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1
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Tembhare P, Chen X, Chan JKC, Wood B, Naresh KN. Fifth edition WHO classification: precursor lymphoid neoplasms, acute leukaemias of mixed or ambiguous lineage, myeloid/lymphoid neoplasms, and histiocytic and dendritic cell neoplasms, including strategies for application in resource-limited settings. J Clin Pathol 2025:jcp-2025-210135. [PMID: 40318860 DOI: 10.1136/jcp-2025-210135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/13/2025] [Indexed: 05/07/2025]
Abstract
The fifth edition of the WHO classification of haematolymphoid tumours (WHO-HEM5) introduces significant updates to the classification of acute lymphoblastic leukaemia, ALAL (including mixed phenotype acute leukaemia (MPAL)), myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK), and histiocytic and dendritic cell neoplasms, reflecting the advances in the understanding of the genetic basis of these diseases. This review provides an overview of these changes, highlighting a shift to a more refined molecular-genetic approach. The incorporation of newly recognised genetic subtypes into the classification scheme underscores the evolving landscape of these entities. Challenges in diagnosing ALAL/MPAL and MLN-TK are discussed, along with recent insights into histiocytic and dendritic cell neoplasms, including newly defined entities such as ALK-positive histiocytosis.The review also explores the practical implications of WHO-HEM5, particularly in resource-limited settings, where comprehensive molecular testing may be unavailable. While morphology and immunohistochemistry remain essential diagnostic tools, strategic use of flow cytometry and targeted fluorescence in situ hybridisation can facilitate risk-adapted classification and improve survival in regions with limited resources and therapeutic options. Future large-scale studies are necessary to establish the diagnostic and prognostic value of these newly genetically defined entities for diverse healthcare environments, and to standardise guidelines in refining disease classification and optimising patient outcomes.
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Affiliation(s)
- Prashant Tembhare
- Hematopathology Department, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Homi Bhabha National Institute, Navi Mumbai, India
| | - Xueyan Chen
- Section of Pathology, Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Laboratory Medicine & Pathology, University of Washington, Seattle, Washington, USA
| | - John K C Chan
- Pathology, Queen Elizabeth Hospital, Kowloon, Hong Kong
| | - Brent Wood
- Diagnostic Immunology & Flow Cytometry, Children's Hospital Los Angeles, Los Angeles, California, USA
| | - Kikkeri N Naresh
- Department of Laboratory Medicine & Pathology, University of Washington, Seattle, Washington, USA
- Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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2
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Sakamoto K, Takeuchi K. Diagnostic approach to blastic plasmacytoid dendritic cell neoplasm: historical perspectives and current understanding. J Clin Exp Hematop 2025; 65:1-16. [PMID: 40159280 PMCID: PMC12051425 DOI: 10.3960/jslrt.24069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 12/16/2024] [Accepted: 12/16/2024] [Indexed: 04/02/2025] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy composed of immature cells that exhibit plasmacytoid dendritic cell (pDC) differentiation. The diagnosis of BPDCN is often challenging due to its rarity and morphologic and phenotypic overlap with other hematologic malignancies, such as acute myeloid leukemia (AML). The emergence of tagraxofusp, a CD123-directed cytotoxin, and other novel therapies has underscored the importance of accurately diagnosing BPDCN. This review initially outlined the clinical and histopathological features of BPDCN, including patients with immunoblastoid morphology. Various proposed diagnostic criteria based on flow cytometry and immunohistochemistry findings were presented, highlighting critical points of caution in the diagnostic process. Strategies for detecting minimal residual disease or microinvasion in BPDCN, a significant clinical issue, were also discussed. Additionally, we reviewed the recurrent 8q24 (MYC) and MYB rearrangements observed in BPDCN, which can aid in diagnosis. Furthermore, we explored mature plasmacytoid dendritic cell proliferation (MPDCP) associated with myeloid neoplasm, which is characterized by a clonal proliferation of pDCs in cases with a defined myeloid neoplasm and may also serve as a potential differential diagnosis for BPDCN. Lastly, we discussed pDC-AML, characterized by pDC proliferation in AML cases, which can also be part of MPDCP and is often associated with frequent RUNX1 mutations. Overall, this review provides insights into BPDCN diagnosis and highlights the current challenges in its detection and differential diagnosis.
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3
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Nganya C, Bryant S, Alnakhalah A, Allen-Boswell T, Cunningham S, Kanu S, Williams A, Philio D, Dang K, Butler E, Player A. Analyses of the MYBL1 Gene in Triple Negative Breast Cancer: Evidence of Regulation of the VCPIP1 Gene and Identification of a Specific Exon Overexpressed in Tumor Cell Lines. Int J Mol Sci 2024; 26:279. [PMID: 39796135 PMCID: PMC11719811 DOI: 10.3390/ijms26010279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/20/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
Previous data show that the knockdown of the MYBL1 gene in the MDA-MB-231 cell line leads to the downregulation of VCPIP1 gene expression. In addition, MYBL1 and VCPIP1 genes are co-expressed and dysregulated in some of the same triple negative breast cancer patient samples. We propose that the co-expression of the two genes is attributed to the MYBL1 transcription factor regulation of the VCPIP1 gene. We identify the MYBL1 transcription factor binding site upstream of the VCPIP1 start site and show that the MYBL1 protein can bind to the sequence identified in the VCPIP1 promoter region. Combined with the results from the knockdown study, these data support the ability of MYBL1 to regulate the VCPIP1 gene. The VCPIP1 gene functions as a deubiquitinating enzyme involved in DNA repair, protein positioning, and the assembly of the Golgi apparatus during mitotic signaling. The transcriptional regulation of VCPIP1 by the MYBL1 gene could implicate MYBL1 in these processes, which might contribute to tumor processes in TNBC. Although both genes are involved in cell cycle regulatory mechanisms, converging signaling mechanisms have not been identified. In a separate study, we performed sequence alignment of the MYBL1 transcript variants and identified an exon unique to the canonical variant. Probes that specifically target the unique MYBL1 exon show that the exon is overexpressed in tumor cell lines compared to non-tumor breast cells. We are classifying this unique MYBL1 exon as a tumor-associated exon.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Audrey Player
- Department of Biology, Texas Southern University, Houston, TX 77004, USA; (C.N.); (S.B.); (A.A.); (T.A.-B.); (S.C.); (S.K.); (A.W.); (D.P.); (K.D.); (E.B.)
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4
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Booth CA, Bouyssou JM, Togami K, Armand O, Rivas HG, Yan K, Rice S, Cheng S, Lachtara EM, Bourquin JP, Kentsis A, Rheinbay E, DeCaprio JA, Lane AA. BPDCN MYB fusions regulate cell cycle genes, impair differentiation, and induce myeloid-dendritic cell leukemia. JCI Insight 2024; 9:e183889. [PMID: 39499902 DOI: 10.1172/jci.insight.183889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/30/2024] [Indexed: 12/21/2024] Open
Abstract
MYB fusions are recurrently found in select cancers, including blastic plasmacytoid DC neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared with other blood cancers and, in some patients, are the only obvious somatic mutation detected. This suggests that they may alone be sufficient to drive DC transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but, mechanistically, how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that, in BPDCN leukemogenesis, MYB switches from being a regulator of DC lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in patients with BPDCN increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired DC differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN.
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Affiliation(s)
- Christopher Ag Booth
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Juliette M Bouyssou
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Katsuhiro Togami
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Olivier Armand
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Hembly G Rivas
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
- Program in Virology, Graduate School of Arts and Sciences, Harvard University, Cambridge, Massachusetts, USA
| | - Kezhi Yan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Siobhan Rice
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Shuyuan Cheng
- Tow Center for Developmental Oncology, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York, USA
- Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York, USA
| | - Emily M Lachtara
- Krantz Family Center for Cancer Research, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - Jean-Pierre Bourquin
- Division of Oncology, Children's Research Center, University Children's Hospital, Zurich, Switzerland
| | - Alex Kentsis
- Tow Center for Developmental Oncology, Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USA
- Molecular Pharmacology Program, Sloan Kettering Institute, New York, New York, USA
- Departments of Pediatrics, Pharmacology, and Physiology & Biophysics, Weill Medical College of Cornell University, New York, New York, USA
| | - Esther Rheinbay
- Krantz Family Center for Cancer Research, Boston, Massachusetts, USA
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
| | - James A DeCaprio
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Andrew A Lane
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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5
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Alhalaseh Y, Krishnamurthy K, Pradhan D. Blastic Plasmacytoid Dendritic Cell Neoplasm Presenting as Solitary Violaceous Thigh Plaque: Answer. Am J Dermatopathol 2024; 46:878-879. [PMID: 39565672 DOI: 10.1097/dad.0000000000002850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Affiliation(s)
- Yazan Alhalaseh
- Department of Pathology, Loyola University Medical Center, Maywood, IL
| | | | - Dinesh Pradhan
- Department of Pathology and Dermatology, University of Nebraska Medical Center, Omaha, NE
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Hernández DC, Rueda DÁ, Rapan L, Iastrebner M, Sorrentino M. A 31-year-old male with a plasmacytoid dendritic blast cell neoplasm. Ecancermedicalscience 2024; 18:1806. [PMID: 39816397 PMCID: PMC11735132 DOI: 10.3332/ecancer.2024.1806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Indexed: 01/18/2025] Open
Abstract
Plasmacytoid blast dendritic cell neoplasm is a rare subtype of acute leukaemia that represents less than 1% of haematologic neoplasms. It is characterised by skin involvement and leukaemic dissemination in the rest of the body. The immunophenotype is represented by the expression of CD4, CD56 and CD123. Due to its low incidence, there is no standardised treatment. For most authors, acute lymphoblastic leukaemia) regimens with or without consolidation with allogeneic transplantation seem to be the most appropriate. We present the case of a 31-year-old male with a history of von Willebrand's disease, who was diagnosed with plasmacytoid blast dendritic cell neoplasm with central nervous system involvement. After receiving first-line immunopolychemotherapy with rituximab, the patient achieved complete haematologic remission with the high-dose ara-C regimen. Subsequently, he consolidated with allogeneic haploidentical transplantation.
