Facts About Blastic Plasmacytoid Dendritic Cell Neoplasm .
HEALTHCAREPROFESSIONALSNo. 2 in a seriesproviding the latestinformationFacts About Blastic PlasmacytoidDendritic Cell Neoplasm (BPDCN)IntroductionBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive, historically difficult-to-diagnosehematologic malignancy with a poor prognosis. In recent years, better understanding of the biology of BPDCN has ledto improved diagnosis. Additionally, the US Food and Drug Administration (FDA) recently approved the targetedtherapy tagraxofusp-erzs (ELZONRIS ) for the treatment of BPDCN. This approval, improved diagnosis, and additionaltherapies currently in development have the potential to improve outcomes moving forward. This publication will explainthe history, diagnosis, and current treatment practices for BPDCN, detail the efficacy and safety data for tagraxofusp-erzs,and review several investigational therapies currently in clinical trials.HighlightsBPDCN has an estimated incidence of 1,000 to 1,400annually in the US and Europe combined.l l lWhile BPDCN can occur at any age, the median age atdiagnosis is in the mid-60s, with approximately 75% ofcases occurring in men.Historically, initial response to combinationchemotherapy has been high, but patients regularlyrelapse with a median overall survival of approximately1 year. These regimens are often associated withsignificant side effects and poor tolerability. l l l 80%–90% of patients with BPDCN present with skinlesions. Early recognition can lead to timely diagnosisand management.l l Accurate diagnosis requires a biopsy showing themorphology of plasmacytoid dendritic blast cellsand immunophenotypic criteria established by eitherimmunohistochemistry or flow cytometry.Immunohistochemical criteria for BPDCN includepositivity for CD123, CD4, CD56 and TCL1 in theabsence of myeloperoxidase and lysozyme.lWhile never evaluated in a prospective trial, historically,patients who have received high-dose acute leukemiabased chemotherapy followed by an allogeneic stem celltransplant during the first remission appeared to havethe best outcomes.Tagraxofusp-erzs (SL-401; ELZONRIS ) is approvedfor the treatment of BPDCN in adults and children 2years of age and older. Tagraxofusp-erzs is a targetedtherapy directed to CD123 (IL-3R), a cell surfacereceptor highly expressed in BPDCN.Additional therapies are currently under investigationfor the treatment of BPDCN.Background and PrevalenceBPDCN is a highly aggressive malignancy derived from the precursors of plasmacytoid dendritic cells (pDCs),immune cells that specialize in the production of type I interferons in response to bacterial and viral stimuli.1-3 Accuratediagnosis of this malignancy has been complicated by a number of factors, including shifting nomenclature over theyears – BPDCN has been referred to as agranular CD4 natural killer cell leukemia, blastic natural killer-cell leukemia/lymphoma and CD4 /CD56 hematodermic neoplasm.1,4-6 As understanding of the biology and origin of thismalignancy has improved, the World Health Organization (WHO) established the term blastic plasmacytoid dendriticcell neoplasm (BPDCN) in 2008.6 BPDCN is currently classified by the WHO as a distinct entity within the myeloidneoplasm and acute leukemia classification.7Support for this publication provided by Stemline Therapeutics, Inc.www.LLS.orgRevised July 2019 Information Specialist: 800.955.4572FSHP2 BPDCN Facts I page 1
Facts about BPDCNBackground and Prevalence, cont.Figure 1. Cutaneous lesions in BPDCNIt is difficult to precisely estimate the incidence ofBPDCN due to its rarity, evolving terminology and likelyunderdiagnosis, but it is thought to represent an estimated1,000 to 1,400 cases annually in the US and Europecombined.1 BPDCN is typically a disease of the middle-agedand elderly, with a median age at diagnosis in themid- 60s.1,2,8,9 Approximately 3 times as many males asfemales are affected.1,2,8 Pediatric cases have also beendescribed in children as young as 8 months of age.10,11Historically, patients diagnosed with BPDCN have a poorprognosis with a median overall survival (OS) from diagnosisof approximately 1 year despite the use of ly recognition of BPDCN has been challenging,because its clinical features can be heterogeneous and canoverlap other hematologic malignancies.3,4,15,16 There canbe a significant delay between