Cases Of Blastic Plasmacytoid Dendritic Cell Neoplasm Research Articles

Site-discordant expression of myeloid cell nuclear differentiation antigen in blastic plasmacytoid dendritic cell neoplasm

Abstract Objectives Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic neoplasm that can show clinical, morphologic, and immunophenotypic overlap with acute myeloid leukemia. Myeloid cell nuclear differentiation antigen (MNDA) is a nuclear protein expressed by myelomonocytic cells previously reported to be reliably absent in BPDCN and proposed as a useful adjunct for the distinction of BPDCN and acute myeloid leukemia. We encountered a case of BPDCN that showed strong nuclear expression of MNDA in bone marrow and breast samples and weak to absent expression in skin samples, prompting us to reevaluate the expression of MNDA in BPDCN. Methods We collected all available BPDCN cases from the Stanford University archives collected in the past 10 years and subjected them to MNDA immunohistochemistry. In select cases, molecular profiling by next-generation sequencing was performed. Results We found 4 cases (of 8 total examined [50%]) with convincing site-discordant MNDA expression. This expression was seen in 3 of 6 (50%) bone marrow samples, 1 of 2 (50%) breast soft tissue samples, and 3 of 14 (up to 21%) skin samples and was not obviously predicted by age, sex, history of myeloid neoplasm, or treatment history. In 2 cases, MNDA was strongly expressed in 2 distinct sites (breast/bone marrow, skin/bone marrow) and negative in subsequent samples. Conclusions Our findings suggest that MNDA expression in BPDCN is anatomic site dependent and transient, with noncutaneous infiltrates showing more frequent expression than cutaneous infiltrates. These results caution against the use of MNDA to exclude BPDCN when considering the differential diagnosis of a blastic extramedullary infiltrate.

Diagnostic Challenges in the Leukemia Phase of Blastic Plasmacytoid Dendritic Cell Neoplasm without Skin Involvement: A Clinical and Pathological Study

Objective: To improve the accurate diagnosis and treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) without skin involvement. Methods: One case of BPDCN with skin involvement progressing to the leukemia phase was used as a positive reference for bone marrow specimens, and a comparative study was conducted on one case of leukemia phase of BPDCN without skin involvement. Results: The male control was 70 years old and presented with a mass on the right forearm skin. Pathological examination indicated BPDCN. Only one cycle of decitabine + CAG was given and 5 months later, the disease progressed to the leukemia phase. Tumor cells expressed HLA-DR, CD123, CD4, CD56, CD7, CD36, TCL1 and CD304. NGS analysis of bone marrow tumor indicated ASXL1, IDH2, and TP53 mutations. The patient survived only 6 months during follow-up. Another female patient was 73 years old and was initially diagnosed with “T lymphoblastic leukemia” based on partial immunophenotyping results for 81.5% blast cells and the morphology of blast cells showing tailing phenomena. Further immunophenotyping showed that blast cells expressed CD56, HLA-DR, and CD304, partially expressed CD4, CD33, and CD117, and did not express CD34, CD13, CD3, CD5, CD7, CD8, CD10, CD11b, CD14, CD15, CD16, CD19, CD20, CD64, CD303 or MPO. Additional immunohistochemistry of bone marrow biopsy showed that CD43 was negative, TdT was mostly positive, CD4 was slightly positive, CD56 was mostly positive, CD123 was positive, CD117 was slightly positive, and lysozyme was partially weakly positive. The above results implied that after excluding BPDCN, acute myeloid leukemia subtype M5 should be considered. According to the diagnostic criteria of BPDCN in WHO 5th edition hematologic lymphoma, two scenarios can be established for diagnosing BPDCN: (1) CD4 and/or CD56 are positive and CD123 and one of pDC markers (TCL1, CD303, CD304) are expressed. (2) If any three pDC markers are expressed (CD123, TCL1, CD303, CD304), and all expected negative markers (CD3, CD14, CD19, CD34, Lysozyme, Myeloperoxidase) are negative, So the final diagnosis of BPDCN can be established according the former creteria. The latter case had ASXL1 and TET2 mutations detected by NGS analysis, achieved complete remission after receiving venetoclax + azacitidine for one cycle, followed by intermittent venoclax +demethylation agent or low-dose chemotherapy maintenance treatment and live for more than two years now. Conclusion:BPDCN without skin lesions is clinically rare, and its diagnosis is challenging. Comprehensive immunophenotyping and cautious interpretation of immunohistochemistry results such as dim lysozyme expression are crucial. Venetoclax-containing regimens have shown promising therapeutic effects.