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Affiliation(s)
| | - Darío Álvaro Rueda
- Internal Medicine Service, Sanatorio Sagrado Corazón, Buenos Aires, CP 1039, Argentina
| | - Leticia Rapan
- Bone Marrow Transplant Service, Sanatorio Sagrado Corazón, Buenos Aires, CP 1039, Argentina
| | - Marcelo Iastrebner
- Bone Marrow Transplant Service, Sanatorio Sagrado Corazón, Buenos Aires, CP 1039, Argentina
| | - Miguel Sorrentino
- Internal Medicine Service, Sanatorio Sagrado Corazón, Buenos Aires, CP 1039, Argentina
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7
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Taka M, Toyoshima S, Takamatsu S, Kobayashi S. Radiation Therapy for Cutaneous Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Report and Review of the Literature. Curr Oncol 2024; 31:7117-7128. [PMID: 39590155 PMCID: PMC11593096 DOI: 10.3390/curroncol31110524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 11/09/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from plasmacytoid dendritic cells. It commonly presents as cutaneous lesions. To date, no standard treatment protocol for BPDCN exists. Traditionally treated similarly to acute leukemia or lymphoma, its prognosis remains poor. Radiation therapy is employed for isolated skin lesions, for patients that are ineligible for chemotherapy due to age or comorbidities and for post-chemotherapy recurrence. However, very limited reports are available on radiotherapy for BPDCN. We present a case involving a 94-year-old BPDCN patient treated with radiation therapy, highlighting an atypical situation of two separate radiotherapy sessions with different dosages for isolated skin lesions. Initially, 45 Gy was administered in 15 fractions (45 Gy/15 Fr), followed by a second session of 30 Gy in 10 fractions (30 Gy/10 Fr) after disease recurrence. This case is unique in detailing radiation therapy for the exceedingly rare BPDCN, particularly dose fractionation. The findings indicate that 45 Gy/15 Fr can provide adequate local control, while even a lower dose of 30 Gy/10 Fr may be effective. This case report contributes to the limited literature by proposing potential therapeutic approaches and dosage guidelines to refine future BPDCN treatment protocols.
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Affiliation(s)
- Masashi Taka
- Department of Radiotherapy, Toyama Prefectural Central Hospital, 2-2-78, Nishinagae, Toyama City 930-8550, Japan;
| | - Shinichiro Toyoshima
- Department of Radiotherapy, Toyama Prefectural Central Hospital, 2-2-78, Nishinagae, Toyama City 930-8550, Japan;
| | - Shigeyuki Takamatsu
- Department of Radiology, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takara-machi, Kanazawa City 920-8641, Japan; (S.T.); (S.K.)
| | - Satoshi Kobayashi
- Department of Radiology, Graduate School of Medical Sciences, Kanazawa University, 13-1, Takara-machi, Kanazawa City 920-8641, Japan; (S.T.); (S.K.)
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8
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Luo Y, Wang LJ, Wang CL. Advancing the understanding and management of blastic plasmacytoid dendritic cell neoplasm: Insights from recent case studies. World J Clin Cases 2024; 12:6441-6446. [PMID: 39507120 PMCID: PMC11438698 DOI: 10.12998/wjcc.v12.i31.6441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Revised: 07/15/2024] [Accepted: 07/26/2024] [Indexed: 09/11/2024] Open
Abstract
We specifically discuss the mechanisms of the pathogenesis, diagnosis, and management of blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare but aggressive haematologic malignancy characterized by frequent skin manifestations and systemic dissemination. The article enriches our understanding of BPDCN through detailed case reports showing the clinical, immunophenotypic, and histopathological features that are critical for diagnosing this disease. These cases highlight the essential role of pathologists in employing advanced immunophenotyping techniques to accurately identify the disease early in its course and guide treatment decisions. Furthermore, we explore the implications of these findings for management strategies, emphasizing the use of targeted therapies such as tagraxofusp and the potential of allogeneic haematopoietic stem cell transplantation in achieving remission. The editorial underscores the importance of interdisciplinary approaches in managing BPDCN, pointing towards a future where precision medicine could significantly improve patient outcomes.
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Affiliation(s)
- Yan Luo
- Department of Stomatology, The People's Hospital of Dadukou District, Chongqing 400084, China
| | - Li-Juan Wang
- Department of Pathology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
| | - Cheng-Long Wang
- Department of Pathology, The Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400021, China
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9
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Suzuki K, Koyama D, Oka Y, Sato Y, Sekine R, Fukatsu M, Hayashi K, Takano M, Hashimoto Y, Ikezoe T. Myeloid sarcoma with plasmacytoid dendritic cell-like proliferation associated with IKZF1, ETV6 and DNMT3A mutations. Int J Hematol 2024; 120:382-388. [PMID: 38861243 DOI: 10.1007/s12185-024-03806-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 05/30/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
The classification of clonal plasmacytoid dendritic cell (pDC) proliferation associated with myeloid neoplasms remains a topic of ongoing debate. Although the fifth edition of the World Health Organization classification classifies clonal pDC proliferation into two categories, it is unclear whether this classification adequately captures the complexities of clonal pDC pathogenesis. We present a clinical case featuring myeloid sarcoma with pDC-like cells in cervical lymph nodes and bone marrow (BM). Analysis of biopsy specimens and BM aspirate revealed two distinct cellular populations expressing myeloid and pDC markers. One population exhibited myeloid leukemia and monocyte markers, including MPO, CD13, CD33, CD11b, and CD14, while the other manifested an immunophenotype reminiscent of pDCs, characterized by expression of CD56 and CD123. Additionally, whole exome sequencing and RNA sequencing of BM mononuclear cells were conducted to explore the pathophysiology of this rare malignancy, and unveiled pDC-like cell proliferation driven by IKZF1 and ETV6 mutations originating from clonal hematopoiesis initiated by a DNMT3A mutation. Notably, venetoclax-based therapy exhibited efficacy for achieving and sustaining complete remission. This case provides pivotal insights into the mechanistic aspects of pDC/pDC-like cell proliferation in myeloid sarcoma, offering valuable perspectives on therapeutic strategies.
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Affiliation(s)
- Kengo Suzuki
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Daisuke Koyama
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan.
| | - Yuka Oka
- Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Yuki Sato
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Rei Sekine
- Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Masahiko Fukatsu
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Kiyohito Hayashi
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Motoki Takano
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Yuko Hashimoto
- Department of Diagnostic Pathology, Fukushima Medical University, Fukushima, 960-1295, Japan
| | - Takayuki Ikezoe
- Department of Hematology, Fukushima Medical University, Fukushima, 960-1295, Japan
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10
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Künstner A, Schwarting J, Witte HM, Xing P, Bernard V, Stölting S, Lohneis P, Janke F, Salehi M, Chen X, Kusch K, Sültmann H, Chteinberg E, Fischer A, Siebert R, von Bubnoff N, Merz H, Busch H, Feller AC, Gebauer N. Genome-wide DNA methylation-analysis of blastic plasmacytoid dendritic cell neoplasm identifies distinct molecular features. Leukemia 2024; 38:1086-1098. [PMID: 38600314 DOI: 10.1038/s41375-024-02240-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/12/2024]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) constitutes a rare and aggressive malignancy originating from plasmacytoid dendritic cells (pDCs) with a primarily cutaneous tropism followed by dissemination to the bone marrow and other organs. We conducted a genome-wide analysis of the tumor methylome in an extended cohort of 45 BPDCN patients supplemented by WES and RNA-seq as well as ATAC-seq on selected cases. We determined the BPDCN DNA methylation profile and observed a dramatic loss of DNA methylation during malignant transformation from early and mature DCs towards BPDCN. DNA methylation profiles further differentiate between BPDCN, AML, CMML, and T-ALL exhibiting the most striking global demethylation, mitotic stress, and merely localized DNA hypermethylation in BPDCN resulting in pronounced inactivation of tumor suppressor genes by comparison. DNA methylation-based analysis of the tumor microenvironment by MethylCIBERSORT yielded two, prognostically relevant clusters (IC1 and IC2) with specific cellular composition and mutational spectra. Further, the transcriptional subgroups of BPDCN (C1 and C2) differ by DNA methylation signatures in interleukin/inflammatory signaling genes but also by higher transcription factor activity of JAK-STAT and NFkB signaling in C2 in contrast to an EZH2 dependence in C1-BPDCN. Our integrative characterization of BPDCN offers novel molecular insights and potential diagnostic applications.
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Affiliation(s)
- Axel Künstner
- Medical Systems Biology Group, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany
| | - Julian Schwarting
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Hanno M Witte
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
- Department of Hematology and Oncology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081, Ulm, Germany
| | - Pengwei Xing
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Veronica Bernard
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Stephanie Stölting
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Philipp Lohneis
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Florian Janke
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Maede Salehi
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Xingqi Chen
- Department of Immunology, Genetics and Pathology, Uppsala University, 751 85, Uppsala, Sweden
| | - Kathrin Kusch
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Holger Sültmann
- Division of Cancer Genome Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany
- German Cancer Consortium (DKTK), 69120, Heidelberg, Germany
| | - Emil Chteinberg
- Institute of Human Genetics Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
| | - Anja Fischer
- Institute of Human Genetics Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
| | - Reiner Siebert
- Institute of Human Genetics Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
| | - Nikolas von Bubnoff
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
| | - Hartmut Merz
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Hauke Busch
- Medical Systems Biology Group, University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany
| | - Alfred C Feller
- Hämatopathologie Lübeck, Consultation Centre for Lymph Node Pathology and Hematopathology, 23562, Lübeck, Germany
| | - Niklas Gebauer
- University Cancer Center Schleswig-Holstein, University Hospital of Schleswig-Holstein, Campus Lübeck, 23538, Lübeck, Germany.
- Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany.
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11
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Sasaki Y, Murai S, Shiozawa E, Yamochi T, Hattori N. Blastic Plasmacytoid Dendritic Cell Neoplasm in Long-Term Complete Remission After Venetoclax Monotherapy. Cureus 2024; 16:e52446. [PMID: 38371152 PMCID: PMC10871153 DOI: 10.7759/cureus.52446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/17/2024] [Indexed: 02/20/2024] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematological malignancy associated with a poor prognosis and limited treatment options. Although allogeneic hematopoietic stem cell transplantation or intensive chemotherapy prolongs overall survival in patients with BPDCN, intensive chemotherapy is inappropriate for older or unfit patients. Venetoclax (VEN), an oral BCL2 inhibitor, is approved for use in patients with acute myeloid leukemia (AML). BPDCN cells require BCL2 protein and are uniformly sensitive to VEN in vivo. Moreover, patients with AML who have achieved complete remission after induction therapy are reportedly considered to receive VEN monotherapy as maintenance therapy, especially older patients. However, the efficacy of VEN monotherapy as a maintenance therapy for patients with BPDCN remains controversial. Recently, BPDCN has been classified into MYC+ and MYC- subtypes, which show clinical differences. Hence, BPDCN treatment strategies based on the MYC classification may be necessary. Here, we report a case of MYC- BPDCN in an older patient in long-term complete remission after VEN monotherapy following VEN and azacitidine induction chemotherapy.