the onset of symptoms anddiagnosis.17 Improved understanding of the biology ofBPDCN in recent years and increased awareness by cliniciansand pathologists will likely lead to improved diagnostictimelines.CutaneousApproximately 80%-90% of patients diagnosed withBPDCN present with skin lesions. These lesions may appearto be indolent initially, but progression invariably occurswith involvement of multiple sites including bone marrow,peripheral blood, lymph nodes, liver, spleen and, in some cases,the central nervous system (CNS).2,4,9,13,16Cutaneous lesions vary in size, shape, color and distributionand can be confused with other benign and malignant skinlesions (Figure 1).1,17,18 They can appear as bruise-like orerythematous papules, plaques or tumors measuring upto 10 cm, commonly on the face, trunk and extremities,although they can occur anywhere.1,17,18 BPDCN is oftendetected incidentally by dermatologists, and differentiatingBPDCN from other lesions is critically important. WhenBPDCN is suspected, consultation with a dermatopathologistor hematopathologist is advised and assessment for theimmunohistochemical criteria for BPDCN is recommended(see below).1,13A significant percentage (40% to 50%) of patients initiallypresent with involvement of the bone marrow and lymphnodes.8,18 Extracutaneous involvement that may be observed atpresentation includes lymph nodes, spleen, liver, tonsils, andthe CNS.16,18Revised July 2019Courtesy of Shapiro R, et al. J Cell Sci Ther. 2015;S8. doi:10.4172/21577013.S8-008.8LeukemicIn over half of cases, BPDCN patients present with skinlesions and bone marrow involvement characteristic of acuteleukemia.19 In fewer cases, BPDCN patients may presentwith bone marrow disease without skin involvement.1,4,13,17,19In most of these cases cytopenia is also present, with highlyvariable rates of bone marrow infiltration.19 BPDCNmay co-exist with or have a preceding malignancysuch as myelodysplastic syndrome (MDS) or chronicmyelomonocytic leukemia (CMML) in approximately 10%to 20% of cases,20 and thus hematologic malignancies withBPDCN markers and/or skin lesions should be screened forthe presence of BPDCN.1,8,18DiagnosisMany patients with BPDCN present with what may appearto be indolent disease, but due to the invariable progressionand extremely poor prognosis, rapid and accurate diagnosisis critical for planning appropriate therapy. Identificationof several pDC-related antigens in recent years has aidedthis effort.17 Diagnosis of BPDCN requires a biopsyshowing the morphology of plasmacytoid dendritic blastcells and immunophenotypic criteria established by eitherimmunohistochemistry or flow cytometry, depending onwhat tissue is available for analysis.1 Most cases of BPDCNare diagnosed with a skin biopsy.17The immunohistochemical criteria for BPDCN includepositivity for CD123, CD4, CD56 and TCL-1 in theabsence of other myeloid leukemia markers, particularlymyeloperoxidase and lysozyme. CD56 can be negative inrare cases, which does not rule out BPDCN if the othermarkers are positive.FSHP2 BPDCN Facts I page 2
Facts about BPDCNOther pDC-associated markers, such as CD2AP orCD303/BDCA2 may also be used to confirm thediagnosis.1-3,8,15,17,19 Markers that can be used to distinguishBPDCN from acute myeloid leukemia (AML), leukemiacutis (LC), and myeloid sarcoma (MS) are shown in Table1.1 Atypical immunophenotypes have been reported,however, in which common markers such as CD4 andCD56 are absent.4,17 Myeloid markers, including CD33,CD68 and CD43, may also be expressed in BPDCN.1,3,4,13Table 1. Immunohistochemical markers for %5%-20%CD2APMPOCD303/BDCA-2LysozymeUNIQUE MARKERSCD34CD14CD11cCD163Range of positive cases are shown for shared markers. AML acutemyeloid leukemia; LC leukemia cutis; MS myeloid sarcoma;CD “cluster of differentiation”; TCL1 T-cell leukemia 1;CD2AP CD2-associated protein; BDCA-2 blood dendriticcell antigen 2; MPO myeloperoxidase.Reproduced with permission from Sullivan JM, Rizzieri DA. Hematology Am SocHematol Educ Program. 