Profiling endogenous, environmental, and infectious disease mutational signatures in blastic plasmacytoid dendritic cell neoplasms.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic disease derived from plasmacytoid dendritic lineage cells. The disease typically shows skin as well as frequent bone marrow and peripheral blood involvement. However, the pathogenesis of this disease is still not well understood. While somatic point mutations and genetic rearrangements have been described in BPDCN, the types and origins of these mutations and relationships to other cancer types is not well understood. To probe the origins of BPDCN, we analyzed the exome sequence data of 9 tumor-normal pair cases of BPDCN. We utilized SignatureAnalyzer, SigProfiler and a custom microbial analysis pipeline to understand the relevance of endogenous and environmental mutagenic processes. Our results identified a significant tobacco exposure and aging genetic signature as well as signatures related to nucleotide excision repair deficiency, ultra violet (UV) exposure, and endogenous deamination in BPDCN. We also assessed the samples for microbial infectious disease organisms but did not find a link to a microbial etiology. The identification of a tobacco exposure and aging genetic signature in patients with BPDCN suggests that environmental and endogenous genetic changes may be central to the oncogenesis of BPDCN.

Expanding the Immunophenotypic Spectrum of Neoplastic and Reactive Plasmacytoid Dendritic Cells.

Targeted therapies for blastic plasmacytoid dendritic cell neoplasm (BPDCN) have presented a diagnostic dilemma for differentiating residual BPDCN from reactive plasmacytoid dendritic cells (pDCs) because these conditions have a similar immunoprofile, necessitating discovery of additional diagnostic markers. Fifty cases of BPDCN involving bone marrow (26/50) and skin (24/50) as well as other hematologic malignancies (67) and nonneoplastic samples (37) were included. Slides were stained using a double-staining protocol for the following immunohistochemical marker combinations: TCF4/CD123, TCF4/CD56, SOX4/CD123, and IRF8/CD123. The nuclear marker SOX4 is expressed in neoplastic pDCs; in our cohort, SOX4/CD123 showed 100% sensitivity and 98% specificity in distinguishing BPDCN from reactive pDCs and other neoplasms. TCF4/CD56 had a 96% sensitivity and 100% specificity for BPDCN. IRF8 is a nonspecific marker that is positive in BPDCN and pDCs as well as other myeloid malignancies. The novel immunohistochemical combination SOX4/CD123 distinguishes BPDCN, including CD56-negative BPDCN, from both reactive pDCs and other neoplasms. Because of their high diagnostic sensitivity and specificity, the double-staining marker combinations TCF4/CD123, TCF4/CD56, and SOX4/CD123 can be used to confirm lineage in BPDCN cases and detect minimal/measurable residual disease in tissue specimens.

Biallelic TET2 mutations and canonical ASXL1 mutations are frequent and cooccur in Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): An institutional experience and review of literature.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is recurrently mutated in epigenetic pathway genes. We studied the myeloid-related genetic mutations in a cohort of five patients with BPDCN and one paired relapse case at our institution and identified a high frequency of biallelic TET2 and canonical ASXL1 (c.1934dupG) mutations. The number of cases is small, but the variant allele fraction (VAF) sums of the TET2 mutations, as well as the persistence of TET2 mutations in a case of relapsed BPDCN, suggest an ancestral/founder nature of TET2 clones in the cases. Further literature review shows a high frequency of biallelic TET2 mutations in reported cases of BPDCN.