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Affiliation(s)
- Yohei Sasaki
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, JPN
| | - So Murai
- Department of Pathology, Showa University School of Medicine, Tokyo, JPN
| | - Eisuke Shiozawa
- Department of Pathology, Showa University School of Medicine, Tokyo, JPN
| | - Toshiko Yamochi
- Department of Pathology, Showa University School of Medicine, Tokyo, JPN
| | - Norimichi Hattori
- Division of Hematology, Department of Medicine, Showa University School of Medicine, Tokyo, JPN
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12
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Aran BM, Duran J, Whittemore D, Gru AA. A CD56- immunoblastoid variant of blastic plasmacytoid dendritic cell neoplasm. J Cutan Pathol 2024; 51:40-44. [PMID: 37612885 DOI: 10.1111/cup.14517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/31/2023] [Accepted: 08/08/2023] [Indexed: 08/25/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive malignant hematologic neoplasm arising from plasmacytoid dendritic cells. It is a very rare tumor that constitutes less than 0.1% of all hematologic malignancies. Most patients with BPDCN present clinically with cutaneous lesions as the first sign of disease. Immunophenotypic variability with aberrant marker profiles has been reported. We report a case of a transcription factor 4 (TCF-4) + BPDCN, with negative CD56 expression in an 85-year-old woman with multiple skin nodules. A punch biopsy revealed a diffuse, monomorphous, and non-epidermotropic cell infiltrate involving the entire dermis. The infiltrate was composed of intermediate-sized cells with immunoblastoid morphology, which is an unusual morphologic variant. The neoplastic cells were strongly positive for CD45 and co-expressed CD4, CD123, TCF-4, BCL-2, and CD10. The Ki-67 proliferative rate was very high (90%). Negative immunostains included CD56, an unusual finding in BPDCN. This case illustrates the challenges encountered in the diagnosis of this entity, particularly in unusual morphologic variants and phenotypes. The elucidation of molecular signatures and development of targeted therapies for its management have been recently introduced and differ from acute myeloid leukemias. Hence, accurate diagnosis of BPDCN is critical for dermatopathologists.
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Affiliation(s)
- Brenna M Aran
- University of Virginia, Charlottesville, Virginia, USA
| | - Juanita Duran
- Department of Pathology, University of Virginia, Charlottesville, Virginia, USA
| | | | - Alejandro A Gru
- Department of Pathology, University of Virginia, Charlottesville, Virginia, USA
- Department of Dermatology, University of Virginia, Charlottesville, Virginia, USA
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13
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Zheng JX, Betts EV, Dwyre DM, Chung JH, Mitra AD. Pediatric Blastic Plasmacytoid Dendritic Cell Neoplasm: A Case Report. CLINICAL PATHOLOGY (THOUSAND OAKS, VENTURA COUNTY, CALIF.) 2024; 17:2632010X241304564. [PMID: 39687328 PMCID: PMC11648018 DOI: 10.1177/2632010x241304564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 11/16/2024] [Indexed: 12/18/2024]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive neoplastic process of precursor plasmacytoid dendritic cells. The diagnostic evaluation of this heterogenous entity is challenging, requiring a comprehensive approach of incorporating clinical, morphologic, immunohistochemical, and molecular/cytogenetic evaluations. Optimal management of BPDCN remains controversial, and clinical outcomes continues to be poor. Pediatric cases of BPDCN are rare and to our knowledge, this is the second case of BPDCN described in a Hispanic child, first one was described outside the US in Peru. Here, we report a case of a juvenile patient of Hispanic origin presenting with cutaneous and bone marrow involvement and initially misdiagnosed as a cutaneous infection that resulted in subsequent delaying of necessary chemotherapy for 2 months. Biopsy of the lesion showed diffuse infiltration of immature cells involving the dermis with classical sparring of epidermis. A huge panel of immunohistochemical stains were performed to reach the diagnosis of BPDCN. Staging bone marrow biopsy also revealed involvement by BPDCN. Treatment was not only delayed in this patient but also due to the rarity of BPDCN in pediatric population, the subsequent therapeutic decisions were challenging for the primary oncology team as it was based solely on published literature on adult population. Our case report will not only add one more case in the pediatric age group, but also will also emphasize that although BPDCN has a grave prognosis in the elderly, timely diagnosis with prompt treatment is the key to complete remission in pediatric BPDCN population.
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Affiliation(s)
- Jasper X Zheng
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | - Elham Vali Betts
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | - Denis M Dwyre
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
| | - Jong H Chung
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, University of California Davis, Sacramento, CA, USA
| | - Ananya Datta Mitra
- Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA
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14
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Sahin Y, Wang YL, Pei J, Mansoor N, Styler M, Testa JR, Nejati R. Multiple Genomic Alterations, Including a Novel AFF4::IRF1 Fusion Gene, in a Treatment-Refractory Blastic Plasmacytoid Dendritic-Cell Neoplasm: A Case Report and Literature Review. Int J Mol Sci 2023; 25:305. [PMID: 38203475 PMCID: PMC10778852 DOI: 10.3390/ijms25010305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/20/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with an aggressive clinical course and poor prognosis. The genetic abnormalities in BPDCN are heterogeneous; therefore, its molecular pathogenesis and the prognostic importance of genomic alterations associated with the disease are not well defined. Here we report a case of BPDCN with a novel AFF4::IRF1 fusion predicted to lead to a loss-of-function of the IRF1 tumor suppressor, somatic mutations of ASXL1, TET2, and MYD88, as well as multiple intrachromosomal deletions. The patient showed resistance to Tagraxofusp and Venetoclax, and he died about 16 months after diagnosis. Considering the predicted effect of the AFF4::IRF1 fusion on IRF1's antitumor effects and immune regulation, and the possibility of its relevance to the aggressive course observed in this case, we propose further evaluation of the clinical significance of this fusion in BPDCN in future cooperative group studies and the consideration of therapeutic strategies aimed at restoring IRF1-dependent antineoplastic effects in such cases.
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Affiliation(s)
- Yavuz Sahin
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.S.); (Y.L.W.); (J.P.); (N.M.)
| | - Y. Lynn Wang
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.S.); (Y.L.W.); (J.P.); (N.M.)
- Molecular Diagnostics Lab, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Jianming Pei
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.S.); (Y.L.W.); (J.P.); (N.M.)
- Molecular Diagnostics Lab, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Nashwa Mansoor
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.S.); (Y.L.W.); (J.P.); (N.M.)
| | - Michael Styler
- Department of Bone Marrow Transplant and Cellular Therapies, Fox Chase Cancer Center, Philadelphia, PA 19111, USA;
| | - Joseph R. Testa
- Clinical Cytogenomics Lab, Fox Chase Cancer Center, Philadelphia, PA 19111, USA;
- Cancer Prevention and Control Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Reza Nejati
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA; (Y.S.); (Y.L.W.); (J.P.); (N.M.)
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15
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Cazzato G, Capuzzolo M, Bellitti E, De Biasi G, Colagrande A, Mangialardi K, Gaudio F, Ingravallo G. Blastic Plasmocytoid Dendritic Cell Neoplasm (BPDCN): Clinical Features and Histopathology with a Therapeutic Overview. Hematol Rep 2023; 15:696-706. [PMID: 38132278 PMCID: PMC10742669 DOI: 10.3390/hematolrep15040070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 11/09/2023] [Accepted: 12/04/2023] [Indexed: 12/23/2023] Open
Abstract
Blastic Plasmacytoid Dendritic Cell Neoplasms (BPDCNs) are a rare, highly aggressive hematological malignant neoplasm that primarily involve the skin, bone marrow, lymph nodes and even extra-nodal sites. The rarity and relative poor description of cases in the literature make it necessary to review and further studies that deeply investigate this entity not only in a histopathological but also molecular field. In August-September 2023, we searched MEDLINE, PubMed and Scopus for randomized controlled trials (RCTs), narrative and systematic reviews, meta-analyses, observational studies (either longitudinal or retrospective), and case series published in English in the last 25 years using the keywords BPDCN, PDCs, Blastic NK-cell lymphoma, agranular CD4+ NK leukemia/lymphoma, agranular CD4+ CD56+ hematodermic neoplasm/tumor. Despite the progress made in recent years in the diagnosis and biological understanding of the disease, until 2018 there was no clear consensus regarding its treatment and the main therapeutic schemes used were based on chemotherapy regimens already used in the treatment of lymphomas, acute lymphoblastic leukemia (ALL) and/or acute myeloid leukemia (AML). In this narrative review, we address the definition and epidemiological features of BPDCN, provide the different theories on the etiopathogenesis with particular attention to the presumed cell of origin, discuss the main clinical manifestations that provide a sign of its presence, summarize the main histopathological and immunophenotypic characteristics with special attention to the most important markers, and finally, we provide some of the most effective information on the therapeutic treatment modalities of BPDCN.
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Affiliation(s)
- Gerardo Cazzato
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.C.); (G.D.B.); (A.C.); (G.I.)
| | - Marialessandra Capuzzolo
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.C.); (G.D.B.); (A.C.); (G.I.)
| | - Emilio Bellitti
- Anatomic Pathology Unit, “A. Perrino” Hospital, 72100 Brindisi, Italy;
| | - Giovanni De Biasi
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.C.); (G.D.B.); (A.C.); (G.I.)
| | - Anna Colagrande
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.C.); (G.D.B.); (A.C.); (G.I.)
| | - Katia Mangialardi
- Hematology Section, Department of Emergency and Transplantation, University of Bari Medical School, 70124 Bari, Italy; (K.M.); (F.G.)
| | - Francesco Gaudio
- Hematology Section, Department of Emergency and Transplantation, University of Bari Medical School, 70124 Bari, Italy; (K.M.); (F.G.)
| | - Giuseppe Ingravallo
- Section of Molecular Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.C.); (G.D.B.); (A.C.); (G.I.)
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16
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Fukuchi K, Koyama D, Takada M, Mori H, Hayashi K, Asano N, Sato Y, Fukatsu M, Takano M, Takahashi H, Shirado-Harada K, Kimura S, Yamamoto T, Ikezoe T. Mutated ZRSR2 and CUL3 accelerate clonal evolution and confer venetoclax resistance via RAS signaling pathway in blastic plasmacytoid dendritic cell neoplasm. Int J Hematol 2023; 118:489-493. [PMID: 37029861 DOI: 10.1007/s12185-023-03597-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2023] [Revised: 04/02/2023] [Accepted: 04/03/2023] [Indexed: 04/09/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive subtype of myeloid malignancy characterized by skin, lymph node and central nervous system (CNS) involvement. Although various regimens are used, a standard therapeutic strategy for BPDCN has not been established. Recent studies revealed that BPDCN patients frequently have a mutation in ZRSR2, which is a minor spliceosome component. However, the association between the clinical features of BPDCN and ZRSR2 mutational status remains unknown. A 70-year-old man was referred to our hospital with skin rash and enlarged lymph nodes, as well as blasts in the peripheral blood. BPDCN was diagnosed based on the immunophenotype of the blasts derived from bone marrow. Whole exome sequencing revealed that BPDCN cells collected at diagnosis had mutations in ZRSR2, ZBTB33, CUL3, TET2 and NRAS. RNA sequencing analysis indicated that U12-type intron retention occurred in LZTR1, caused by ZRSR2 loss. After seven cycles of venetoclax combined with azacitidine therapy, BPDCN cells appeared in the peripheral blood and infiltrated the CNS. Two KRAS mutated clones appeared at BPDCN recurrence. These findings are important for understanding the pathogenesis of BPDCN, which will inform development of novel therapeutic strategies.
