ARID1A mutation in blastic plasmacytoid dendritic cell neoplasm.
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ABSTRACT:
SUBMITTER: Wang L
PROVIDER: S-EPMC5664412 | biostudies-literature | 2017 Nov
REPOSITORIES: biostudies-literature
Publications
<i>ARID1A</i> mutation in blastic plasmacytoid dendritic cell neoplasm.
Wang Lei L Yang Min M Zhang Xiang X Yang Chunmei C Huang Xin X Wang Zhaoming Z Jin Jie J
Haematologica 20170727 11
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Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that presents with characteristic dark purple skin papules, plaques, and tumors, but may also involve the bone marrow, blood, lymph nodes, and central nervous system. The disease, which commonly affects older men but can also present in children, is associated with a distinct immunophenotype including universal expression of CD123, the α chain of the interleukin 3 receptor. Recently, tagraxofusp, a CD123-targeting drug consisting of the ligand for CD123, interleukin 3, conjugated to a truncated diphtheria toxin payload was approved for treatment of BPDCN. This was the first agent specifically approved for BPDCN and the first CD123 targeted agent in oncology. Here, we review the development of tagraxofusp, and the key preclinical insights and clinical data that led to approval. Tagraxofusp treatment is associated with a unique toxicity, capillary leak syndrome (CLS), which can be severe but is manageable with proper patient selection and monitoring, early recognition, and directed intervention. We outline our approach to the use of tagraxofusp and discuss open questions in the treatment of BPDCN. Overall, tagraxofusp represents a unique targeted therapy and a step forward in meeting an unmet need for patients with this rare disease.
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Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive haematological malignancy in the elderly, with a high frequency of cutaneous and bone marrow involvement and poor prognosis. We report a case of BPDCN with classic presentation and discuss its treatment and the value of different investigation tools used in diagnosis and response assessment.
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Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare CD4+ CD56+ myeloid malignancy that is challenging to diagnose and treat. BPDCN typically presents with nonspecific cutaneous lesions with or without extra-cutaneous manifestations before progressing to leukemia. Currently, there is no standard of care for the treatment of BPDCN and various approaches have been used including acute myeloid leukemia, acute lymphoblastic leukemia, and lymphoma-based regimens with or without stem cell transplantation. Despite these treatment approaches, the prognosis of BPDCN remains poor and there is a lack of prospective data upon which to base treatment decisions. Recent work examining the mutational landscape and gene expression profiles of BPDCN has identified a number of potential therapeutic targets. One such target is CD123, the α subunit of the human interleukin-3 receptor, which is the subject of intervention studies using the novel agent SL-401. Other investigational therapies include UCART123, T-cell immunotherapy, and venetoclax. Prospective trials are needed to determine the best treatment for this uncommon and aggressive neoplasm.
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Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy believed to originate from plasmacytoid dendritic cells (pDCs), the immune cells responsible for producing type 1 interferons during infection. Nearly all patients with BPDCN have prominent skin involvement, with cutaneous infiltration occupying the dermis and subcutis. One half of patients present with BPDCN cells only in the skin, with no evidence of disease elsewhere. Because normal pDCs are rare or absent in cutaneous sites, and they only traffic to the skin after activation by pathogen or inflammation, our aim was to determine if a microorganism is associated with BPDCN. We performed RNA sequencing in BPDCN skin and bone marrow, with cutaneous T-cell lymphoma (CTCL) and normal skin as controls. GATK-PathSeq was used to identify known microbial sequences. Bacterial reads in BPDCN skin were components of normal flora and did not distinguish BPDCN from controls. We then developed a new computational tool, virID (Viral Identification and Discovery; https://github.com/jnoms/virID), for identification of microbial-associated reads remaining unassigned after GATK-PathSeq. We found no evidence for a known or novel virus in BPDCN skin or bone marrow, despite confirming that virID could identify Merkel cell polyomavirus in Merkel cell carcinoma, human papillomavirus in head and neck squamous cell carcinoma, and Kaposi's sarcoma herpesvirus in Kaposi's sarcoma in a blinded fashion. Thus, at the level of sensitivity used here, we found no clear pathogen linked to BPDCN.
| S-EPMC7094006 | biostudies-literature
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically challenging hematologic malignancy with dismal outcomes. With a median age of ∼70 years, the majority of patients with BPDCN have experienced historically suboptimal responses with intensive chemotherapy regimens. The major scientific breakthrough in this field was the recognition of overexpression of a surface receptor, CD123/interleukin 3 (IL-3) receptor α, in all patients. Importantly, a novel therapeutic agent consisting of a truncated diphtheria toxin (DT) payload fused to recombinant human IL-3 was being developed, one that targeted CD123, initially known as DT-IL-3 (later known as SL401; tagraxofusp; tagraxofusp-erzs [Elzonris]). The identification of this agent, and subsequent clinical trials specifically dedicated to patients with BPDCN (including a pilot study, followed by a larger phase 1/2 multicenter study [90% overall response rate [ORR] in frontline and 67% ORR in relapsed/refractory setting]), in part led to approval of tagraxofusp-erzs on 21 December 2018. Tagraxofusp-erzs was the first agent approved for BPDCN (for patients ages 2 years and older), and importantly, established this drug as the first CD123-targeted agent ever approved. The most notable toxicity of tagraxofusp-erzs is occurrence of the capillary leak syndrome, which occurs frequently at all grades, and has also been observed to be life-threatening, appropriately leading to a US Food and Drug Administration "black box" warning in the package insert. The preclinical and clinical aspects of drug development of tagraxofusp-erzs as monotherapy leading to drug approval are reviewed herein, with discussion of future directions of this novel agent, including consideration for rational combinations in BPDCN and beyond.