Genetic Landscape of BPDCN Arising in CML Remission

Background BPDCN (blastic plasmacytoid dendritic cell neoplasm) is a rare and highly aggressive hematologic malignancy which often affects skin lesion. BPDCN initially responds to traditional chemotherapy, but has a high relapse rate and a poor prognosis even after autologous or allogeneic stem cell transplantation (SCT). Almost all patients have CD123 positive tumor, and CD123 targeting therapies are being developed. BPDCN mainly develops de novo, however, up to 20% of BPDCN patients have prior history of other hematologic malignancies (CMML, AML, MDS). Some groups propose to classify BPDCN with PCHM (preexisting or concurrent hematologic malignancies) into a unique subtype based on the clinical course (Blood (2019) 134 (Supp.1): 2723). On the other hand, there are attempts to classify BPDCN according to molecular profile, and they defined two subclasses based on somatic mutations (Blood Cancer Journal (2022) 12:101). Thus substantial efforts are being made to classify BPDCN from various aspects, the classification is still under development due to insufficient number of cases. Herein we experienced a rare case of BPDCN arising in the course of CML as a history of PCHM. Unexpectedly, there have been no reports of BPDCN with preexisting CML, therefore, we report the clinical course and genetic background in our case. Case: 70 year old male Clinical course of CML: He was referred to our hospital at age 60 with elevated white blood cell count (93,550/ul, blast 1.0%). Diagnosis of CML (chronic phase) was made; Sokal score was 0.31 (low risk). With initial therapy of dasatinib 100 mg, his disease status achieved complete molecular response (CMR) at 24 months of treatment; achieved CMR (MR 4.5) at 43 months. Due to side effects (pleural effusion and cytopenia), dasatinib was discontinued at month 74 of treatment, and however, CMR has been maintained. Clinical course of BPDCN: At 48 months after completion of dasatinib treatment, multiple bruise-like skin lesions appeared on the head and abdomen. Skin biopsy revealed diffuse proliferation of blastic cells. Immunohistochemistry and flow cytometry were positive for CD4, CD56, and CD123, and a diagnosis of BPDCN was made. Bone marrow involvement (13%) was also observed. HyperCVAD/MA (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and arabinocytocine) was selected as induction therapy. The skin and bone marrow lesions rapidly improved and the patient achieved hematological remission, but a few CD123-positive tumor cells remained in the bone marrow. Considering autologous SCT, peripheral blood stem cell collection was performed. Unfortunately, the graft was contaminated with CD123-positive cells, and it was determined that autologous SCT was not expected. Allogeneic SCT was not planned due to age and regimen related toxicity. We are currently preparing to conduct a clinical trial of CD123-targeting agent. Molecular Analysis WES of peripheral blood and bone marrow samples was performed. At the hematological remission after 2 cycles of HyperCVAD/MA, high VAF mutations in the splicing factor ZRSR2 gene (p.Y292X (84.6-85.2% VAF)) as well as the histone modifiers ASXL1 (p.L743fs (40.6-43.1% VAF)) and TET2 (c.3955-2A>G (36.2-38.3% VAF), p.T1959fs (42.1-47.0% VAF)) were observed. ZRSR2 nonsense mutation site in our case was located 3 residues upstream of the previously reported site, which has not been reported in previous BPDCN cases (Cancer Discovery (2022) 12: 522-541). Although the tumor cell rate in each sample was less than 10%, the VAF of ZRSR2 mutation was high (84.6-85.2%), indicating that clonal hematopoiesis with ZRSR2 mutations underlies the development of BPDCN. Conclusion This is the first report of BPDCN with a history of CML as a preceding hematologic malignancy. Based on WES data at the remission of BPDCN, we confirmed that the patient had clonal hematopoiesis with not only ASXL1 and TET2 mutations, but also ZRSR2 mutation, a driver mutation characteristic of BPDCN. Despite the fact that clonal hematopoiesis with ASXL1 and TET2 mutations is occasionally observed after CML treatment with TKIs (Blood (2017) 129: 38-47), there were no case reports of BPDCN in patients with preexisting CML. These facts suggest that the presence of mechanism is essential for the development of BPDCN other than driver mutation in ZRSR2. Further investigation of BPDCN with PCHM would provide useful information on the pathogenesis of BPDCN. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A101 BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM OCCURRING POST-LIVER TRANSPLANT FOR PSC WITH CLINICAL REMISSION OF ULCERATIVE COLITIS AFTER STEM CELL TRANSPLANTATION