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Affiliation(s)
- Koichiro Fukuchi
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Daisuke Koyama
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan.
| | - Maki Takada
- Department of Dermatology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Hirotaka Mori
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Kiyohito Hayashi
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Naomi Asano
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Yuki Sato
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Masahiko Fukatsu
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Motoki Takano
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Hiroshi Takahashi
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Kayo Shirado-Harada
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Satoshi Kimura
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Toshiyuki Yamamoto
- Department of Dermatology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
| | - Takayuki Ikezoe
- Department of Hematology, Fukushima Medical University, Fukushima, Fukushima, 960-1295, Japan
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17
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Bidet A, Quessada J, Cuccuini W, Decamp M, Lafage-Pochitaloff M, Luquet I, Lefebvre C, Tueur G. Cytogenetics in the management of acute myeloid leukemia and histiocytic/dendritic cell neoplasms: Guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH). Curr Res Transl Med 2023; 71:103421. [PMID: 38016419 DOI: 10.1016/j.retram.2023.103421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/29/2023] [Accepted: 10/15/2023] [Indexed: 11/30/2023]
Abstract
Genetic data are becoming increasingly essential in the management of hematological neoplasms as shown by two classifications published in 2022: the 5th edition of the World Health Organization Classification of Hematolymphoid Tumours and the International Consensus Classification of Myeloid Neoplasms and Acute Leukemias. Genetic data are particularly important for acute myeloid leukemias (AMLs) because their boundaries with myelodysplastic neoplasms seem to be gradually blurring. The first objective of this review is to present the latest updates on the most common cytogenetic abnormalities in AMLs while highlighting the pitfalls and difficulties that can be encountered in the event of cryptic or difficult-to-detect karyotype abnormalities. The second objective is to enhance the role of cytogenetics among all the new technologies available in 2023 for the diagnosis and management of AML.
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Affiliation(s)
- Audrey Bidet
- Laboratoire d'Hématologie Biologique, CHU Bordeaux, Avenue Magellan, Bordeaux, Pessac F-33600, France.
| | - Julie Quessada
- Laboratoire de Cytogénétique Hématologique, Hôpital des enfants de la Timone, Assistance Publique-Hôpitaux de Marseille (APHM), Faculté de Médecine, Aix Marseille Université, Marseille 13005, France; CNRS, INSERM, CIML, Aix Marseille Université, Marseille 13009, France
| | - Wendy Cuccuini
- Laboratoire d'Hématologie, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | | | - Marina Lafage-Pochitaloff
- Laboratoire de Cytogénétique Hématologique, Hôpital des enfants de la Timone, Assistance Publique-Hôpitaux de Marseille (APHM), Faculté de Médecine, Aix Marseille Université, Marseille 13005, France
| | - Isabelle Luquet
- Laboratoire d'Hématologie, CHU Toulouse, Site IUCT-O, Toulouse, France
| | - Christine Lefebvre
- Unité de Génétique des Hémopathies, Service d'Hématologie Biologique, CHU Grenoble Alpes, Grenoble, France
| | - Giulia Tueur
- Laboratoire d'Hématologie, CHU Avicenne, APHP, Bobigny, France
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18
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Sakamoto K, Baba S, Okumura Y, Momose S, Ono S, Tonooka A, Ichinohasama R, Takakuwa E, Nakasone H, Ohshima K, Takeuchi K. Comparison and Development of Immunohistochemical Diagnostic Criteria for Blastic Plasmacytoid Dendritic Cell Neoplasm. Mod Pathol 2023; 36:100253. [PMID: 37380058 DOI: 10.1016/j.modpat.2023.100253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/15/2023] [Accepted: 06/17/2023] [Indexed: 06/30/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy derived from the precursors of plasmacytoid dendritic cells. Diagnostic criteria for BPDCN have not been fully established. BPDCN is often diagnosed without other BPDCN markers than the 3 conventional markers (CD4, CD56, and CD123) in practice and case reports, although acute myeloid leukemia/myeloid sarcoma (AML/MS), which is always considered in the differential diagnosis of BPDCN, can express them. We reviewed published case reports on BPDCN and found that the diagnosis was made without any other BPDCN markers than the conventional markers in two-thirds of the cases. Next, 4 representative existing diagnostic criteria were applied to 284 cases of our cohort of BPDCN and mimics. The results differed in 20% (56/284) of the cases. The criterion based on the 3 conventional markers alone had a low concordance rate (80%-82%) with the other 3 criteria, which were almost concordant with each other. However, newly found minor limitations in these criteria prompted us to devise new diagnostic criterion for BPDCN composed of TCF4, CD123, TCL1, and lysozyme. We also revealed that CD123-positive AML/MS patients had a significantly poorer outcome than those with BPDCN and that 12% (24/205) of the cases were non-BPDCN even if all 3 conventional markers were positive, thus clarifying the risk of diagnosing BPDCN without more specific markers. In addition, histopathological features, such as the reticular pattern, which is not seen in BPDCN and suggests AML/MS, were also identified.
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Affiliation(s)
- Kana Sakamoto
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Satoko Baba
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuka Okumura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
| | - Shuji Momose
- Department of Pathology, Saitama Medical Center, Saitama Medical University, Saitama, Japan
| | - Sawako Ono
- Department of Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Akiko Tonooka
- Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Komagome Hospital, Tokyo, Japan
| | - Ryo Ichinohasama
- Division of Hematopathology, Tohoku University Hospital, Sendai, Japan
| | - Emi Takakuwa
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Hideki Nakasone
- Division of Hematology, Saitama Medical Center, Jichi Medical University, Saitama, Japan
| | - Koichi Ohshima
- Department of Pathology, Kurume University, School of Medicine, Kurume, Japan
| | - Kengo Takeuchi
- Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Clinical Pathology Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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19
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Lee YJ, Kim Y, Park SH, Jo JC. Plasmacytoid dendritic cell neoplasms. Blood Res 2023; 58:90-95. [PMID: 37105563 PMCID: PMC10133850 DOI: 10.5045/br.2023.2023052] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/16/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are type I interferon-producing cells that modulate immune responses. There are two types of pDC neoplasms: 1) mature pDC proliferation (MPDCP) associated with myeloid neoplasm and 2) blastic pDC neoplasm (BPDCN). MPDCP is a clonal expansion of mature pDCs that is predominantly associated with chronic myelomonocytic leukemia. In contrast, BPDCN is a clinically aggressive myeloid malignancy involving the skin, bone marrow, lymphatic organs, and central nervous system. There are various types of skin lesions, ranging from solitary brown or violaceous to disseminated cutaneous lesions, which often spread throughout the body. The expression of CD4, CD56, CD123, and pDC markers (TCL-1, TCF4, CD303, and CD304, etc.) are typical immunophenotype of BPDCN. Historically, BPDCN treatment has been based on acute leukemia regimens and allogeneic hematopoietic cell transplantation in selected patients. Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms.
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Affiliation(s)
- Yoo Jin Lee
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Youjin Kim
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Sang Hyuk Park
- Department of Laboratory Medicine, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
| | - Jae-Cheol Jo
- Department of Hematology and Oncology, Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea
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20
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Hyrcza MD, Lindenmuth TR, Auerbach A. Top Ten Lymphoproliferative Lesions Not to Miss When Evaluating Oral Ulcer Biopsies. Head Neck Pathol 2023; 17:99-118. [PMID: 36928739 PMCID: PMC10063747 DOI: 10.1007/s12105-023-01532-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/12/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Oral ulcers represent a full thickness loss of the mucosal epithelium leading to exposure of the submucosal connective tissue. These are common and usually self-limited lesions, although they may sometimes result from neoplasms, most commonly squamous cell carcinoma. Lymphoproliferative disorders may be difficult to diagnose in apthous ulcers since they mimic reactive inflammation. METHODS This review presents ten rare oral lymphoid proliferations which should not be missed when assessing oral ulcer biopsies. RESULTS The ten lesions include several with diagnostic cells which look similar to the histiocytes of a reactive inflammatory ulcer, including Rosai-Dorfman disease, reticulohistiocytoma, Langerhans cell histiocytosis, and traumatic ulcerative granuloma. Other lesions, such as EBV-positive mucocutaneous ulcer, extranodal marginal zone lymphoma of mucosal-associated lymphoid tissue, and plasmablastic lymphoma have lymphoid and/or plasma cell differentiation that mimic the reactive lymphocytes and plasma cells found in reactive ulcers. Two dendritic cell lesions, follicular dendritic cell sarcoma and blastic plasmacytoid dendritic cell neoplasm, both have distinct phenotypes which are required to make an accurate diagnosis. CONCLUSION Each of these lesions are diagnosed by evaluating their histology, along with their phenotypic profile, which is sometimes enhanced by pertinent molecular findings.
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Affiliation(s)
- Martin D. Hyrcza
- Department of Pathology and Laboratory Medicine, University of Calgary, Arnie Charbonneau Cancer Institute, Calgary, AB Canada
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21
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Voci S, Clarke TB, Dick JE. Abiotic microcompartments form when neighbouring droplets fuse: an electrochemiluminescence investigation. Chem Sci 2023; 14:2336-2341. [PMID: 36873831 PMCID: PMC9977408 DOI: 10.1039/d2sc06553c] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 12/26/2022] [Indexed: 12/28/2022] Open
Abstract
Many studies have shown chemistry proceeds differently in small volumes compared to bulk phases. However, few studies exist elucidating spontaneous means by which small volumes can form in Nature. Such studies are critical in understanding the formation of life in microcompartments. In this study, we track in real-time the coalescence of two or more water microdroplets adsorbed on an electrified surface in a 1,2-dichloroethane continuous phase by electrogenerated chemiluminescence (ECL) imaging, uncovering the spontaneous generation of multiple emulsions inside the resulting water droplets. During the fusion of adsorbed water droplets with each other on the electrode surface, volumes of organic and water phases are entrapped in between and detected respectively as ECL not-emitting and emitting regions. The diameter of those confined environments inside the water droplets can be less than a micrometer, as described by scanning electron microscopy data. This study adds a new mechanism for the generation of micro- and nano-emulsions and provides insight into confinement techniques under abiotic conditions as well as new potential strategies in microfluidic devices.
