 14 patients diagnosed with BPDCN between 2004 and 2021. Clinical, morphological, and cytogenetic data were collected. Conventional karyotyping and targeted NGS were performed. Network analysis was used to link gene variants with known BPDCN-associated genes. The median age at diagnosis was 52 yrs; the male:female ratio was 1.8:1. Cutaneous and bone marrow (BM) involvement were observed in 79% and 57% of patients at diagnosis, respectively; 85% of those not lost to follow-up eventually showed BM involvement. Allogeneic hematopoietic stem cell transplantation was associated with longer survival compared with chemotherapy alone (P=0.015). Complex karyotypes were common (87%), with novel chromosomal deletions at 1p, 18q, and 22q. BPDCN samples showed recurrent variations in TET2, ASXL1, and RAS-pathway genes, as well as novel variations in 22 genes, including SMARCD2, DDX3X, and GNB1. Network analysis revealed functional associations between these novel alterations and established BPDCN-related genes. We present the first network-based analysis of Korean patients with BPDCN, along with conventional genetic assessments, highlighting the potential genetic drivers of BPDCN and facilitating the development of targeted therapies for the disease.
2025-10-15 | [Analysis of 7 cases of childhood blastic plasmacytoid dendritic cell neoplasm].
Objective: To evaluate the clinical characteristics, pathology, treatment, and prognosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in children. Methods: Clinical data (including gender, age of disease onset, affected sites, treatment, timing of allogeneic hematopoietic stem cell transplantation (allo-HSCT), etc.) of 7 children with BPDCN who were admitted to Beijing Children's Hospital, Capital Medical University from December 2018 to December 2023 were analyzed retrospectively. Clinical outcomes were also assessed, with patients followed up until December 2024. Results: Among 7 patients, there were 3 males and 4 females. Age at disease onset ranged from 3.2 to 12.9 years. Initial presentations included subcutaneous nodules in 5 cases, rash in 1 case, and ankle pain in 1 case. Extra-cutaneous involvement was seen in the bone marrow, lymph nodes, and central nervous system. six patients received induction chemotherapy using a modified Lymphoblastic lymphoma LBL regimen, 1 patient received the high-risk protocol for pediatric lymphoblastic lymphoma/leukemia and salvage therapy regimens. Allo-HSCT was performed soon after chemotherapy remission. The time to bridge allo-HSCT was 3.5 to 6.5 months. The follow-up time was 1.6 to 6.0 years. Six patients were in disease-free survival, while one patient survived with disease after recurrence following transplantation. Conclusions: BPDCN is rare in children and presents were with diverse clinical manifestations, with skin involvement being the predominant feature. Early allo-HSCT following complete remission with chemotherapy can improve prognosis.
antibodies
2026-01-05 | Hematopoietic effects of tagraxofusp in treatment-naive patients with blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic neoplasm that expresses CD123, is often observed in the bone marrow (BM), as well as skin, blood, and viscera. Tagraxofusp, a first-in-class CD123-targeted therapy, is the only drug approved to treat BPDCN. The authors conducted a post hoc analysis of the pivotal phase 2 trial to evaluate hematopoietic and BM effects of first-line tagraxofusp treatment (12 µg/kg per day on days 1-5 of a 21-day cycle) over time. This trial was registered at www. gov (ClinicalTrials.gov identifier NCT02113982). Of 66 treatment-naive patients in this analysis, 32 had baseline BM disease, and 34 had no BM disease. Over the course of tagraxofusp monotherapy treatment, neutrophil levels restored to normal, mirrored by a decreasing incidence of neutropenia and granulocyte-colony-stimulating factor administration from baseline with each cycle of treatment. Similarly, platelet counts recovered during treatment, whereas thrombocytopenia incidence and requirement for platelet transfusions decreased from baseline. Hemoglobin levels improved during tagraxofusp treatment, correlating with a decrease in the incidence of anemia and the number of transfusions from baseline. By cycle 2, all patients had peripheral blast clearance regardless of BM status. Patients with BM disease who did or did not achieve a complete response/clinical complete response during treatment experienced similar restoration of hematopoiesis, including peripheral blast eradication. These findings demonstrate the on-target effect and unique BM-sparing profile of tagraxofusp, which are paramount when treating myelosuppressive, CD123-positive hematologic diseases. The results support single-agent tagraxofusp as standard-of-care, nonmyelosuppressive first-line treatment for BPDCN and as a potential combination partner for other CD123-positive hematologic malignancies.
2025-12-25 | The role of targeted therapies in blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an ultra-rare disease that arises from malignant precursor dendritic cells. Historically, there was no uniform standard-of-care chemotherapy. In this setting, outcomes were substandard, especially for patients not eligible for intensive chemotherapy, clinical trials, and/or hematopoietic stem cell transplantation, which constituted the majority of patients. The development of targeted therapy, namely the anti-CD123 agent tagraxofusp, marked the beginning of a new era in the treatment of BPDCN. This review summarizes current targeted therapies in BPDCN, highlights recent therapeutic strategies and emerging approaches with the potential to improve patient outcomes. We also discuss key barriers to clinical implementation, including adverse events associated with anti-CD123-directed therapies and limitations related to treatment cost and accessibility. The approval of tagraxofusp established a foundation for targeted therapy in BPDCN and demonstrated high response rates, leading to the development of additional antibody - drug conjugates and cellular therapies targeting CD123. Other promising investigational targeted approaches may include BCL2 inhibitors, proteasome inhibitors, and therapies directed against surface antigens such as CD38 and CD303, as well as bromodomain and extraterminal (BET) inhibitors. Collectively, these strategies represent important advances that may significantly improve the historically poor outcomes associated with BPDCN.
2025-12-06 | A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma.
Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; n = 34) or ciltacabtagene autoleucel (Cilta-cel; n = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4+ cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8+ T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease. Greater reductions in soluble BCMA correlate with enhanced CAR T expansion and systemic inflammation. These findings reveal cellular mechanisms driving differential efficacy and toxicity of BCMA-directed immunotherapy.