BackgroundPrimary sclerosing cholangitis (PSC) is a rare autoimmune fibroinflammatory disease that is associated with inflammatory bowel disease (IBD) and can progress to end-stage liver disease (ESLD) requiring liver transplantation (LT). Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and rare hematologic malignancy (HM) that usually affects elderly males. High-dose chemotherapy followed by allogenic stem cell transplantation (SCT) offers the best chance of long-term remission in BPDCN. While it is well described that there is an increased risk of de-novo cancer development after solid organ transplantation (SOT), these are less commonly HMs. There are currently no documented cases of BPDCN in post-SOT patients in the literature.AimsTo describe one of the first cases of BPDCN in a patient post-SOT, and subsequent clinical resolution of UC post SCT.MethodsCase ReportResultsA 19-year-old previously healthy male initially presented with cholangitis and was diagnosed with PSC. Two years after the diagnosis of PSC, he progressed to ESLD and underwent live donor LT in India. He subsequently presented with episodes of bloody diarrhea and a colonoscopy then revealed diffuse mucosal edema, erosions, and spontaneous bleeding, with scattered inflammatory polyps throughout the colon. UC was diagnosed and Infliximab therapy was started. He later presented with a UC flare and Vedolizumab therapy was initiated. A liver biopsy showed recurrent sclerosing cholangitis and ultimately the patient required a second liver transplant. After the second LT he developed weight loss, arthralgias, and progressive splenomegaly following which BPCDN was diagnosed. His Vedolizumab was subsequently stopped. He received induction chemotherapy followed by a single antigen mismatched allogenic SCT. Whilst he had numerous complications associated with his chemotherapy induction, his UC appeared to be in clinical remission. No repeat colonoscopies were completed, however, on follow-up assessments, he denied abdominal pain and reported having formed, non-bloody stools. Unfortunately, he suffered an aggressive relapse of his BPCDN, and he was palliated.ConclusionsThe development of de-novo cancers after LT is common, and patients with PSC are at particularly high risk. PSC-LT patients have also been found to have the highest rate of hematological malignancies post LT; however, these are most commonly post-transplant lymphoproliferative disorder. Additionally, there have been a few reports of complete resolution of IBD after allogenic mismatched SCT. Here we describe one of the first cases of BPCDN post-LT in a PSC-UC patient and display another example of UC clinical remission post allogenic SCT. These findings emphasize that close follow-up of these patients after LT is imperative.Funding AgenciesNone

Cutaneous manifestations of blastic plasmacytoid dendritic cell neoplasm: a retrospective study of morphological and immunophenotypic features.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive malignancy which is diagnostically challenging To characterize clinical, histopathological and immunophenotypic features of BPDCN with cutaneous involvement. Cases of BPDCN with skin lesions diagnosed between 2010 and 2020 were retrospectively studied The age at diagnosis presented a bimodal pattern. The morphological features of skin lesions of BPDCN were heterogeneous, manifesting as disseminated, sporadic or solitary plaques, nodules or tumours. Histopathologically, tumour cells in 67.9% of lesions infiltrated in a diffuse and nodular pattern. Interstitial, lichenoid and perivascular patterns were observed in 14.3%, 7.1% and 10.7% lesions, respectively. Angioinvasion and necrosis were absent. All tumour cells were lymphoblastic-like with polymorphic and irregular nuclei except for one lesion revealing monomorphous immunoblastic-like cells. Immunohistochemically, CD4, CD56, CD123 and TCL-1 were positive in 82.1%, 92.9%, 96.0% and 100% cases of BPDCN, respectively. Simultaneous expression of the four markers were observed in 65.0% of stained lesions. Notably, E2-2 was positively expressed in the nuclei of tumour cells in all BPDCN lesions, but was negative in all myeloid sarcoma lesions. Moreover, peripheral blood flow cytometry of six BPDCN cases revealed varying degrees of tumour cells with heterogeneous expression of CD56. The morphological and phenotypic features of cutaneous BPDCN are heterogeneous. E2-2 may serve as a useful marker to definitively diagnose BPDCN.