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Affiliation(s)
- Silvia Voci
- Department of Chemistry, Purdue University West Lafayette IN 47907 USA
| | - Thomas B Clarke
- Department of Chemistry, Purdue University West Lafayette IN 47907 USA
| | - Jeffrey E Dick
- Department of Chemistry, Purdue University West Lafayette IN 47907 USA .,Elmore Family School of Electrical and Computer Engineering, Purdue University West Lafayette IN 47907 USA
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22
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Unmet Clinical Needs and Management Recommendations for Blastic Plasmacytoid Dendritic Cell Neoplasm: A Consensus-based Position Paper From an Ad Hoc International Expert Panel. Hemasphere 2023; 7:e841. [PMID: 36844178 PMCID: PMC9946418 DOI: 10.1097/hs9.0000000000000841] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 01/03/2023] [Indexed: 02/23/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with overall survival. The rarity of the disease results in a few large-scale studies, a lack of controlled clinical trials for its management, and a lack of evidence-based guidelines. Here, we present a review of unmet clinical needs on the management of BPDCN by a panel of eleven experts involved in the research and clinical practice of BPDCN. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel analyzed the critical issues of diagnostic pathway, prognostic stratification, therapy for young and fit patients and elderly and unfit patients, indication for allotransplant and for autotransplant, indication for central nervous system prophylaxis, and management of pediatric BPDCN patients. For each of these issues, consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of BPDCN and inform the design and implementation of new studies in the field.
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23
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Wang Y, Xiao L, Yin L, Zhou L, Deng Y, Deng H. Diagnosis, treatment, and genetic characteristics of blastic plasmacytoid dendritic cell neoplasm: A review. Medicine (Baltimore) 2023; 102:e32904. [PMID: 36800625 PMCID: PMC9936012 DOI: 10.1097/md.0000000000032904] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and extremely rare hematologic disease with a poor prognosis, involving mainly the skin and bone marrow. The immunophenotype of these tumor cells is characterized by the expression of CD4, CD56, CD123, TCL-1, and CD303. To date, no consensus has been reached on the standard of care for BPDCN. Currently, clinical treatment is mainly based on high-dose chemotherapy combined with hematopoietic stem cell transplantation. However, this treatment method has limitations for elderly, frail, and relapsed/refractory patients. In recent years, breakthroughs in molecular biology and genetics have not only provided new ideas for the diagnosis of BPDCN but also helped develop targeted treatment strategies for this disease. The emergence of targeted drugs has filled the gap left by traditional therapies and shown great clinical promise. This article focuses on the latest advances in genetics and targeted therapies for BPDCN, especially the emerging therapies that may provide new ideas for the clinical treatment of BPDCN.
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Affiliation(s)
- Yemin Wang
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Li Xiao
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lili Yin
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Lv Zhou
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Yanjuan Deng
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Mol. Med. & Genet. Center, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Huan Deng
- Department of Pathology, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- Mol. Med. & Genet. Center, Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
- * Correspondence: Huan Deng, Department of Pathology, Fourth Affiliated Hospital of Nanchang University, 133 South Guangchang Road, Nanchang, Jiangxi 330003, China (e-mail: )
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24
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North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need. Blood 2023; 141:567-578. [PMID: 36399715 DOI: 10.1182/blood.2022017865] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 10/25/2022] [Accepted: 10/28/2022] [Indexed: 11/19/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.
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25
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Loss of METTL3 attenuates blastic plasmacytoid dendritic cell neoplasm response to PRMT5 inhibition via IFN signaling. Blood Adv 2022; 6:5330-5344. [PMID: 35482445 PMCID: PMC9631685 DOI: 10.1182/bloodadvances.2021006306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 04/08/2022] [Indexed: 02/05/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with poor clinical outcomes. Dysregulated MYC expression, which is associated with protein arginine methyltransferase 5 (PRMT5) dependency, is a recurrent feature of BPDCN. Although recent studies have reported a PRMT5 gene signature in BPDCN patient samples, the role of PRMT5 in BPDCN remains unexplored. Here, we demonstrate that BPDCN is highly sensitive to PRMT5 inhibition. Consistent with the upregulation of PRMT5 in BPDCN, we show that pharmacological inhibition (GSK3326595) of PRMT5 inhibits the growth of the patient-derived BPDCN cell line CAL-1 in vitro and mitigated tumor progression in our mouse xenograft model. Interestingly, RNA-sequencing (RNA-seq) analysis revealed that PRMT5 inhibition increases intron retention in several key RNA methylation genes, including METTL3, which was accompanied by a dose-dependent decrease in METTL3 expression. Notably, the function of cellular m6A RNA modification of METTL3 was also affected by PRMT5 inhibition in CAL-1 cells. Intriguingly, METTL3 depletion in CAL-1 caused a significant increase in interferon (IFN) signaling, which was further elevated upon PRMT5 inhibition. Importantly, we discovered that this increase in IFN signaling attenuated the sensitivity of METTL3-depleted CAL-1 cells to PRMT5 inhibition. Correspondingly, stimulation of IFN signaling via TLR7 agonists weakened CAL-1 cell sensitivity to PRMT5 inhibition. Overall, our findings implicate PRMT5 as a therapeutic target in BPDCN and provide insight into the involvement of METTL3 and the IFN pathway in regulating the response to PRMT5 inhibition.
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26
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Renosi F, Callanan M, Lefebvre C. Genetics and Epigenetics in Neoplasms with Plasmacytoid Dendritic Cells. Cancers (Basel) 2022; 14:cancers14174132. [PMID: 36077669 PMCID: PMC9454802 DOI: 10.3390/cancers14174132] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 12/16/2022] Open
Abstract
Simple Summary Differential diagnosis between Blastic pDC Neoplasm (BPDCN) and Acute Myeloid Leukemia with pDC expansion (pDC-AML) is particularly challenging, and genomic features can help in diagnosis. This review aims at clarifying recent data on genomics features because the past five years have generated a large amount of original data regarding pDC neoplasms. The genetic landscape of BPDCN is now well-defined, with important updates concerning MYC/MYC rearrangements, but also epigenetic defects and novel concepts in oncogenic and immune pathways. Concerning pDC-AML, they now appear to exhibit an original mutation landscape, especially with RUNX1 mutations, which is of interest for diagnostic criteria and for therapeutic purposes. We highlight here these two different profiles, which contribute to differential diagnosis between BPDCN and pDC-AML. This point is particularly important for the study of different therapeutic strategies between BPDCN and AML. Abstract Plasmacytoid Dendritic Cells (pDC) are type I interferon (IFN)-producing cells that play a key role in immune responses. Two major types of neoplastic counterparts for pDC are now discriminated: Blastic pDC Neoplasm (BPDCN) and Mature pDC Proliferation (MPDCP), associated with myeloid neoplasm. Two types of MPDCP are now better described: Chronic MyeloMonocytic Leukemia with pDC expansion (pDC-CMML) and Acute Myeloid Leukemia with pDC expansion (pDC-AML). Differential diagnosis between pDC-AML and BPDCN is particularly challenging, and genomic features can help for diagnosis. Here, we systematically review the cytogenetic, molecular, and transcriptional characteristics of BPDCN and pDC-AML. BPDCN are characterized by frequent complex karyotypes with recurrent MYB/MYC rearrangements as well as recurrent deletions involving ETV6, IKZF1, RB1, and TP53 loci. Epigenetic and splicing pathways are also particularly mutated, while original processes are dysregulated, such as NF-kB, TCF4, BCL2, and IFN pathways; neutrophil-specific receptors; and cholinergic signaling. In contrast, cytogenetic abnormalities are limited in pDC-AML and are quite similar to other AML. Interestingly, RUNX1 is the most frequently mutated gene (70% of cases). These typical genomic features are of potential interest for diagnosis, and also from a prognostic or therapeutic perspective.
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Affiliation(s)
- Florian Renosi
- INSERM, EFS BFC, UMR1098 RIGHT, University of Bourgogne Franche-Comté, F-25000 Besancon, France
- Laboratoire d’Hématologie et d’Immunologie Régional, Etablissement Français du Sang Bourgogne Franche-Comté, F-25000 Besancon, France
- Correspondence:
| | - Mary Callanan
- INSERM 1231 and 1209, University of Bourgogne-Franche Comté, F-21000 Dijon, France
- Service d’Oncologie Génétique, CHU Dijon Bourgogne, F-21000 Dijon, France
| | - Christine Lefebvre
- INSERM 1209 and CNRS UMR 5309, Université Grenoble-Alpes, F-38000 Grenoble, France
- Laboratoire de Génétique des hémopathies, Institut de Biologie et de Pathologie, CHU Grenoble Alpes, F-38000 Grenoble, France
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27
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Zhang Y, Sokol L. Clinical Insights into the Management of Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancer Manag Res 2022; 14:2107-2117. [PMID: 35789956 PMCID: PMC9250318 DOI: 10.2147/cmar.s330398] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 06/01/2022] [Indexed: 12/02/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is aggressive hematologic malignancy derived from plasmacytoid dendritic cell precursors of myeloid cell lineage. Patients frequently present with bruise-like skin lesions, which typically are followed months later by progressive cytopenias. Historically, BPDCN prognosis has been dismal, with median overall survival ranging from 9 to 13 months. In the past 2 decades, our understanding of BPDCN pathogenesis has led to the successful development of novel therapeutics. In December 2018, the FDA approved tagraxofusp-erzs for adults and pediatric patients older than 2 years who have either treatment-naïve or relapsed/refractory BPDCN. Acute lymphoblastic leukemia (ALL)-based chemotherapy regimens also provide comparable outcomes to tagraxofusp. In our practice, for patients with good performance status, we use tagraxofusp, ALL-based chemotherapy regimens, or clinical trials as frontline induction therapy, followed by consolidation with allogeneic stem cell transplant once the first complete response has been achieved. Our induction regimen also includes intrathecal chemotherapy for central nervous system prophylaxis. Patients with poor performance status who are treatment-naïve or patients with relapsed/refractory disease have limited therapeutic options, and we strongly recommend enrollment in clinical trials; several novel agents and combinations are currently under clinical investigation for both treatment-naïve and relapsed/refractory BPDCN.