2025-11-12 | Multi-organ single-cell analysis reveals PLD4 as a biomarker and potential therapeutic target of blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy originating from precursors of plasmacytoid dendritic cells. This study aimed to understand the relationship between malignant clones in different tissues and determine new biomarkers to improve the management of BPDCN. We conducted a comprehensive analysis by integrating single-cell transcriptomic data from bone marrow (BM)-derived cells, peripheral blood mononuclear cells (PBMCs), and skin-derived cells from one BPDCN patient and matched healthy controls (HCs). Validation was performed in two independent cohorts consisting of 12 BPDCN patients and control groups, including common skin tumors, cutaneous lymphomas, inflammatory skin diseases and HCs. Our study revealed that malignant cells in the skin exhibited greater maturity and differentiation compared with those from BMs, suggesting that the BM is a more likely origin for BPDCN. Additionally, malignant cells across different tissues in the BPDCN patient displayed significant transcriptional heterogeneity. The multiplex immunohistochemistry (mIHC) analysis revealed that the expression of PLD4 was significantly elevated in the dermis of BPDCN patients compared with the control groups. Furthermore, most PLD4-positive cells were found to co-localize with CD123 in BPDCN skin lesions. This study suggested a potential clonal origin of tumor cells, and revealed the transcriptional heterogeneity among malignant cells across different tissues in BPDCN. PLD4 was identified as a specific marker of malignant cells, aiding in the diagnosis of BPDCN and showing potential as a therapeutic target.
2025-09-12 | CD123‐Targeted Therapy to Achieve Negative Measurable Residual Disease in Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm Prior to Transplantation
The authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
proteins
2026-08-12 | Longer survival and favorable healthcare resource utilization of tagraxofusp versus venetoclax in patients with blastic plasmacytoid dendritic cell neoplasm: results of a real-world analysis
Background Tagraxofusp is a first-in-class CD123-targeted therapy approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN). Although venetoclax is not approved for BPDCN, limited use has been reported. We evaluated overall survival (OS) and healthcare resource utilization in patients with BPDCN treated with tagraxofusp- or venetoclax-based regimens in a US real-world setting. Methods Claims data were analyzed from patients with ≥1 BPDCN diagnosis (January 2016-December 2023) and initiation of tagraxofusp- or venetoclax-based therapy. Index date was defined as first inpatient tagraxofusp dosing or venetoclax-based therapy initiation. Patients were matched 1:1 by line of therapy (LOT). Results Each cohort had 47 patients. Tagraxofusp-based treatment was associated with longer median OS versus venetoclax-based (35.3 vs 10.5 months), consistent across patients receiving monotherapy, combination, or transplantation. Tagraxofusp-treated patients were more likely to proceed to subsequent LOT versus venetoclax-treated (47% vs 11%). During months 2-6, tagraxofusp reduced median inpatient hospitalization duration (3 vs 7 days) and transfusion rates (3% vs 32%) versus venetoclax. Conclusion In this retrospective claims-based analysis, tagraxofusp was associated with longer survival versus venetoclax, including across treatment contexts. These real-world results are consistent with the established role of tagraxofusp as the first-line standard of care for patients with BPDCN, irrespective of transplant eligibility, and support continued evaluation of tagraxofusp-based regimens as a backbone for future combinations.
2026-07-18 | Abstract B038: Multi-omic Analyses in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Tagraxofusp
Abstract Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematologic malignancy with mixed cellular states encompassing dendritic, myeloid, and lymphoid features. Presentation of BPDCN is heterogeneous, starting predominantly in the skin before spreading to other sites such as the bone marrow and lymph nodes. Based on the overexpression of IL3RA/CD123 in BPDCN patients, a CD123-targeted therapy, tagraxofusp, comprised of recombinant IL-3 with diphtheria toxin payload, was developed that has improved outcomes and prolonged survival. We conducted gene panel and single-cell RNA profiling in parallel on pre- and multiple on-treatment bone marrow aspirates from 12 BPDCN patients enrolled in the pivotal Phase II trial of tagraxofusp (NCT02113982) to identify molecular determinants of response. Residual tumor cell detected post-tagraxofusp treatment expressed lower levels of TXNRD1, which was expected to reduce the efficacy of the diphtheria toxin payload. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp treatement. Responders had either wildtype or missense TET2 mutations whereas transient and non-responders had at least one truncating TET2 mutation, consistent with our previous report that these truncating TET2 mutations portend worse overall survival to multiple types of treatment. Our in vitro results demonstrate that missense and truncating TET2 mutants displayed reduced sensitivities to tagraxofusp and hypomethylating agents. In addition, TET2 mutants delayed S-phase progression in CAL-1 cells, possibly implicating TET2 in genomic instability. Analysis of an independent cohort of BPDCN epigenetic data suggests that TET2 mutation status may not determine global methylation profiles. However, we uncovered a differentially methylated region in TXNRD1 with significantly lower beta values in samples with TET2 truncating mutations as compared to TET2 wildtype/missense samples. This region is an alternative start site in TXNRD1 and decreased CpG methylation is associated with reduced TXNRD1 gene expression in bone marrow, but not skin samples. Our single-cell data patient cohort of bone marrow samples suggests that cells with low TET2 expression also have low levels of TXNRD1. Together, these results suggest that there are tiers of molecular determinants of response to tagraxofusp. First, intrinsic TET2 truncating mutations may be prognostic rather than predictive determinant of response, likely acting through broad alterations to the epigenetic landscape. Second, reduced TXNRD1 expression directly diminishes translocation of the diphtheria toxin into the cytosol and represents a dynamic, on-treatment reduction in diphtheria toxin payload efficacy. Citation Format: Hannah C. Beird, Sankaranarayanan C. Kannan, Jingjing Liu, Janice Chen, Arturo Olguin, Marcos C. Estecio, Axel Künstner, Jennifer L. Cotton, Marina Konopleva, Phillip Andrew. Futreal, Naveen C. Pemmaraju. Multi-omic Analyses in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Tagraxofusp [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B038.