Integrated Clinical Genotype-Phenotype Characteristics of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Simple SummaryMutation and protein-level profiling has expanded our understanding of the pathogenesis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) and offered insights into potential therapeutic vulnerabilities. However, the prognostic impact of gene mutations in this disease remains controversial, and studies integrating the mutational landscape with cytogenetic and immunophenotypic characteristics in a real-world clinical context remain limited. We provide an overview of genotypic and phenotypic characteristics of a large, single-institution cohort of BPDCN patients. Besides gene mutations in DNA methylation and histone modification, BPDCN cells often harbor mutations affecting signal transduction, RNA splicing components, and transcription factors, particularly ETV6 and IKZF1. Older age, multiple mutations, and mutations in the DNA methylation pathway are poor prognostic factors.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.

Experience with IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Frontline Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Experience with IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Frontline Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in Pediatric Patients with Tagraxofusp, a CD123-Targeted Therapy

BACKGROUNDBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematological malignancy that overexpresses CD123, the interleukin-3 (IL3) receptor alpha subunit. Although BPDCN predominantly affects older adults (median age of 65 years at diagnosis), cases of BPDCN have been reported across all age groups, including infants and children. There is limited data available in the literature on the efficacy and safety of treatments for pediatric patients with BPDCN. Tagraxofusp (TAG, SL-401) is a CD123-directed targeted therapy consisting of recombinant human IL3 linked to a truncated diphtheria toxin payload. A published multicohort prospective study, with prespecified multisystem endpoints, demonstrated the benefit of TAG in adult patients with untreated or relapsed BPDCN. Among the untreated patients, 72% had a complete response and 90% overall response rate; of these patients, 45% were bridged to stem cell transplantation. Adverse events included transaminase elevations, hypoalbuminemia, thrombocytopenia, and capillary leak syndrome (CLS). In a previous case report including 3 pediatric patients with BPDCN, TAG was well-tolerated without significant toxicities and showed encouraging initial clinical responses. TAG was FDA approved in 2018 for BPDCN treatment in adult and pediatric (≥2 years) patients and was recently approved in the EU as monotherapy for first-line treatment in adults.METHODSHere, we report on a multicenter, retrospective case series investigation involving pediatric patients diagnosed with BPDCN at 3 centers in the United States. All patients were treated with TAG according to local institutional guidelines as either first-line treatment (1L) or as a therapy for relapsed/refractory disease (R/R). Data was collected retrospectively via chart review and summarized descriptively. Assessments included tumor response to therapy, survival and safety (adverse events and laboratory abnormalities).RESULTSA total of 6 pediatric patients diagnosed with BPDCN and treated with TAG were included in this analysis. The median age for patients in this study was 15.5 years (range 10 - 21 years), and 4 of the 6 patients were female. Three patients were R/R and received systemic therapy prior to TAG administration, while 3 patients were treatment-naive. Four patients had bone marrow involvement, 2 patients had lymph node involvement, and all 6 patients had skin lesions at diagnosis. All patients received a TAG dose of 12 mcg/kg, with the exception of 1 patient who received 9 mcg/kg. At the time of data cut off, the number of cycles administered ranged from 1 to 4. TAG was well tolerated in these 6 patients. One patient experienced headaches, hot flashes, fatigue, and mouth sores, and low albumin was observed in one patient. No other adverse events were reported and CLS was not observed in these patients. One patient had a complete response to TAG therapy (bone marrow minimal residual disease negative), 2 patients had stable disease, and 3 patients did not have an observed response. In the three 1L patients, one patient had stable disease (no progression after 4 TAG cycles), and 1 patient with extensive disease (skin, bone marrow and central nervous system) had a complete response. Three patients bridged to a stem cell transplant (SCT); 2 were R/R and 1 was 1L. Median survival data for this cohort will be presented (5 of 6 patients remain alive).CONCLUSIONSThis multicenter, retrospective case series of 6 pediatric patients with BPDCN expands our base of knowledge of BPDCN treatment in younger individuals. At the time of data cut off for this abstract, TAG, an approved treatment for BPDCN, was well tolerated in all patients. Treatment with TAG was associated with promising efficacy, including half of the patients with responses that allowed for bridging to SCT. DisclosuresPemmaraju: CareDx, Inc.: Consultancy; Plexxicon: Other, Research Funding; Samus: Other, Research Funding; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Consultancy; Springer Science + Business Media: Other; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Sager Strong Foundation: Other; Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Clearview Healthcare Partners: Consultancy; Protagonist Therapeutics, Inc.: Consultancy; Affymetrix: Consultancy, Research Funding; Incyte: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Hijiya: Novartis: Consultancy; Stemline Therapeutics: Consultancy. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau.