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Affiliation(s)
- Yumeng Zhang
- Department of Internal Medicine, University of South Florida, Tampa, FL, USA.,Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
| | - Lubomir Sokol
- Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
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28
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Wang X, Tang G, Hu Z, Fang H, Wang W, Tang Z, Toruner GA, Zhou T, DiNardo CD, Garcia-Manero G, Verstovsek S, Bueso-Ramos CE, Medeiros LJ, Hu S. Myeloid neoplasms with 8q24/MYC rearrangement are frequently associated with myelodysplasia, complex karyotype, TP53 alterations, and inferior survival. Br J Haematol 2022; 198:604-608. [PMID: 35645146 DOI: 10.1111/bjh.18278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/03/2022] [Accepted: 05/10/2022] [Indexed: 11/26/2022]
Affiliation(s)
- Xiaoqiong Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Guilin Tang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhihong Hu
- Department of Pathology, The University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Hong Fang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Wei Wang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Zhenya Tang
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Gokce A Toruner
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ting Zhou
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Courtney D DiNardo
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Guillermo Garcia-Manero
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Srdan Verstovsek
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carlos E Bueso-Ramos
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - L Jeffrey Medeiros
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shimin Hu
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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29
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Karube K, Nakada N, Sakamoto K, Takeuchi K. Blastic plasmacytoid dendritic cell neoplasm with prominent intracytoplasmic vacuoles: A challenging diagnosis. Pathol Int 2022; 72:211-213. [DOI: 10.1111/pin.13201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/19/2021] [Accepted: 12/24/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Kennosuke Karube
- Department of Pathology and Laboratory Medicine, Graduate School of Medicine Nagoya University Nagoya Japan
- Laboratory of Hematoimmunology, School of Health Science, Faculty of Medicine University of the Ryukyus Okinawa Japan
| | | | - Kana Sakamoto
- Pathology Project for Molecular Targets The Cancer Institute, Japanese Foundation for Cancer Research Tokyo Japan
- Division of Pathology The Cancer Institute, Japanese Foundation for Cancer Research Tokyo Japan
| | - Kengo Takeuchi
- Pathology Project for Molecular Targets The Cancer Institute, Japanese Foundation for Cancer Research Tokyo Japan
- Division of Pathology The Cancer Institute, Japanese Foundation for Cancer Research Tokyo Japan
- Clinical Pathology Center, The Cancer Institute Hospital Japanese Foundation for Cancer Research Tokyo Japan
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30
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Yin CC, Pemmaraju N, You MJ, Li S, Xu J, Wang W, Tang Z, Alswailmi O, Bhalla KN, Qazilbash MH, Konopleva M, Khoury JD. Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm. Cancers (Basel) 2021; 13:cancers13235888. [PMID: 34884997 PMCID: PMC8656770 DOI: 10.3390/cancers13235888] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 11/17/2021] [Accepted: 11/18/2021] [Indexed: 11/16/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive neoplasm derived from plasmacytoid dendritic cells. While advances in understanding the pathophysiology of the disease have been made, integrated systematic analyses of the spectrum of immunophenotypic and molecular alterations in real-world clinical cases remain limited. We performed mutation profiling of 50 BPDCN cases and assessed our findings in the context of disease immunophenotype, cytogenetics, and clinical characteristics. Patients included 42 men and 8 women, with a median age of 68 years (range, 14-84) at diagnosis. Forty-two (84%) patients had at least one mutation, and 23 (46%) patients had ≥3 mutations. The most common mutations involved TET2 and ASXL1, detected in 28 (56%) and 23 (46%) patients, respectively. Co-existing TET2 and ASXL1 mutations were present in 17 (34%) patients. Other recurrent mutations included ZRSR2 (16%), ETV6 (13%), DNMT3A (10%), NRAS (10%), IKZF1 (9%), SRSF2 (9%), IDH2 (8%), JAK2 (6%), KRAS (4%), NOTCH1 (4%), and TP53 (4%). We also identified mutations that have not been reported previously, including ETNK1, HNRNPK, HRAS, KDM6A, RAD21, SF3A1, and SH2B3. All patients received chemotherapy, and 20 patients additionally received stem cell transplantation. With a median follow-up of 10.5 months (range, 1-71), 21 patients achieved complete remission, 4 had persistent disease, and 24 died. Patients younger than 65 years had longer overall survival compared to those who were ≥65 years (p = 0.0022). Patients who had ≥3 mutations or mutations in the DNA methylation pathway genes had shorter overall survival (p = 0.0119 and p = 0.0126, respectively). Stem cell transplantation significantly prolonged overall survival regardless of mutation status. In conclusion, the majority of patients with BPDCN have somatic mutations involving epigenetic regulators and RNA splicing factors, in addition to ETV6 and IKZF1, which are also frequently mutated. Older age, multiple mutations, and mutations in the DNA methylation pathway are poor prognostic factors.
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Affiliation(s)
- C. Cameron Yin
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
- Correspondence: (C.C.Y.); (J.D.K.); Tel.: +1-(713)-745-6134 (C.C.Y.); +1-(713)-745-6452 (J.D.K.)
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (N.P.); (K.N.B.); (M.K.)
| | - M. James You
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Shaoying Li
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Jie Xu
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Wei Wang
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Zhenya Tang
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Omar Alswailmi
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
| | - Kapil N. Bhalla
- Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (N.P.); (K.N.B.); (M.K.)
| | - Muzaffar H. Qazilbash
- Department of Stem Cell Transplantation, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA;
| | - Marina Konopleva
- Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (N.P.); (K.N.B.); (M.K.)
| | - Joseph D. Khoury
- Department of Hematopathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; (M.J.Y.); (S.L.); (J.X.); (W.W.); (Z.T.); (O.A.)
- Correspondence: (C.C.Y.); (J.D.K.); Tel.: +1-(713)-745-6134 (C.C.Y.); +1-(713)-745-6452 (J.D.K.)
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31
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Cianga VA, Dănăilă CD, Antohe I, Oană R, Mențel M, Ivanov I, Dragoș L, Dăscălescu AS. A very rare case of FLT3-D835 positive blastic plasmacytoid dendritic cell neoplasm. Arch Clin Cases 2021; 7:57-62. [PMID: 34754929 PMCID: PMC8565708 DOI: 10.22551/2020.29.0704.10174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are extremely rare and aggressive hematological malignancies that derive from precursors of plasmacytoid dendritic cells (pDC) and frequently involve skin lesions and bone marrow infiltration. They mostly affect the elderly population and the prognosis is poor with the therapeutic choices currently available. Diagnosis is made with the help of tools such as immunohistochemistry and flow cytometry. Here, we present a particular case of BPDCN with a positive FLT3-D835 mutation and we discuss the possible impact this may have on the evolution of the disease and response to treatment.
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Affiliation(s)
- Vlad Andrei Cianga
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Cătălin Doru Dănăilă
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Ion Antohe
- Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Raluca Oană
- Department of Cytology, Regional Institute of Oncology, Iasi, Romania
| | - Mihaela Mențel
- Department of Immunophenotyping, Regional Institute of Oncology, Iasi, Romania
| | - Iuliu Ivanov
- Department of Molecular Diagnostics, Regional Institute of Oncology, Iasi, Romania
| | - Loredana Dragoș
- Department of Molecular Diagnostics, Regional Institute of Oncology, Iasi, Romania
| | - Angela Smaranda Dăscălescu
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
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32
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Cheng W, Yu TT, Tang AP, He Young K, Yu L. Blastic Plasmacytoid Dendritic Cell Neoplasm: Progress in Cell Origin, Molecular Biology, Diagnostic Criteria and Therapeutic Approaches. Curr Med Sci 2021; 41:405-419. [PMID: 34218354 DOI: 10.1007/s11596-021-2393-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 06/23/2021] [Indexed: 12/13/2022]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with poor overall survival. BPDCN is derived from plasmacytoid dendritic cells (pDCs) and its pathogenesis is unclear. The tumor cells show aberrant expression of CD4, CD56, interleukin-3 receptor alpha chain (CD123), blood dendritic cell antigen 2 (BDCA 2/CD303), blood dendritic cell antigen 4 (BDCA4) and transcription factor (E protein) E2-2 (TCF4). The best treatment drugs are based on experience by adopting those used for either leukemia or lymphoma. Relapse with drug resistance generally occurs quickly. Stem cell transplantation after the first complete remission is recommended and tagraxofusp is the first targeted therapy. In this review, we summarize the differentiation of BPDCN from its cell origin, its connection with normal pDCs, clinical characteristics, genetic mutations and advances in treatment of BPDCN. This review provides insights into the mechanisms of and new therapeutic approaches for BPDCN.
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Affiliation(s)
- Wei Cheng
- Department of Hematology, the Second Affiliate Hospital of Nanchang University, Nanchang, 330006, China
| | - Tian-Tian Yu
- Department of Hematology, the Second Affiliate Hospital of Nanchang University, Nanchang, 330006, China
| | - Ai-Ping Tang
- Department of Hematology, the Second Affiliate Hospital of Nanchang University, Nanchang, 330006, China
| | - Ken He Young
- Division of Hematopathology and Department of Pathology, Duke University Medical Center, Durham, 27710, USA
| | - Li Yu
- Department of Hematology, the Second Affiliate Hospital of Nanchang University, Nanchang, 330006, China.
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33
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Wilson NR, Konopleva M, Khoury JD, Pemmaraju N. Novel Therapeutic Approaches in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): Era of Targeted Therapy. CLINICAL LYMPHOMA MYELOMA & LEUKEMIA 2021; 21:734-740. [PMID: 34226167 DOI: 10.1016/j.clml.2021.05.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/17/2021] [Accepted: 05/18/2021] [Indexed: 12/13/2022]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy arising from the aberrant transformation of plasmacytoid dendritic cells (pDCs) and involving skin, bone marrow, lymph nodes, and central nervous system. Characteristically unique from other myeloid neoplasms, BPDCN cells express CD4, CD56, and CD123 as well as TCL-1 and TCF4 in almost all cases. Historically, this malignancy has exhibited a poor prognosis, with median survival of less than 2 years. Traditional treatment approaches have involved conventional cytotoxic chemotherapy followed by hematopoietic stem cell transplantation; however, patients frequently relapse with chemotherapy-resistant disease. We have recently entered a modern era of therapy with targeting of CD123, with first-in-class agent tagraxofusp, a CD123- targeted agent approved by the US Food and Drug Administration for therapy of patients with BPDCN ages 2 and older. Relapsed and refractory BPDCN remains an elusive therapeutic challenge, but better understanding of the underlying pathophysiology has led to the development of other CD123-targeted agents and combination therapy, as well as agents targeting beyond CD123. Specifically, the use of venetoclax in targeting BCL2 has been promising in BPDCN treatment. This review will focus on the underlying diagnostic markers of BPDCN which have led to novel targeted treatment strategies, as well as future directions in therapy we can expect in coming years.
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Affiliation(s)
- Nathaniel R Wilson
- Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX
| | - Marina Konopleva
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Joseph D Khoury
- Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX.