2026-06-24 | Tagraxofusp in adult blastic plasmacytoid dendritic cell neoplasm: clinical trials and real-world outcomes: a systematic review.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy. Tagraxofusp, a CD123-directed cytotoxin, was approved based on phase I/II data, and subsequent studies have expanded evidence across trial and real-world settings. We systematically searched PubMed, Scopus, and Google Scholar for English-language human studies through January 25, 2026. We included adults (≥18 years) with BPDCN treated with tagraxofusp who reported efficacy and/or safety outcomes; abstracts without extractable data, narrative reviews, expert guidance, pediatric-only studies, and preclinical studies were excluded. Twenty-seven studies were included, representing 343 unique adult patients treated with tagraxofusp after adjustment for overlapping analyses from the pivotal NCT02113982 trial program. Frontline trials reported overall response rates (ORR) of 71%-90% with CR/CRc rates of 56%-72%. Real-world cohorts showed ORR of 65%-90% and highlighted superior survival among patients bridged to allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome (CLS) was the defining toxicity, with variable incidence across clinical trials and observational cohorts. Tagraxofusp demonstrates consistent remission-inducing activity in adults with BPDCN across prospective and real-world settings. Long-term survival appears strongly influenced by successful bridging to HSCT. Evidence remains predominantly non-randomized, underscoring the need for comparative and combination studies.
2026-06-08 | Table 2_Tagraxofusp in adult blastic plasmacytoid dendritic cell neoplasm: clinical trials and real-world outcomes: a systematic review.docx
Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy. Tagraxofusp, a CD123-directed cytotoxin, was approved based on phase I/II data, and subsequent studies have expanded evidence across trial and real-world settings. Methods We systematically searched PubMed, Scopus, and Google Scholar for English-language human studies through January 25, 2026. We included adults (≥18 years) with BPDCN treated with tagraxofusp who reported efficacy and/or safety outcomes; abstracts without extractable data, narrative reviews, expert guidance, pediatric-only studies, and preclinical studies were excluded. Results Twenty-seven studies were included, representing 343 unique adult patients treated with tagraxofusp after adjustment for overlapping analyses from the pivotal NCT02113982 trial program. Frontline trials reported overall response rates (ORR) of 71%–90% with CR/CRc rates of 56%–72%. Real-world cohorts showed ORR of 65%–90% and highlighted superior survival among patients bridged to allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome (CLS) was the defining toxicity, with variable incidence across clinical trials and observational cohorts. Conclusions Tagraxofusp demonstrates consistent remission-inducing activity in adults with BPDCN across prospective and real-world settings. Long-term survival appears strongly influenced by successful bridging to HSCT. Evidence remains predominantly non-randomized, underscoring the need for comparative and combination studies.
2026-05-14 | Blastic Plasmacytoid Dendritic Cell Neoplasm in the Era of Targeted Therapies
Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, characterized by the involvement of multiple organs, including the skin, bone marrow and blood, lymph nodes and the central nervous system. According to tumor location, the disease is classified as skin-only, systemic-only, and skin and systemic. The cutaneous manifestations of disease are typical and are represented by violaceous single tumors or multiple plaques present in sun-exposed cutaneous areas. BPDCN is issued from the malignant transformation of dendritic cell progenitors and is diagnosed using the classical immunophenotypes CD123, CD4 and CD56 in addition to specific membrane markers of plasmocytoid dendritic cells. BPDCN is an aggressive disease and is associated with a short survival. Upfront therapies involve either chemotherapy regimens in fit patients and CD123-targeted therapies, including interleukin-3 conjugated with diphtheria toxin (Tagraxofusp, SL-401), or Pivekimab sunirine, an anti-IL-3R-drug conjugate, for both fit and unfit patients. Targeted treatments limit the toxicities of chemotherapy and allow the bridging of a consistent proportion of patients to hematopoietic stem cell transplantation, the only treatment associated with potential long-term survival.
small molecules
2026-08-15 | Anti-CD123 CAR-T therapy combined with autologous SCT and venetoclax maintenance in refractory BPDCN ineligible for allogeneic transplantation: a case report and review of the literature.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with limited therapeutic options for patients ineligible for allogeneic hematopoietic stem cell transplantation (allo-HSCT). While CD123-targeted therapies and CAR T-cell infusion have shown promise, achieving durable remission without consolidative transplantation remains challenging. We report a pioneering "triple-integrated" consolidation strategy in a 55-year-old male with relapsed/refractory BPDCN and central nervous system involvement who lacked a suitable HLA-matched donor. After achieving a complete metabolic response with persistent bone marrow minimal residual disease (MRD) following Hyper-CVAD chemotherapy, the patient underwent high-dose conditioning and autologous stem cell transplantation (ASCT) sequentially followed by autologous CD123 CAR T-cell infusion (1.74×106/kg). The clinical course was complicated by Grade 3 cytokine release syndrome and suspected immune effector cell-associated HLH-like syndrome (IEC-HS), which were successfully managed with glucocorticoid and emapalumab. Notably, ASCT served as a "hematopoietic rescue" for CAR-T-induced prolonged cytopenia. To prevent late clonal escape, maintenance therapy with the BCL-2 inhibitor venetoclax was initiated post-transplant. The patient achieved sustained MRD-negative CR with a disease-free survival exceeding 13 months. This multimodal paradigm-combining intensive cytoreduction, targeted immunotherapy with marrow rescue, and molecular maintenance-provides a feasible and potentially curative alternative for BPDCN patients in the "no-donor" setting.
2026-07-07 | Decreased TXNRD1 is associated with resistance to tagraxofusp in blastic plasmacytoid dendritic cell neoplasms, as seen in phase II.
Tagraxofusp is a CD123-targeted therapy comprised of a recombinant human interleukin-3 (IL-3) fused to a truncated diphtheria toxin payload. It is the first approved treatment specifically for patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). To identify biomarkers of response, bone marrow samples from 12 BPDCN patients who were treated with tagraxofusp in the pivotal phase II trial (NCT02113982) were profiled longitudinally using a gene panel and single-cell RNA sequencing. Residual tumor cells following tagraxofusp expressed lower levels of TXNRD1 that would reduce the efficacy of tagraxofusp. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp. Responders had either wild-type or missense TET2 mutations, while transient and non-responders had at least one truncating TET2 mutation. Examples of these mutations within the catalytic domain of TET2 were constructed and transduced into cells. Missense and truncating mutants displayed reduced sensitivities to hypomethylating agents and prolonged S-phase stasis. These results suggest that the levels of TXNRD1 interact with intrinsic TET2 truncating mutations within the bone marrow to modulate patient response to tagraxofusp.