2016;2016(1):16-23.1 Reprinted with permission from theAmerican Society of Hematology.If BPDCN presents as the leukemic form or if there isbone marrow involvement, flow cytometry is appropriate.A recent study has demonstrated that BPDCN can besuccessfully distinguished from AML, T-cell lymphoblasticleukemia/lymphoma, and NK-cell lymphoma/leukemiausing a 10-color AML flow cytometry panel.3Revised July 2019TreatmentPrior to the approval of tagraxofusp-erzs in December2018, there were no approved therapies for the treatmentof BPDCN. Additionally, due to the lack of prospectiveclinical trials there had been no universally acceptedstandard of care.1,2,4,9 The tagraxofusp-erzs clinical trial thatled to its approval was the first prospective multicenter trialin BPDCN.Historically, induction therapy with non-Hodgkinlymphoma (NHL)-, acute lymphoblastic leukemia (ALL)-,or acute myeloid leukemia (AML)-type chemotherapyregimens had resulted in high initial response rates(complete response [CR] 40% to 90%).1,3 While nevercompared prospectively, patients given ALL-like regimensappear to do better.2,3,19 Relapse occurs frequently withany of these regimens (50% to 90%), with a median OSof approximately 1 year.1,3,4,13,14 Today, tagrazofusp-erzsshould be considered in all eligible patients diagnosedwith BPDCN.Stem cell transplantation (SCT) should be consideredwhen patients have achieved a complete remission andare sufficiently fit. Long-term remissions have been seenwith allo-SCT done during the first remission.1,2 Relapsefollowing transplantation occurs in approximately 30%of patients.1 Transplantation beyond the first remission orin patients who have not achieved a complete remissionappears to have a negative effect on OS and progression-freesurvival.1,2 While auto-SCT has been used for consolidationand can improve survival, allo-SCT during the firstremission has appeared to offer the best results.1,2A recent study has shown CNS involvement in themajority of BPDCN cases at presentation (60%) despitepatients having no neurologic symptoms.21 The CNS isalso a potential site of relapse.1,4 Systemic or intrathecalchemotherapy for CNS prophylaxis during treatmenthas been recommended for BPDCN patients in someguidelines, although prospective data supporting thisapproach is lacking.2,3,21BPDCN is generally a disease of people in their 60s andolder, and fitness for aggressive systemic chemotherapyand conditioning for transplant have been recognized aschallenges in this population. The approval of tagraxofusperzs and several additional therapies currently in clinicaltrials are welcome developments.FSHP2 BPDCN Facts I page 3
Facts about BPDCNTherapies Targeting CD123CD123 (interleukin-3 receptor alpha subunit, or IL-3Rα) is highly expressed in BPDCN (in addition to a wide range ofother hematologic malignancies) and minimally expressed on normal cells, suggesting it is an appropriate target for therapy.1,2There is currently 1 approved therapy for BPDCN that targets CD123, and 3 additional such therapies under investigation.Tagraxofusp-erzs (SL-401)Tagraxofusp-erzs (SL-401, ELZONRIS ) is a recombinantfusion protein consisting of human IL-3 (the natural ligandof CD123) fused to a truncated diphtheria toxin (DT)engineered such that IL-3 replaces the native DT receptorbinding domain.2,22-24 The IL-3 domain of SL-401 directsthe cytotoxic DT payload to cells expressing CD123. Uponinternalization, tagraxofusp-erzs inhibits protein synthesisand induces apoptosis of the target cell.Tagraxofusp-erzs received FDA approval in December 2018for the treatment of BPDCN in adults and children 2 yearsof age and older.25In 29 first-line patients who received the optimal dose oftagraxofusp-erzs in the pivotal trial (12 mcg/kg/day), theoverall response rate was 90%, with a 72% rate of completeresponse (CR) plus complete response with minimal residualskin abnormality (CRc). Of these patients, 45% weresuccessfully bridged to SCT.26In 15 patients with relapsed or refractory disease, 1 patientachieved a CR and 1 patient achieved a CRc (duration 111and 424 days, respectively), for a CR/CRc rate of 13.3%.26Among 94 patients with newly-diagnosed or relapsed/refractory myeloid malignancies, including 58 patientswith BPDCN, who received tagraxofusp-erzs at therecommended dose and schedule, the most common adversereactions ( 30%) were capillary leak syndrome, nausea,fatigue, peripheral edema, pyrexia and weight increase. Themost common laboratory abnormalities (incidence 50%)were decreases in albumin, platelets, hemoglobin, calcium,sodium, and increases in glucose, ALT and AST.25Investigational TherapiesCD123CAR with Truncated EpidermalGrowth Factor ReceptorChimeric antigen receptor (CAR) T- cell therapy