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Transcriptomic and genomic heterogeneity in blastic plasmacytoid dendritic cell neoplasms: from ontogeny to oncogenesis. Blood Adv 2021; 5:1540-1551. [PMID: 33687433 DOI: 10.1182/bloodadvances.2020003359] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 12/30/2020] [Indexed: 12/12/2022] Open
Abstract
Oncogenesis and ontogeny of blastic plasmacytoid dendritic cell neoplasm (BPDCN) remain uncertain, between canonical plasmacytoid dendritic cells (pDCs) and AXL+ SIGLEC6+ DCs (AS-DCs). We compared 12 BPDCN to 164 acute leukemia by Affymetrix HG-U133 Plus 2.0 arrays: BPDCN were closer to B-cell acute lymphoblastic leukemia (ALL), with enrichment in pDC, B-cell signatures, vesicular transport, deubiquitination pathways, and AS-DC signatures, but only in some cases. Importantly, 1 T-cell ALL clustered with BPDCN, with compatible morphology, immunophenotype (cCD3+ sCD3- CD123+ cTCL1+ CD304+), and genetics. Many oncogenetic pathways are deregulated in BPDCN compared with normal pDC, such as cell-cycle kinases, and importantly, the transcription factor SOX4, involved in B ontogeny, pDC ontogeny, and cancer cell invasion. High-throughput sequencing (HaloPlex) showed myeloid mutations (TET2, 62%; ASXL1, 46%; ZRSR2, 31%) associated with lymphoid mutations (IKZF1), whereas single-nucleotide polymorphism (SNP) array (Affymetrix SNP array 6.0) revealed frequent losses (mean: 9 per patient) involving key hematological oncogenes (RB1, IKZF1/2/3, ETV6, NR3C1, CDKN2A/B, TP53) and immune response genes (IFNGR, TGFB, CLEC4C, IFNA cluster). Various markers suggest an AS-DC origin, but not in all patients, and some of these abnormalities are related to the leukemogenesis process, such as the 9p deletion, leading to decreased expression of genes encoding type I interferons. In addition, the AS-DC profile is only found in a subgroup of patients. Overall, the cellular ontogenic origin of BPDCN remains to be characterized, and these results highlight the heterogeneity of BPDCN, with a risk of a diagnostic trap.
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Summerer I, Walter W, Meggendorfer M, Kern W, Haferlach T, Haferlach C, Stengel A. Comprehensive analysis of the genetic landscape of 21 cases with blastic plasmacytoid dendritic cell neoplasm by whole genome and whole transcriptome sequencing. Leuk Lymphoma 2021; 62:2543-2546. [PMID: 34034604 DOI: 10.1080/10428194.2021.1924372] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Sagou K, Ito M, Kawamura Y, Ukai S, Goto M, Fukushima N, Ozeki K, Fukuyama R, Kohno A. Severe tumor lysis syndrome during the induction therapy for the treatment of blastic plasmacytoid dendritic cell neoplasm arising from myelodysplastic/myeloproliferative neoplasms. Clin Case Rep 2021; 9:878-882. [PMID: 33598264 PMCID: PMC7869312 DOI: 10.1002/ccr3.3690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 09/07/2020] [Accepted: 09/19/2020] [Indexed: 02/02/2023] Open
Abstract
BPDCN shows clinically heterogeneous characteristics. And as other hematological malignancies, symptoms of BPDCN suggesting a high tumor burden, such as high white blood cell count or splenomegaly, should be carefully considered to prevent TLS.
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Affiliation(s)
- Ken Sagou
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
- Department of Hematology and OncologyNagoya University Graduate School of MedicineAichiJapan
| | - Makoto Ito
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Yuma Kawamura
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Shun Ukai
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Miyo Goto
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Nobuaki Fukushima
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Kazutaka Ozeki
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Ryuichi Fukuyama
- Department of Diagnostic PathologyJA Aichi Konan Kosei HospitalAichiJapan
| | - Akio Kohno
- Department of Hematology and OncologyJA Aichi Konan Kosei HospitalAichiJapan
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How should we diagnose and treat blastic plasmacytoid dendritic cell neoplasm patients? Blood Adv 2020; 3:4238-4251. [PMID: 31869411 DOI: 10.1182/bloodadvances.2019000647] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Accepted: 08/14/2019] [Indexed: 11/20/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia for which we developed a nationwide network to collect data from new cases diagnosed in France. In a retrospective, observational study of 86 patients (2000-2013), we described clinical and biological data focusing on morphologies and immunophenotype. We found expression of markers associated with plasmacytoid dendritic cell origin (HLA-DRhigh, CD303+, CD304+, and cTCL1+) plus CD4 and CD56 and frequent expression of isolated markers from the myeloid, B-, and T-lymphoid lineages, whereas specific markers (myeloperoxidase, CD14, cCD3, CD19, and cCD22) were not expressed. Fifty-one percent of cytogenetic abnormalities impact chromosomes 13, 12, 9, and 15. Myelemia was associated with an adverse prognosis. We categorized chemotherapeutic regimens into 5 groups: acute myeloid leukemia (AML)-like, acute lymphoid leukemia (ALL)-like, lymphoma (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP])-like, high-dose methotrexate with asparaginase (Aspa-MTX) chemotherapies, and not otherwise specified (NOS) treatments. Thirty patients received allogeneic hematopoietic cell transplantation (allo-HCT), and 4 patients received autologous hematopoietic cell transplantation. There was no difference in survival between patients receiving AML-like, ALL-like, or Aspa-MTX regimens; survival was longer in patients who received AML-like, ALL-like, or Aspa-MTX regimens than in those who received CHOP-like regimens or NOS. Eleven patients are in persistent complete remission after allo-HCT with a median survival of 49 months vs 8 for other patients. Our series confirms a high response rate with a lower toxicity profile with the Aspa-MTX regimen, offering the best chance of access to hematopoietic cell transplantation and a possible cure.
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Nozawa RS, Yamamoto T, Takahashi M, Tachiwana H, Maruyama R, Hirota T, Saitoh N. Nuclear microenvironment in cancer: Control through liquid-liquid phase separation. Cancer Sci 2020; 111:3155-3163. [PMID: 32594560 PMCID: PMC7469853 DOI: 10.1111/cas.14551] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/16/2020] [Accepted: 06/19/2020] [Indexed: 12/20/2022] Open
Abstract
The eukaryotic nucleus is not a homogenous single‐spaced but a highly compartmentalized organelle, partitioned by various types of membraneless structures, including nucleoli, PML bodies, paraspeckles, DNA damage foci and RNA clouds. Over the past few decades, these nuclear structures have been implicated in biological reactions such as gene regulation and DNA damage response and repair, and are thought to provide “microenvironments,” facilitating these reactions in the nucleus. Notably, an altered morphology of these nuclear structures is found in many cancers, which may relate to so‐called “nuclear atypia” in histological examinations. While the diagnostic significance of nuclear atypia has been established, its nature has remained largely enigmatic and awaits characterization. Here, we review the emerging biophysical principles that govern biomolecular condensate assembly in the nucleus, namely, liquid‐liquid phase separation (LLPS), to investigate the nature of the nuclear microenvironment. In the nucleus, LLPS is typically driven by multivalent interactions between proteins with intrinsically disordered regions, and is also facilitated by protein interaction with nucleic acids, including nuclear non–coding RNAs. Importantly, an altered LLPS leads to dysregulation of nuclear events and epigenetics, and often to tumorigenesis and tumor progression. We further note the possibility that LLPS could represent a new therapeutic target for cancer intervention.
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Affiliation(s)
- Ryu-Suke Nozawa
- Division of Experimental Pathology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Tatsuro Yamamoto
- Division of Cancer Biology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Motoko Takahashi
- Division of Experimental Pathology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Hiroaki Tachiwana
- Division of Cancer Biology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Reo Maruyama
- Project for Cancer Epigenomics, The Cancer Institute of JFCR, Tokyo, Japan
| | - Toru Hirota
- Division of Experimental Pathology, The Cancer Institute of JFCR, Tokyo, Japan
| | - Noriko Saitoh
- Division of Cancer Biology, The Cancer Institute of JFCR, Tokyo, Japan
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Lee SS, McCue D, Pemmaraju N. Tagraxofusp as treatment for patients with blastic plasmacytoid dendritic cell neoplasm. Expert Rev Anticancer Ther 2020; 20:543-550. [PMID: 32460559 DOI: 10.1080/14737140.2020.1776120] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy that previously lacked standardized therapeutic approaches. CD123 (interleukin-3 receptor alpha unit) is highly expressed in many hematologic malignancies, including BPDCN. Tagraxofusp-ezrs (tagraxofusp from herein) is an agent that consists of interleukin-3 fused to a truncated diphtheria toxin, targeting CD123. The Food and Drug Administration recently approved tagraxofusp as therapy for BPDCN for adults and children aged 2 years and older. AREAS COVERED We discuss the history and clinical background of BPDCN along with tagraxofusp as its first-line therapy. We review the clinical efficacy and safety profile of tagraxofusp in adults including proposed sensitivity and resistance. Finally, we summarize tagraxofusp use in the pediatric population. EXPERT OPINION Tagraxofusp is a newly approved therapy for BPDCN, a hematologic malignancy that has overall historically poor outcomes. With its significant efficacy, many patients were successfully bridged to stem cell transplantation in the clinical trial leading to its ultimate approval. Clinical awareness for major toxicities, including capillary leak syndrome will be a critical aspect of using this novel agent. In the future, investigation of its use in other hematologic malignancies and expansion of clinical trials in pediatric populations with BPDCN are warranted.
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Affiliation(s)
- Sophia S Lee
- Department of Internal Medicine, The University of Texas School of Health Sciences at Houston , Houston, TX, USA
| | - Deborah McCue
- Division of Pharmacy, The University of Texas MD Anderson Cancer Center , Houston, TX, USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center , Houston, TX, USA
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Blastic plasmacytoid dendritic cell neoplasm: diagnosis, manifestations, and treatment. Curr Opin Hematol 2020; 27:103-107. [PMID: 31972688 DOI: 10.1097/moh.0000000000000569] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with historically poor outcomes. It typically manifests as asymptomatic skin lesions and cytopenias, which result from bone marrow involvement. Less commonly, it will present in lymph nodes or visceral organs as well. Although rare, BPDCN has been discussed more frequently in recent years as new drugs have been developed that could be effective at treating this disease. RECENT FINDINGS Until recently, treatment for BPDCN commonly included intensive chemotherapy regimens, which are generally reserved for management of acute myeloid leukemia or acute lymphoblastic leukemia. However, in 2018 tagraxofusp (SL-401) was approved as the only treatment specifically indicated for BPDCN. Additional clinical trials are ongoing evaluating the efficacy of newer agents, which could potentially further improve the long-term outcomes for patients with BPDCN. SUMMARY This manuscript reviews the diagnosis, manifestations and treatment of BPDCN.