2026-06-22 | Metformin dual-targets metabolism and survival pathways in BPDCN.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with limited therapeutic options. Metformin, a commonly prescribed antidiabetic drug, has recently gained attention for its anticancer potential, but its effects on BPDCN remain unknown. Here, we show that metformin reduces cell viability and induces caspase-dependent apoptosis in both established (CAL-1, GEN2.2) and primary BPDCN cells, partly through activation of the intrinsic apoptotic pathway. Mechanistically, metformin activates AMPK and disrupts mitochondrial respiration and glycolysis, while inhibiting key oncogenic signaling pathways including Akt/mTOR, NF-κB, STAT3, and STAT5. In vivo, metformin reduces tumor cell infiltration in the spleen and modulates NF-κB and STAT5 signaling, although its effect on overall disease progression is limited. These results identify metformin as a multifaceted agent targeting both metabolic and survival pathways in BPDCN, supporting its potential as a therapeutic strategy in this rare malignancy.
2026-05-27 | A phase II trial of tagraxofusp, hyper-CVAD, and venetoclax for patients with newly diagnosed or relapsed/refractory BPDCN.
6502 Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy with (w/) historically dismal outcomes, including median (med) overall survival (OS) of 8 – 12 months (mos) and frequent central nervous system (CNS) involvement (Martin-Martin Oncotarget 2016, Pemmaraju Blood 2021). Tagraxofusp (TAG; first CD123-targeted therapy approved for BPDCN) improves responses (Pemmaraju JCO 2022), but relapse remains common. Venetoclax (VEN) demonstrates activity in BPDCN (Montero Cancer Disc 2017), and intensified chemotherapy may improve outcomes. We report the results of a phase II investigator-initiated trial (NCT04216524) of TAG, Hyper-CVAD, and VEN in newly diagnosed (ND) or relapsed/refractory (R/R) BPDCN. Methods: Adults (≥18 years [yrs]) w/ ND or R/R BPDCN received: Cycle [C] 1: TAG days [d] 1-5; C2, 4, 6, 8: TAG d1 – 5 w/ VEN d2 – 14 (C2) and d1 – 7 (C4, 6, 8); C3, 7: VEN d1 – 7 w/ Hyper-CVAD or mini-hyper-CVD; C5: VEN d1 – 7 w/ high-dose methotrexate/cytarabine or mini-methotrexate/cytarabine. Cycles were 28 days for up to 8 cycles, followed by POMP, VEN, and TAG maintenance. Pts received ≥8 intrathecals. Results: Nineteen pts were enrolled (14 ND; 5 R/R). Med age was 61 yrs (range, 20 – 79); 79% male. Disease sites included 84% skin, 63% bone marrow, 16% CNS, 16% extramedullary. Co-occurring mutations were TET2 (60%), ASXL1 (33%), DNMT3A (20%), NRAS (13%), KRAS (13%). Two pts had prior/concomitant MDS. For ND, overall response rate (ORR; complete remission [CR] plus CR w/ incomplete count recovery [CRi] plus partial response [PR]) was 93% (13/14, all CR/CRi). Pts received a med of 2 (1 – 6) cycles w/ 2 (1 – 3) cycles to best response. The 30- and 60-day mortality was 0%. After a 55-mos med follow-up, (19.5 – NR), med OS was 15 mos w/ 24-month OS of 42%. Med EFS was 14.6 mos w/ 24-month EFS of 42%. Nine pts (65%) went to stem cell transplant (SCT) (2 died in CR, 6 remain alive in CR; of these, 3 remain alive in CR almost 5 yrs; with only 1 post-SCT relapse). In the 4 responding pts who did not go to SCT, 3 relapsed, 1 died in CR. For R/R, ORR was 100%; CR/CRi of 50%. Pts received a med of 2 (2 – 4) prior lines; 3 (60%) had prior SCT. Pts received a med of 3 (1 – 7) cycles w/ 3 (1 – 3) to best response. Two pts went to SCT (1 auto, 1 allo); 1 pt is alive on active treatment. The 30- and 60-day mortality was 0% and 20%. With f/u ranging 1.4 – 21.8 mos, med OS and EFS is 8.9 mos; 12-month OS and EFS was 30%. In responding pts, causes of death were progression n = 4; died in CR n = 5 (3 ND, 2 R/R, 1 post SCT, 1 unknown, 3 sepsis). The most common any grade adverse events (AE) were edema (n = 13) and fatigue (n = 11). There were 2 grade 5 AE (progression, respiratory failure). Two grade 3 capillary leak events were observed. Conclusions: As frontline therapy, TAG with Hyper-CVAD, and VEN shows promising safety with no early mortality or high-grade CLS, with high response rates enabling frequent SCT consolidation and no CNS relapse. Clinical trial information: NCT04216524 .
2026-05-18 | Case Report: Tumor-related hemorrhage determined treatment sequencing in blastic plasmacytoid dendritic cell neoplasm coexisting with gastric cardia adenocarcinoma.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive hematologic malignancy that commonly presents with skin involvement and may also involve the bone marrow, peripheral blood, and lymph nodes. The coexistence of BPDCN with a primary solid tumor is extremely uncommon and poses substantial diagnostic and therapeutic challenges. We report a 70-year-old man who was first diagnosed with BPDCN after excision of a left forearm lesion and later developed recurrent hematemesis during chemotherapy. Subsequent endoscopic evaluation revealed a bleeding cardia lesion, and repeat biopsy confirmed poorly differentiated gastric cardia adenocarcinoma. After multidisciplinary evaluation, radical gastrectomy was performed first to control tumor-related bleeding, after which systemic chemotherapy for BPDCN was resumed. This case suggests that, in BPDCN patients who develop hematemesis, progressive anemia, or weight loss during treatment, prompt evaluation for a second primary gastrointestinal malignancy is warranted, and control of active tumor-related bleeding may need to precede hematologic therapy.