The diagnostics of blastic plasmocytoid dendritic cell neoplasm: report of five cases

The diagnosis of rare hematological disorders requires a comprehensive clinical and laboratory investigation with careful interpretation of all test results. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is one of such rare entities. We have performed a retrospective analysis of the results of immunophenotyping, cytomorphology and cytogenetics of bone marrow tumor cells from 5 patients with BPDCN aged from 8 to 51 years. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. No specific characteristics of blasts were found. No correlation with the treatment and outcomes was noted as well: 3 patients died of progression or relapse (2 and 1, respectively). Bone marrow immunophenotyping is probably the most valuable laboratory test which allows physicians to establish the proper diagnosis in the absence of skin lesions. Flow cytometry immunophenotyping is the only technique used to determine the antigen profile that enables us to distinguish normal plasmacytoid dendritic cells from tumor ones by the presence (or absence) of the expression of CD2, CD7, CD38, CD56, CD303 etc. In the present paper, we provide a detailed description of five cases of BPDCN and main methods for flow cytometry data analysis. The parents of the patients agreed to use the information, including photos of children, in scientific research and publications.

Blastic plasmacytoid dendritic cell neoplasm with genetic mutations in multiple epigenetic modifiers: a case report

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematodermic malignancy derived from plasmacytoid dendritic cell precursors. Despite advances in our understanding of tumor cell surface markers, the pathogenesis of BPDCN remains largely unknown. No standard or optimal treatments are available for BPDCN, and the prognosis is usually poor. We report herein a case of BPDCN that harbored multiple genetic mutations in epigenetic modifiers such as TET2 and ZRSR2. Genetic studies in patients with BPDCN may provide insights into the underlying pathogenesis, prediction of clinical prognosis, and development of better targeted therapeutics for this rare clinical entity.

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Clinical Characteristics, Immunophenotype and Outcomes of Blastic Plasmacytoid Dendritic Cell Neoplasms in a Peruvian Cohort