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Novel Therapies for Blastic Plasmacytoid Dendritic Cell Neoplasm. Hematol Oncol Clin North Am 2020; 34:589-600. [DOI: 10.1016/j.hoc.2020.01.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
PURPOSE OF REVIEW The purpose of this review was to summarize the clinical, diagnostic, and therapeutic features of blastic plasmacytoid dendritic cell neoplasm (BPDCN). RECENT FINDINGS Several case reports and series revealed new clinical, molecular, diagnostic, and therapeutic aspects of the disease. The clinical presentation diversity has been confirmed, with frequent leukemic non-cutaneous or rare atypical manifestations. The clonal evolution in the development of BPDCN has not been sufficiently elucidated. Although certain immunophenotypic markers (CD4, TCL1, CD123, CD56, CD303) are indicative of BPDCN, the diagnosis remains in certain cases challenging. Adult (ALL)-type chemotherapy followed by hematopoietic stem cell transplantation (HSCT) is related to a favorable outcome, while chemotherapy alone seems enough in children. Future studies should continue to investigate whether CD123-directed therapies could be utilized. BPDCN is a rare aggressive malignancy that needs an aggressive induction therapy. Although a diagnostic consensus is still lacking, and large retrospective studies are also needed to obtain standardized treatment guidelines, the future perspectives are encouraging, because of novel therapeutic agents that are under investigation.
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Affiliation(s)
- Nikolaos J Tsagarakis
- Department of Immunology, "G. Gennimatas" General Hospital, Mesogion Avenue 154, 11527, Athens, Greece.
| | - Georgios Paterakis
- Department of Immunology, "G. Gennimatas" General Hospital, Mesogion Avenue 154, 11527, Athens, Greece
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Yoshizawa T, Nozawa RS, Jia TZ, Saio T, Mori E. Biological phase separation: cell biology meets biophysics. Biophys Rev 2020; 12:519-539. [PMID: 32189162 PMCID: PMC7242575 DOI: 10.1007/s12551-020-00680-x] [Citation(s) in RCA: 128] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 03/02/2020] [Indexed: 12/12/2022] Open
Abstract
Progress in development of biophysical analytic approaches has recently crossed paths with macromolecule condensates in cells. These cell condensates, typically termed liquid-like droplets, are formed by liquid-liquid phase separation (LLPS). More and more cell biologists now recognize that many of the membrane-less organelles observed in cells are formed by LLPS caused by interactions between proteins and nucleic acids. However, the detailed biophysical processes within the cell that lead to these assemblies remain largely unexplored. In this review, we evaluate recent discoveries related to biological phase separation including stress granule formation, chromatin regulation, and processes in the origin and evolution of life. We also discuss the potential issues and technical advancements required to properly study biological phase separation.
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Affiliation(s)
- Takuya Yoshizawa
- Department of Biotechnology, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, Japan
| | - Ryu-Suke Nozawa
- Division of Experimental Pathology, Cancer Institute of the Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan
| | - Tony Z Jia
- Earth-Life Science Institute, Tokyo Institute of Technology, Tokyo, Japan
- Blue Marble Space Institute of Science, Seattle, WA, USA
| | - Tomohide Saio
- Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo, Hokkaido, Japan
| | - Eiichiro Mori
- Department of Future Basic Medicine, Nara Medical University, Kashihara, Nara, Japan.
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Deconinck E, Petrella T, Garnache Ottou F. Blastic Plasmacytoid Dendritic Cell Neoplasm: Clinical Presentation and Diagnosis. Hematol Oncol Clin North Am 2020; 34:491-500. [PMID: 32336414 DOI: 10.1016/j.hoc.2020.01.010] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Clinical and biological presentation of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) is depicted to highlight criteria that might alert physicians. Diagnosis of BPDCN is still challenging and requires (1) immunophenotyping of blood or bone marrow aspiration using several markers (CD4, CD56, HLA-DR, myeloid and lymphoid lineage markers) and should include pDC markers such as CD123, cTCL1, CD303, and CD304, and/or (2) pathologic analysis of cutaneous lesions, also with immunohistochemistry using markers specific to BPDCN.
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Affiliation(s)
- Eric Deconinck
- Service Hématologie, Université de Bourgogne Franche-Comté, INSERM Unite Mixte de Recherche (UMR) 1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Centre Hospitalier Universitaire de Besançon, 3 Boulevard Alexandre Fleming, Besançon Cedex 25030, France
| | - Tony Petrella
- Department of Pathology, University of Montréal, Hôpital Maisonneuve-Rosemont, 2900 Boulevard Edouard-Montpetit, Montréal QC H3T 1J4, Quebec, Canada
| | - Francine Garnache Ottou
- Université de Bourgogne Franche-Comté, INSERM Unite Mixte de Recherche (UMR) 1098, RIGHT Interactions Greffon-Hôte-Tumeur/Ingénierie Cellulaire et Génique, Etablissement Français du sang Bourgogne Franche-Comté, 8 rue du Dr JFX Girod, Besançon 25000, France.
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Sakamoto K, Takeuchi K. Cytogenetics of Blastic Plasmacytoid Dendritic Cell Neoplasm: Chromosomal Rearrangements and DNA Copy-Number Alterations. Hematol Oncol Clin North Am 2020; 34:523-538. [PMID: 32336417 DOI: 10.1016/j.hoc.2020.01.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a skin-tropic hematopoietic malignancy. Approximately 60% of cases with analyzable karyotyping results show complex karyotypes. Losses are more frequently found than copy-number gains. Recurrently deleted regions include tumor suppressor genes. No specific chromosomal abnormalities have been demonstrated in BPDCN, but genomic rearrangements involving the MYB family genes and MYC were identified. One-third of cases of BPDCN harbor the 8q24 rearrangement, most frequently with 6p21 harboring RUNX2, which is associated with immunoblastoid cytomorphology and MYC expression. MYB rearrangement is detected in 20% of patients with BPDCN. We review copy-number alterations and chromosomal rearrangements.
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Affiliation(s)
- Kana Sakamoto
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan; Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Kengo Takeuchi
- Pathology Project for Molecular Targets, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo 135-8550, Japan; Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan; Clinical Pathology Center, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
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46
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Li Y, Sun V, Sun W, Pawlowska A. Blastic Plasmacytoid Dendritic Cell Neoplasm in Children. Hematol Oncol Clin North Am 2020; 34:601-612. [PMID: 32336423 DOI: 10.1016/j.hoc.2020.01.008] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematological malignancy, derived from plasmacytoid dendritic cells. It mainly occurs in older adults, but has been reported across all age groups. Most patients present with skin lesions with or without marrow involvement and leukemic dissemination. Treatment with high-risk acute lymphoblastic leukemia therapy regimens with central nervous system prophylaxis is recommended in pediatric patients. Stem cell transplant in children is recommended for relapsed/refractory disease or high-risk disease at presentation. New targeted therapies including the recently FDA-approved anti-CD123 cytotoxin show great promise in improving the response rate.
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Affiliation(s)
- Yixian Li
- Pediatric Hematology, Oncology, Marrow and Blood Cell Transplantation, Children's Hospital at Montefiore, 3411 Wayne Avenue, 9th Floor, Bronx, NY 10467, USA
| | - Victoria Sun
- Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA
| | - Weili Sun
- Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA; Janssen Pharmaceuticals, 10990 Wilshire Boulevard, Suite 300, Los Angeles, CA 90024, USA
| | - Anna Pawlowska
- Pediatric Hematology, Oncology and Hematopoietic Stem Cell Transplantation, City of Hope, 1500 East Duarte Road, Duarte, CA 91010, USA.
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Zhang X, Sun J, Yang M, Wang L, Jin J. New perspectives in genetics and targeted therapy for blastic plasmacytoid dendritic cell neoplasm. Crit Rev Oncol Hematol 2020; 149:102928. [PMID: 32234682 DOI: 10.1016/j.critrevonc.2020.102928] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 12/26/2019] [Accepted: 03/02/2020] [Indexed: 01/12/2023] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is one rare but clinically aggressive hematological malignancy, and it is typically characterized by skin lesion and bone marrow involvement. Diagnosis of BPDCN relies on the immunophenotype positive for four of CD4, CD56, CD123, TCL1 and BDCA-2, and commonly without the expression of MPO, cytoplasmic CD3, CD13, CD64, cytoplasmic CD79a, CD19 and CD20. Commonly, BPDCN is characterized by high CD123 expression, aberrant NF-κB activation, dependence on TCF4-/BRD4-network, and deregulated cholesterol metabolism. Under conventional therapy, the survival duration is only improved in a small number of BPDCN patients. Therefore, targeted therapy should be developed. Up to now, tagraxofusp is the leading edge and has been approved for BPDCN treatment. However, most of other targeted therapy agents were still not pushed to clinical trials for BPDCN. In this review, we emphatically discuss recent perspectives on BPDCN genetic features and developments of its targeted therapy.
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Affiliation(s)
- Xiang Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Jiewen Sun
- Center Laboratory, Affiliated Secondary Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
| | - Min Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Lei Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University College of Medicine, Hangzhou, Zhejiang, China; Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, Zhejiang, Hangzhou, Zhejiang, China; Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China.
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48
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Seiwell AP, Buckley K, Pettenati M, Grier DD. Blastic plasmacytoid dendritic cell neoplasm with t(2;8)(p12;q24). Pediatr Blood Cancer 2020; 67:e28097. [PMID: 31782605 DOI: 10.1002/pbc.28097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 10/26/2019] [Indexed: 11/06/2022]
Affiliation(s)
- Andrew P Seiwell
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Kevin Buckley
- Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Mark Pettenati
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - David D Grier
- Division of Pathology & Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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49
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Roy S, Mandal T, Singh S, Lali B, Chowdhury Z, Nayak L. Blastic plasmacytoid dendritic cell neoplasm of the thigh: A case report and narrative review of literature. CANCER RESEARCH, STATISTICS, AND TREATMENT 2020. [DOI: 10.4103/crst.crst_202_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Alfayez M, Konopleva M, Pemmaraju N. Role of tagraxofusp in treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). Expert Opin Biol Ther 2019; 20:115-123. [PMID: 31801379 DOI: 10.1080/14712598.2020.1701651] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Advances and drug development in rare diseases, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), has historically been limited by small numbers of patients in the target population. In recent years, the development of tagraxofusp (SL-401) (ELZONRIS, Stemline Therapeutics) for the treatment of adult and pediatric BPDCN has been a successful story that led to US FDA approval in December 2018.Areas covered: In this evaluation of tagraxofusp, we briefly review chemistry; pharmacokinetics and pharmacodynamics, as we focus on the clinical experience and future directions.Expert Opinion: Tagraxofusp has been a welcome new addition and a successful initial development step in the targeted treatment of BPDCN. In phase I/II clinical trial, major responses were observed in 90% of treatment-naïve patients, with 72% of the responses observed as complete remissions. Limitations on the usage of tagraxofusp and strategies to handle those limitations were further explored in this review.
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Affiliation(s)
- Mansour Alfayez
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Marina Konopleva
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naveen Pemmaraju
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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