cell therapies
2026-06-01 | LY09 Disease status at haematopoietic stem cell transplantation, including skin-limited disease, and survival in blastic plasmacytoid dendritic cell neoplasm: a retrospective, multicentre cohort study of the European Organisation for Research and Treatment of Cancer, Cutaneous Lymphoma Tumour Group
Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive haematological malignancy commonly involving the skin. Haematopoietic stem cell transplantation (HSCT) is the only potentially curative treatment, yet the prognostic relevance of skin-limited disease and disease status at HSCT remains unclear. We aimed to evaluate the association between HSCT and survival in BPDCN, and to assess whether disease status at transplantation provides prognostically relevant information. We performed a retrospective multicentre cohort study across 10 European tertiary centres. Patients diagnosed with BPDCN from 2008 onward were included. Overall survival was analysed using Kaplan–Meier methods and Cox regression, with HSCT modelled as a time-dependent covariate to account for immortal time bias. Post-transplant survival was assessed according to disease status at HSCT. Forty-seven patients were included (median age 60 years, 74% male), of whom 26 (55%) underwent HSCT. In time-dependent Cox analysis, HSCT was strongly associated with improved overall survival (adjusted hazard ratio 0.17, 95% confidence interval 0.05–0.55; P = 0.003). Among transplanted patients, those transplanted in complete remission or with skin-limited residual disease tended to have better post-transplant outcomes than those with active systemic disease. In this pan-European real-world cohort, HSCT was associated with improved survival in BPDCN when analysed using a time-dependent approach. Disease status at the time of transplantation, rather than initial disease presentation, appears to provide clinically relevant prognostic information and supports the importance of achieving deep remission before HSCT whenever feasible.
2026-03-16 | Automated manufacturing of clinical-grade BDCA2 CAR NK cells in a closed system for the treatment of blastic plasmacytoid dendritic cell neoplasm.
Recent progress in chimeric antigen receptor (CAR) natural killer (NK) cell therapy has demonstrated their promising potential in cancer immunotherapy. However, most current CAR NK cell manufacturing processes utilize open systems with multiple manual steps, making it challenging to maintain consistent therapeutic quality and regulatory compliance for clinical applications. We specifically developed blood dendritic cell antigen 2 (BDCA2)-targeting CAR NK cells for treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). Here, we present an automated, current good manufacturing practice (cGMP)-compliant Natural Killer Cell Transduction (NKCT) process for producing clinical-grade CAR NK cells on the CliniMACS Prodigy® platform. This closed system integrates cell separation, activation, transduction, expansion, and harvest, thereby reducing contamination risks and ensuring cell product quality. The NKCT process achieved high transduction efficiency using baboon envelope pseudotyped lentiviral vectors (BaEV-LV) produced under cGMP conditions combined with Vectofusin®-1, yielding CAR NK cells with high viability and purity. Both in vitro and in vivo studies demonstrated the potent antitumor activity of CliniMACS Prodigy-manufactured BDCA2 CAR NK cells, highlighting a promising treatment strategy for BPDCN. In summary, this automated NKCT process enables both centralized and decentralized CAR NK manufacturing and facilitates the efficient clinical translation of CAR NK cell therapies.
2026-01-17 | Paediatric blastic plasmacytoid dendritic cell neoplasm: a single-centre case series of 18 children and review of the literature.
The incidence of paediatric blastic plasmacytoid dendritic cell neoplasm (BPDCN) is extremely low, and little is known about the disease. This study aims to investigate its clinical course and optimal management. We retrospectively analysed the clinical manifestations, laboratory findings, treatment responses, and survival outcomes of 18 paediatric patients with BPDCN treated at our hospital. In this cohort, the male-to-female ratio was 2.6, and the median age of onset was 12 years. Bone marrow involvement was observed in 88.9% of patients (16/18), making it the most commonly affected site, followed by the skin (13/18) and lymph nodes (13/18). Central nervous system infiltration occurred in the youngest patient (Case 13), who experienced relapse after matched sibling donor haematopoietic stem cell transplantation (MSD-HSCT). Immunohistochemical and flow cytometry analyses revealed a distinct immunophenotype, with high expression of CD4 (94.4%), CD56 (100%), CD123 (100%), CD304 (100%), and HLA-DR (100%), and no expression of myeloperoxidase and CD19. In terms of the initial response, 14 patients received acute lymphoblastic leukaemia (ALL)-like regimens, all of whom achieved complete remission (CR) after induction chemotherapy. All 18 patients proceeded to HSCT post-chemotherapy, including 15 haploidentical and 3 MSD transplants. The 4-year overall survival (OS) and event-free survival (EFS) rates for the entire cohort were 94.4% ± 5.4% (95% CI, 83.8%-100.0%) and 87.7% ± 8.2% (95% CI, 71.6%-100.0%), respectively. Paediatric patients with BPDCN who receive allogeneic HSCT-particularly haploidentical HSCT-during CR following ALL-like induction chemotherapy appear to have favorable outcomes in this limited cohort.
2025-10-16 | Clinico-hematopathologic and Genetic Characteristics of Korean Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm: A Retrospective Single-Center Cohort Study.
Blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are rare and aggressive hematologic malignancies with poorly defined molecular characteristics. Genetic data for Korean patients with this condition are scarce. We conducted the first network-based analysis of Korean patients with BPDCN, using next-generation sequencing (NGS) alongside clinical, morphological, and cytogenetic evaluations. We included 14 patients diagnosed with BPDCN between 2004 and 2021. Clinical, morphological, and cytogenetic data were collected. Conventional karyotyping and targeted NGS were performed. Network analysis was used to link gene variants with known BPDCN-associated genes. The median age at diagnosis was 52 yrs; the male:female ratio was 1.8:1. Cutaneous and bone marrow (BM) involvement were observed in 79% and 57% of patients at diagnosis, respectively; 85% of those not lost to follow-up eventually showed BM involvement. Allogeneic hematopoietic stem cell transplantation was associated with longer survival compared with chemotherapy alone (P=0.015). Complex karyotypes were common (87%), with novel chromosomal deletions at 1p, 18q, and 22q. BPDCN samples showed recurrent variations in TET2, ASXL1, and RAS-pathway genes, as well as novel variations in 22 genes, including SMARCD2, DDX3X, and GNB1. Network analysis revealed functional associations between these novel alterations and established BPDCN-related genes. We present the first network-based analysis of Korean patients with BPDCN, along with conventional genetic assessments, highlighting the potential genetic drivers of BPDCN and facilitating the development of targeted therapies for the disease.