| S-EPMC7448601 | biostudies-literature
Project description:Patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN) have poor outcomes despite intensive chemotherapy, underscoring the need for novel therapeutic approaches. The expression status of PD1/PD-L1 in BPDCN remains unknown. We evaluated PD1/PD-L1 by immunohistochemistry and RNAseq expression profiling in a cohort of BPDCN patients. The study group included 28 patients with a median age of 66.8 years (range, 22.8-86.7), 22 men and 6 women. PD-L1 expression was detected by immunohistochemistry in 10/21 (47.6%) cases. PD-L1 expression had a median H-score of 157. The H-score was ≥60 in 7 patients. PD-L1 protein levels (H-score) were proportional to normalized PD-L1 mRNA transcript levels (CD274 mRNA). In addition, high-level PD-L1 expression correlated with higher numbers of PD1-positive cells within BPDCN tumors. There was no correlation between clinicopathologic characteristics and PD-L1 expression status. Similarly, there was no significant difference in overall survival between patients with PD-L1-positive and PD-L1-negative BPDCN (median 12 vs. 23 month, respectively; p = 0.743). In conclusion, PD-L1 expression by tumor cells is detectable in a sizeable subset of patients with BPDCN, suggesting that exploration of the effectiveness of therapeutic inhibition of the PD1/PD-L1 axis in patients with refractory or progressive BPDCN is warranted.
| S-EPMC6562447 | biostudies-literature
Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive hematologic malignancy derived from precursors of dendritic cells and involves most frequently the skin, bone marrow and lymph nodes. Diagnosis depends upon identification of specific tumor markers including CD4, CD56 and CD123. Historically, the median survival has been less than 2 years in most reported series. While for many years, conventional chemotherapy followed by stem cell transplantation was the standard of care, recently tagraxofusp, a cytotoxin directed against CD123, received United States Food and Drug Administration approval specifically for patients with BPDCN. In this review, we will discuss the markers used for diagnosis of BPDCN and focus on the new targeted treatments available. Specifically in BPDCN, tagraxofusp was highly effective with a safety profile found to be acceptable overall, with the noted occurrence of capillary leak syndrome. Future directions in therapy approaches for patients with BPDCN will include the development of other CD123-targeted agents, agents targeting beyond CD123 and investigation of rational combination approaches of CD123-directed therapy with other therapies.
| S-EPMC6759709 | biostudies-literature
Project description:Background Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and poorly understood hematopoietic malignancy. This study aimed to investigate the clinical characteristics and prognostic factors in patients with primary BPDCN. Methods Patients diagnosed with primary BPDCN from 2001 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Survival outcome was analysed with Kaplan-Meier method. Prognostic factors were evaluated based on the univariate and multivariate accelerated failure time (AFT) regression analysis. Results A total of 340 primary BPDCN patients were included in this study. The average age was 53.7 ± 19.4 years, with 71.5% being male. The mostly affected sites were lymph nodes (31.8%). Most patients (82.1%) received chemotherapy, while 14.7% received radiation therapy. For all the patients, the 1-year, 3-year, 5-year, and 10-year overall survival (OS) were 68.7%, 49.8%, 43.9%, and 39.2%, respectively, and the corresponding disease-specific survival (DSS) were 73.6%, 56.0%, 50.2%, and 48.1%, respectively. Univariate AFT analysis showed that older age, marital status of divorced, widowed and separated at diagnosis, primary BPDCN only, treatment delay for 3-6 months and without radiation therapy were significantly associated with poor prognosis of primary BPDCN patients. But multivariate AFT analysis indicated that older age was independently associated with worse survival, while second primary malignancies (SPMs) and radiation therapy were independently associated with extended survival. Conclusions Primary BPDCN is a rare disease with poor prognosis. Advanced age was linked independently to poorer survival, while SPMs and radiation therapy were linked independently to prolonged survival.
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Project description:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an extremely rare and aggressive tumor with an unknown pathogenesis. Myelofibrosis (MF) is a type of myeloproliferative neoplasm. MF can be secondary to several hematological malignancies, including chronic myeloid leukemia, myelodysplastic syndrome and hairy cell leukemia. In the present report, a rare case of BPDCN secondary to MF is described. A 70-year-old male patient developed a large purplish-red rash with recurrent symptoms. BPDCN was confirmed by immunohistochemistry of a biopsy specimen and flow cytometry of bone marrow cells. Bone marrow histopathology revealed MF. Next-generation sequencing of peripheral blood revealed mutations in the Tet methylcytosine dioxygenase 2 and NRAS proto-oncogene GTPase genes. The patient underwent one cycle of chemoimmunotherapy, but the condition progressed, an infection developed and the patient eventually died. The present case suggests that BPDCN can occur in conjunction with MF and that the prognosis of such patients is poor. Pathological examination and genetic testing aided in the diagnosis and treatment. This case emphasizes the need to raise awareness of BPDCN among clinicians and to be alert to the potential for fatal infection in patients with BPDCN combined with MF following myelosuppression triggered during chemotherapy.
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Project description: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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