Background:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and fatal myeloid malignancy characterized by clonal proliferation of immature plasmacytoid dendritic cells. BDCN has been frequently described in men and age above 60 years, and usually involves the skin and bone marrow. Immunophenotyping is based on CD123+, CD4+ and CD56+ expression and is necessary rule out other myeloid malignancies. Objective: We aimed to describe the clinical characteristics and immunophenotype of BPDCN cases diagnosed at two tertiary Peruvian cancer institutions between 2018-2019. Methods: We retrospectively reviewed medical records of patients diagnosed of BPDCN at two tertiary Peruvian cancer centers (Instituto Nacional de Enfermedades Neoplasicas and Oncosalud-AUNA, Lima-Peru) between 2008 and 2019. Clinical characteristics, treatments, outcomes and immunophenotype by pathology or flow cytometry review, were collected. Patients were classified according to their maturation stage using CD34 and CD117 expression into three subgroups: Immature-Intermediate blastic (IIB-BPDCN; partial expression of CD117 and absence or minimal expression of CD34), mature (M-BPDCN; absence of CD34 and CD117) and unknown(U-BPDCN). Overall survival (OS) and event-free survival (EFS) curves were estimated using the Kaplan-Meier method and compared with the Log-rank test to determine the impact of immunophenotype. Results: Thirty-eight cases were included during the study period. The median age at diagnosis was 38 years (7-82), only six (16%) were older than 65 years, and a notorious female predominance (F/M ratio: 1.7:1) was observed. Twenty-four cases had CD34/117 expression available and were classified according to the maturation stage in IIB-BPDCN (13) and M-BPDCN(11), additionally 14 cases had unknown stage (U-BPDCN). Table 1 summarizes clinical characteristics, treatment and outcomes according to their immunophenotype. Bone marrow infiltration was more frequent in immature phenotypes (92% IIB-BPDCN vs 73% M-BPDCN, p=0.001), as well as skin infiltration was more common in mature phenotype (72% vs 31%, p=0.008). CNS infiltration at diagnosis was 15% and 55% in IIB-BPDCN and M-BPDCN, respectively. Sixteen patients received treatment based on ALL-like protocols, 8 AML-like, 5 CHOP-like and 9 patients only palliative care. At 5 years median follow-up, median EFS and OS was 12 and 16 months, respectively. IIB-BPDCN had the lowest survival (4 months EFS and 6 months OS). Conclusions: We describe a Peruvian cohort of BPDCN patients with younger age at diagnosis and female predominance than reported previously by other series, however further studies in Latino population are required to confirm these results. Immature phenotypes based on CD34 and CD117 expression were associated with high rate of bone marrow infiltration and fatal outcomes. New successful target therapies must be warranted for this rare and fatal condition. Disclosures No relevant conflicts of interest to declare.

CD103 Expression on Blastic Plasmacytoid Dendritic Cell Neoplasms in Peripheral Blood and Bone Marrow Samples

Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive neoplasm which is typically CD4+, CD56+, and CD123+. There is limited information regarding CD103 expression on blastic plasmacytoid dendritic cell neoplasms. We identified six cases of BPDCN and all six had at least partial CD103 expression (31-92% positive) with the majority having significant expression of CD103.

Blastic plasmacytoid dendritic cell neoplasm of the uterus

Introduction. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and very aggressive hematological malignancy derived from precursor of the plasmacytoid dendritic cell. We present a case with cervix uteri involvement without skin lesions, which is, to the best of our knowledge, the first case of BPDCN localized in the cervix. Case outline. A 66-year-old previously healthy women initially presented with a four-week history of vaginal bleeding. Gynecologic examination revealed a tumorous bleeding formation on cervix uteri. Except paleness of the skin, physical examination results were normal. Complete blood counts showed anemia and thrombocytopenia. Computed tomography scans showed an expansive tumorous formation at the level of the isthmus and cervix uteri, 60 ? 42 mm in size. Cervical biopsy was done and final pathohistological diagnosis was BPDCN. Karyotype analysis results from the bone marrow aspiration specimen demonstrated tetrasomy of chromosome 2 and monosomy of chromosome 16. The patient did not accept treatment and died two months after the initial diagnosis was established. Conclusion. Attributes such as aggressive clinical course of BPDCN, demonstrated unusual localization, infrequency, and the absence of consensus about standard treatment options, demand constructive clinical reasoning and tight cooperation between medical professionals of various fields.