2025-10-15 | [Analysis of 7 cases of childhood blastic plasmacytoid dendritic cell neoplasm].
Objective: To evaluate the clinical characteristics, pathology, treatment, and prognosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in children. Methods: Clinical data (including gender, age of disease onset, affected sites, treatment, timing of allogeneic hematopoietic stem cell transplantation (allo-HSCT), etc.) of 7 children with BPDCN who were admitted to Beijing Children's Hospital, Capital Medical University from December 2018 to December 2023 were analyzed retrospectively. Clinical outcomes were also assessed, with patients followed up until December 2024. Results: Among 7 patients, there were 3 males and 4 females. Age at disease onset ranged from 3.2 to 12.9 years. Initial presentations included subcutaneous nodules in 5 cases, rash in 1 case, and ankle pain in 1 case. Extra-cutaneous involvement was seen in the bone marrow, lymph nodes, and central nervous system. six patients received induction chemotherapy using a modified Lymphoblastic lymphoma LBL regimen, 1 patient received the high-risk protocol for pediatric lymphoblastic lymphoma/leukemia and salvage therapy regimens. Allo-HSCT was performed soon after chemotherapy remission. The time to bridge allo-HSCT was 3.5 to 6.5 months. The follow-up time was 1.6 to 6.0 years. Six patients were in disease-free survival, while one patient survived with disease after recurrence following transplantation. Conclusions: BPDCN is rare in children and presents were with diverse clinical manifestations, with skin involvement being the predominant feature. Early allo-HSCT following complete remission with chemotherapy can improve prognosis.
antibodies
2026-01-05 | Hematopoietic effects of tagraxofusp in treatment-naive patients with blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), an aggressive hematologic neoplasm that expresses CD123, is often observed in the bone marrow (BM), as well as skin, blood, and viscera. Tagraxofusp, a first-in-class CD123-targeted therapy, is the only drug approved to treat BPDCN. The authors conducted a post hoc analysis of the pivotal phase 2 trial to evaluate hematopoietic and BM effects of first-line tagraxofusp treatment (12 µg/kg per day on days 1-5 of a 21-day cycle) over time. This trial was registered at www. gov (ClinicalTrials.gov identifier NCT02113982). Of 66 treatment-naive patients in this analysis, 32 had baseline BM disease, and 34 had no BM disease. Over the course of tagraxofusp monotherapy treatment, neutrophil levels restored to normal, mirrored by a decreasing incidence of neutropenia and granulocyte-colony-stimulating factor administration from baseline with each cycle of treatment. Similarly, platelet counts recovered during treatment, whereas thrombocytopenia incidence and requirement for platelet transfusions decreased from baseline. Hemoglobin levels improved during tagraxofusp treatment, correlating with a decrease in the incidence of anemia and the number of transfusions from baseline. By cycle 2, all patients had peripheral blast clearance regardless of BM status. Patients with BM disease who did or did not achieve a complete response/clinical complete response during treatment experienced similar restoration of hematopoiesis, including peripheral blast eradication. These findings demonstrate the on-target effect and unique BM-sparing profile of tagraxofusp, which are paramount when treating myelosuppressive, CD123-positive hematologic diseases. The results support single-agent tagraxofusp as standard-of-care, nonmyelosuppressive first-line treatment for BPDCN and as a potential combination partner for other CD123-positive hematologic malignancies.
2025-12-25 | The role of targeted therapies in blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an ultra-rare disease that arises from malignant precursor dendritic cells. Historically, there was no uniform standard-of-care chemotherapy. In this setting, outcomes were substandard, especially for patients not eligible for intensive chemotherapy, clinical trials, and/or hematopoietic stem cell transplantation, which constituted the majority of patients. The development of targeted therapy, namely the anti-CD123 agent tagraxofusp, marked the beginning of a new era in the treatment of BPDCN. This review summarizes current targeted therapies in BPDCN, highlights recent therapeutic strategies and emerging approaches with the potential to improve patient outcomes. We also discuss key barriers to clinical implementation, including adverse events associated with anti-CD123-directed therapies and limitations related to treatment cost and accessibility. The approval of tagraxofusp established a foundation for targeted therapy in BPDCN and demonstrated high response rates, leading to the development of additional antibody - drug conjugates and cellular therapies targeting CD123. Other promising investigational targeted approaches may include BCL2 inhibitors, proteasome inhibitors, and therapies directed against surface antigens such as CD38 and CD303, as well as bromodomain and extraterminal (BET) inhibitors. Collectively, these strategies represent important advances that may significantly improve the historically poor outcomes associated with BPDCN.
2025-12-06 | A longitudinal single-cell atlas to predict outcome and toxicity after BCMA-directed CAR T cell therapy in multiple myeloma.
Chimeric antigen receptor (CAR) T cell therapies targeting B cell maturation antigen (BCMA) are transforming treatment for relapsed or refractory multiple myeloma (RRMM). We analyze 61 RRMM patients receiving idecabtagene vicleucel (Ide-cel; n = 34) or ciltacabtagene autoleucel (Cilta-cel; n = 27) and find that Cilta-cel achieves higher complete response (CR) rates (78% vs. 38%) and longer progression-free survival. Using a longitudinal single-cell multi-omics atlas of 135 blood samples, we show that Cilta-cel induces expansion of CD4+ cytotoxic T cells associated with CR and immune-related toxicities, whereas non-CR CD8+ T cells display impaired effector programs. Among non-B cells, plasmacytoid dendritic cells (pDCs) show the highest BCMA expression and BCMA-targeted agents eradicate a blastic plasmacytoid dendritic cell neoplasm line, suggesting a novel therapeutic avenue for this disease. Greater reductions in soluble BCMA correlate with enhanced CAR T expansion and systemic inflammation. These findings reveal cellular mechanisms driving differential efficacy and toxicity of BCMA-directed immunotherapy.
