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:
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.
2026-08-12 | 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.
2026-07-07 | 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.
2026-06-24 | 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.
2026-08-15 | 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.
2026-08-12 | 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.
2026-07-07 | 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.
2026-06-24 | 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.
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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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