Blastic Plasmacytoid Dendritic Cell Neoplasia: A Single Center Experience

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare malignancy with skin tropism. The entity was recently defined and the diagnosis is generally made by skin biopsies. It is necessary to apply appropriate immunohistochemistry to recognize this rare entity. There is no consensus on therapy and the survival rates are low. The aim of this study is to describe the clinical and histopathological features of BPDCN. We retrospectively reviewed 8 BPDCN cases of the Cerrahpaşa Medical Faculty diagnosed between 2005 and 2019. We documented the clinical findings, histopathologic diagnoses, and outcomes. The mean age of the patients was 58.7 years (range=11-86 years), and 7 patients were male. The patients presented with erythematous or purple papules, plaques, and papulonodular or nodular cutaneous lesions. Two had lymphadenomegaly at presentation. In microscopic evaluations, tumor cells infiltrated the entire dermis with a clear-cut subepidermal Grenz zone in all cases. CD4, CD56, and CD123 were the most frequently expressed immunohistochemical markers. The median follow-up of 7 cases was 14 months, ranging from 6 to 48 months. Three patients died of the disease, while 4 patients were still alive. Out of 7 patients, 5 received chemotherapy. We found that the outcomes of some patients were different from others but we did not link any distinct clinical or histopathological characteristics to these different outcomes.

Dual Expression of TCF4 and CD123 Is Highly Sensitive and Specific For Blastic Plasmacytoid Dendritic Cell Neoplasm.

The diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) has been based on the expression status of multiple markers, including CD123. TCF4 was discovered recently to be an obligatory master regulator of plasmacytoid dendritic cells. We postulated that a tissue-based assay designed to detect dual CD123 and TCF4 expression would provide a highly reliable and practical marker for BPDCN in biopsy material. We designed, optimized, and validated a dual-color TCF4/CD123 immunohistochemistry stain for use in formalin-fixed paraffin-embedded tissue sections. The performance characteristics of the TCF4/CD123 stain were evaluated in 48 confirmed BPDCN cases. TCF4/CD123 coexpression was detected reproducibly in plasmacytoid dendritic cells. In BPDCN, the TCF4/CD123 stain showed coexpression in all (48/48; 100%) cases analyzed. Cases with concurrent samples from different anatomic sites showed comparable staining characteristics. In contrast, of 464 non-BPDCN cases comprising a wide range of hematolymphoid neoplasms and cutaneous lesions that might enter in the differential diagnosis of BPDCN, we identified dual expression of TCF4 and CD123 in only 1 case of B-lymphoblastic leukemia/lymphoma. On the basis of these findings, the TCF4/CD123 dual-color immunohistochemical stain had an analytic sensitivity of 100% and a specificity of 99.8%. Receiver operator characteristic analysis demonstrated an area under the curve of 1.000 (95% confidence interval: 0.999-1.000). In summary, the dual-color TCF4/CD123 immunohistochemistry stain provides a robust standalone and cost-effective assay for the diagnosis of BPDCN.

Recurrent 8q24 rearrangement in blastic plasmacytoid dendritic cell neoplasm: association with immunoblastoid cytomorphology, MYC expression, and drug response.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare skin-tropic hematological malignancy of uncertain pathogenesis and poor prognosis. We examined 118 BPDCN cases for cytomorphology, MYC locus rearrangement, and MYC expression. Sixty-two (53%) and 41 (35%) cases showed the classic and immunoblastoid cytomorphology, respectively. Forty-one (38%) MYC+BPDCN (positive for rearrangement and expression) and 59 (54%) MYC-BPDCN (both negative) cases were identified. Immunoblastoid cytomorphology was significantly associated with MYC+BPDCN. All examined MYC+BPDCNs were negative for MYB/MYBL1 rearrangement (0/36). Clinically, MYC+BPDCN showed older onset, poorer outcome, and localized skin tumors more commonly than MYC-BPDCN. MYC was demonstrated by expression profiling as one of the clearest discriminators between CAL-1 (MYC+BPDCN) and PMDC05 (MYC-BPDCN) cell lines, and its shRNA knockdown suppressed CAL-1 viability. Inhibitors for bromodomain and extra-terminal protein (BETis), and aurora kinases (AKis) inhibited CAL-1 growth more effectively than PMDC05. We further showed that a BCL2 inhibitor was effective in both CAL-1 and PMDC05, indicating that this inhibitor can be used to treat MYC-BPDCN, to which BETis and AKis are probably less effective. Our data will provide a rationale for the development of new treatment strategies for patients with BPDCN, in accordance with precision medicine.