2025-11-12 | Multi-organ single-cell analysis reveals PLD4 as a biomarker and potential therapeutic target of blastic plasmacytoid dendritic cell neoplasm.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy originating from precursors of plasmacytoid dendritic cells. This study aimed to understand the relationship between malignant clones in different tissues and determine new biomarkers to improve the management of BPDCN. We conducted a comprehensive analysis by integrating single-cell transcriptomic data from bone marrow (BM)-derived cells, peripheral blood mononuclear cells (PBMCs), and skin-derived cells from one BPDCN patient and matched healthy controls (HCs). Validation was performed in two independent cohorts consisting of 12 BPDCN patients and control groups, including common skin tumors, cutaneous lymphomas, inflammatory skin diseases and HCs. Our study revealed that malignant cells in the skin exhibited greater maturity and differentiation compared with those from BMs, suggesting that the BM is a more likely origin for BPDCN. Additionally, malignant cells across different tissues in the BPDCN patient displayed significant transcriptional heterogeneity. The multiplex immunohistochemistry (mIHC) analysis revealed that the expression of PLD4 was significantly elevated in the dermis of BPDCN patients compared with the control groups. Furthermore, most PLD4-positive cells were found to co-localize with CD123 in BPDCN skin lesions. This study suggested a potential clonal origin of tumor cells, and revealed the transcriptional heterogeneity among malignant cells across different tissues in BPDCN. PLD4 was identified as a specific marker of malignant cells, aiding in the diagnosis of BPDCN and showing potential as a therapeutic target.
2025-09-12 | CD123‐Targeted Therapy to Achieve Negative Measurable Residual Disease in Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm Prior to Transplantation
The authors declare no conflicts of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
proteins
2026-08-12 | Longer survival and favorable healthcare resource utilization of tagraxofusp versus venetoclax in patients with blastic plasmacytoid dendritic cell neoplasm: results of a real-world analysis
Background Tagraxofusp is a first-in-class CD123-targeted therapy approved for blastic plasmacytoid dendritic cell neoplasm (BPDCN). Although venetoclax is not approved for BPDCN, limited use has been reported. We evaluated overall survival (OS) and healthcare resource utilization in patients with BPDCN treated with tagraxofusp- or venetoclax-based regimens in a US real-world setting. Methods Claims data were analyzed from patients with ≥1 BPDCN diagnosis (January 2016-December 2023) and initiation of tagraxofusp- or venetoclax-based therapy. Index date was defined as first inpatient tagraxofusp dosing or venetoclax-based therapy initiation. Patients were matched 1:1 by line of therapy (LOT). Results Each cohort had 47 patients. Tagraxofusp-based treatment was associated with longer median OS versus venetoclax-based (35.3 vs 10.5 months), consistent across patients receiving monotherapy, combination, or transplantation. Tagraxofusp-treated patients were more likely to proceed to subsequent LOT versus venetoclax-treated (47% vs 11%). During months 2-6, tagraxofusp reduced median inpatient hospitalization duration (3 vs 7 days) and transfusion rates (3% vs 32%) versus venetoclax. Conclusion In this retrospective claims-based analysis, tagraxofusp was associated with longer survival versus venetoclax, including across treatment contexts. These real-world results are consistent with the established role of tagraxofusp as the first-line standard of care for patients with BPDCN, irrespective of transplant eligibility, and support continued evaluation of tagraxofusp-based regimens as a backbone for future combinations.
2026-07-18 | Abstract B038: Multi-omic Analyses in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Tagraxofusp
Abstract Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematologic malignancy with mixed cellular states encompassing dendritic, myeloid, and lymphoid features. Presentation of BPDCN is heterogeneous, starting predominantly in the skin before spreading to other sites such as the bone marrow and lymph nodes. Based on the overexpression of IL3RA/CD123 in BPDCN patients, a CD123-targeted therapy, tagraxofusp, comprised of recombinant IL-3 with diphtheria toxin payload, was developed that has improved outcomes and prolonged survival. We conducted gene panel and single-cell RNA profiling in parallel on pre- and multiple on-treatment bone marrow aspirates from 12 BPDCN patients enrolled in the pivotal Phase II trial of tagraxofusp (NCT02113982) to identify molecular determinants of response. Residual tumor cell detected post-tagraxofusp treatment expressed lower levels of TXNRD1, which was expected to reduce the efficacy of the diphtheria toxin payload. In support of this, enzymatic inhibition of TXNRD1 resulted in higher viability of CAL-1 BPDCN cells following tagraxofusp treatement. Responders had either wildtype or missense TET2 mutations whereas transient and non-responders had at least one truncating TET2 mutation, consistent with our previous report that these truncating TET2 mutations portend worse overall survival to multiple types of treatment. Our in vitro results demonstrate that missense and truncating TET2 mutants displayed reduced sensitivities to tagraxofusp and hypomethylating agents. In addition, TET2 mutants delayed S-phase progression in CAL-1 cells, possibly implicating TET2 in genomic instability. Analysis of an independent cohort of BPDCN epigenetic data suggests that TET2 mutation status may not determine global methylation profiles. However, we uncovered a differentially methylated region in TXNRD1 with significantly lower beta values in samples with TET2 truncating mutations as compared to TET2 wildtype/missense samples. This region is an alternative start site in TXNRD1 and decreased CpG methylation is associated with reduced TXNRD1 gene expression in bone marrow, but not skin samples. Our single-cell data patient cohort of bone marrow samples suggests that cells with low TET2 expression also have low levels of TXNRD1. Together, these results suggest that there are tiers of molecular determinants of response to tagraxofusp. First, intrinsic TET2 truncating mutations may be prognostic rather than predictive determinant of response, likely acting through broad alterations to the epigenetic landscape. Second, reduced TXNRD1 expression directly diminishes translocation of the diphtheria toxin into the cytosol and represents a dynamic, on-treatment reduction in diphtheria toxin payload efficacy. Citation Format: Hannah C. Beird, Sankaranarayanan C. Kannan, Jingjing Liu, Janice Chen, Arturo Olguin, Marcos C. Estecio, Axel Künstner, Jennifer L. Cotton, Marina Konopleva, Phillip Andrew. Futreal, Naveen C. Pemmaraju. Multi-omic Analyses in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Tagraxofusp [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr B038.
2026-06-24 | Tagraxofusp in adult blastic plasmacytoid dendritic cell neoplasm: clinical trials and real-world outcomes: a systematic review.
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy. Tagraxofusp, a CD123-directed cytotoxin, was approved based on phase I/II data, and subsequent studies have expanded evidence across trial and real-world settings. We systematically searched PubMed, Scopus, and Google Scholar for English-language human studies through January 25, 2026. We included adults (≥18 years) with BPDCN treated with tagraxofusp who reported efficacy and/or safety outcomes; abstracts without extractable data, narrative reviews, expert guidance, pediatric-only studies, and preclinical studies were excluded. Twenty-seven studies were included, representing 343 unique adult patients treated with tagraxofusp after adjustment for overlapping analyses from the pivotal NCT02113982 trial program. Frontline trials reported overall response rates (ORR) of 71%-90% with CR/CRc rates of 56%-72%. Real-world cohorts showed ORR of 65%-90% and highlighted superior survival among patients bridged to allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome (CLS) was the defining toxicity, with variable incidence across clinical trials and observational cohorts. Tagraxofusp demonstrates consistent remission-inducing activity in adults with BPDCN across prospective and real-world settings. Long-term survival appears strongly influenced by successful bridging to HSCT. Evidence remains predominantly non-randomized, underscoring the need for comparative and combination studies.
2026-06-08 | Table 2_Tagraxofusp in adult blastic plasmacytoid dendritic cell neoplasm: clinical trials and real-world outcomes: a systematic review.docx
Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy. Tagraxofusp, a CD123-directed cytotoxin, was approved based on phase I/II data, and subsequent studies have expanded evidence across trial and real-world settings. Methods We systematically searched PubMed, Scopus, and Google Scholar for English-language human studies through January 25, 2026. We included adults (≥18 years) with BPDCN treated with tagraxofusp who reported efficacy and/or safety outcomes; abstracts without extractable data, narrative reviews, expert guidance, pediatric-only studies, and preclinical studies were excluded. Results Twenty-seven studies were included, representing 343 unique adult patients treated with tagraxofusp after adjustment for overlapping analyses from the pivotal NCT02113982 trial program. Frontline trials reported overall response rates (ORR) of 71%–90% with CR/CRc rates of 56%–72%. Real-world cohorts showed ORR of 65%–90% and highlighted superior survival among patients bridged to allogeneic hematopoietic stem cell transplantation (HSCT). Capillary leak syndrome (CLS) was the defining toxicity, with variable incidence across clinical trials and observational cohorts. Conclusions Tagraxofusp demonstrates consistent remission-inducing activity in adults with BPDCN across prospective and real-world settings. Long-term survival appears strongly influenced by successful bridging to HSCT. Evidence remains predominantly non-randomized, underscoring the need for comparative and combination studies.
2026-05-14 | Blastic Plasmacytoid Dendritic Cell Neoplasm in the Era of Targeted Therapies
Blastic plasmocytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, characterized by the involvement of multiple organs, including the skin, bone marrow and blood, lymph nodes and the central nervous system. According to tumor location, the disease is classified as skin-only, systemic-only, and skin and systemic. The cutaneous manifestations of disease are typical and are represented by violaceous single tumors or multiple plaques present in sun-exposed cutaneous areas. BPDCN is issued from the malignant transformation of dendritic cell progenitors and is diagnosed using the classical immunophenotypes CD123, CD4 and CD56 in addition to specific membrane markers of plasmocytoid dendritic cells. BPDCN is an aggressive disease and is associated with a short survival. Upfront therapies involve either chemotherapy regimens in fit patients and CD123-targeted therapies, including interleukin-3 conjugated with diphtheria toxin (Tagraxofusp, SL-401), or Pivekimab sunirine, an anti-IL-3R-drug conjugate, for both fit and unfit patients. Targeted treatments limit the toxicities of chemotherapy and allow the bridging of a consistent proportion of patients to hematopoietic stem cell transplantation, the only treatment associated with potential long-term survival.
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Drug Discovery Landscape
7 orphan drug designations for Blastic plasmacytoid dendritic cell neoplasm, including 3 approved therapies.
7 orphan drug designations for Blastic plasmacytoid dendritic cell neoplasm, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD123 | cell therapies | EMA | 2022-05-16 | — | INSERM UMR 1098 |
autologous T cells transduced with lentiviral vector containing a chimeric antigen receptor directed against CD123 | cell therapies | FDA | 2022-04-26 | — | INSERM UMR 1098 |
pivekimab sunirine-pvzy [Decnupaz] | antibodies | FDA | 2020-11-17 | 2026-05-27 | AbbVie Inc. |
Anti-CD123 IgG1 humanised monoclonal antibody conjugated to N1-(2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)ethyl)-N6-((S)-1-(((S)-1-((3-((((S)-8-methoxy-6-oxo-11,12,12a,13-tetrahydro-6H-benzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)-5-((((S)-8-methoxy-6-oxo-12a,13-dihydro-6Hbenzo[5,6][1,4]diazepino[1,2-a]indol-9-yl)oxy)methyl)phenyl)amino)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)adipamide | antibodies | EMA | 2020-06-26 | — | AbbVie Deutschland GmbH & Co. KG |
autologous T cells genetically modified to express CD123 specific hinge-optimized CD28-costimulatory chimeric receptor and a truncated human epidermal growth factor receptor | cell therapies | FDA | 2018-12-17 | — | Mustang Bio, Inc. |
Recombinant human interleukin-3 truncated diphtheria toxin fusion protein [ELZONRIS] | proteins | EMA | 2015-11-11 | 2021-01-13 | Stemline Therapeutics B.V. |
Tagraxofusp-erzs [ELZONRIS] | proteins | FDA | 2013-06-06 | 2018-12-21 | Stemline Therapeutics, Inc. |
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