leverages thenatural ability of the human immune system to attack anddestroy cancer cells. CARs are genetically engineered cell surfacereceptors that equip T cells with the abilities to recognize andbind antigens found on tumor cells and activate the T cellto kill the target cell. (More information about CAR T-celltherapy can be found here: Facts About CAR T-Cell Therapy.)Revised July 2019A phase 1 study with CD123-directed CAR T-cells isunderway in patients with AML and BPDCN. In additionto the CD123-binding domain, this CAR construct includesa truncated epidermal growth factor receptor (EGFRt).The EGFR sequence lacks the EGF binding domain andintracellular signaling domain but retains the epitope forthe anti-EGFR monoclonal antibody cetuximab. Thisprovides a traceable marker for the CAR T cells and apotential mechanism to destroy them – a CAR T-cell“off switch” – in the event of life-threatening toxicities,which could provide a desirable safety measure for thisemerging therapy.27A phase 1 dose-finding and safety study is ongoing inrelapsed/refractory AML and persistent or recurrentBPDCN. (ClinicalTrials.gov Identifier: NCT02159495)XmAb14045XmAb14045 is a bispecific antibody that binds two targets,CD123 and CD3. It functions to “bring together” tumorcells expressing CD123 and cytotoxic T cells, which bindCD3. The T cells are then activated to kill the CD123expressing target cells.A phase 1 study to determine the safety and tolerability ofXmAb14045 is currently underway in patients with CD123expressing hematologic malignancies, including AML, B-cellALL, BPDCN, and chronic myeloid leukemia (CML). InFebruary 2019, the FDA placed the phase 1 trial on partialclinical hold following two patient deaths.28 (ClinicalTrials.gov Identifier NCT02730312)IMGN632IMGN632 is an antibody-drug conjugate that consists ofa humanized anti-CD123 antibody fused to an indolinobenzodiazepine agent (IGN). When delivered to a target cellvia the anti-CD123 antibody, the IGN payload alkylatesDNA without crosslinking, which kills the CD123-expressingtarget cell.29A phase 1 trial in patients with CD123-expressinghematologic malignancies including ALL, BPDCN,myeloproliferative neoplasms and AML is ongoing.(ClinicalTrials.gov Identifier NCT03386513)FSHP2 BPDCN Facts I page 4
Facts about BPDCNAdditional TargetsConclusionNivolumab (Opdivo )Nivolumab is an antibody that blocks programmed deathreceptor-1 (PD-1). PD-1 serves as an immune system“checkpoint,” preventing the immune system fromdestroying normal cells displaying its ligands PD-L1 andPD-L2. Studies have shown that tumor cells often expressPD-L1, allowing them to evade the immune response.Nivolumab can prevent PD-L1 from binding to PD-1,“unleashing” the immune system to destroy the cancer cells.Nivolumab is approved to treat multiple malignancies,including metastatic melanoma, renal cell carcinoma, andnon-small cell lung cancer.BPDCN is a hematologic malignancy with a highlyaggressive clinical course and a historically poor prognosis.The recent FDA-approval of tagraxofusp-erzs (SL-401)is an exciting development for eligible patients, offeringan alternative to aggressive chemotherapy. This approvedtherapy, in addition to numerous targeted therapies inclinical trials, has the potential to improve outcomes.It is recommended that all treated patients that achieveremission be considered for allogeneic SCT.A phase 2 study is currently underway to determinehow patients with relapsed and refractory peripheralT-cell lymphomas or BPDCN respond to nivolumab.(ClinicalTrials.gov Identifier NCT03075553)VenetoclaxVenetoclax (Venclexta ) is an orally bioavailable smallmolecule that inhibits the anti-apoptotic protein BCL-2.Venetoclax is FDA-approved for treatment of patients withchronic lymphocytic leukemia (CLL), and, in combinationwith chemotherapy, in a subset of patients with acutemyeloid leukemia (AML). Venetoclax is currently beingtested alone and as part of combination therapy in manyhematologic malignancies. A recent study found thatBPDCN cells are highly dependent on BCL-2 for survivaland are sensitive to treatment with venetoclax. In thatstudy, 2 patients were treated off-label with venetoclax andexperienced significant clinical benefits.30 A formal clinicaltrial of venetoclax in BPDCN is underway. (ClinicalTrials.gov Identifier: NCT03485547)Revised July 2019FSHP2 BPDCN Facts I page 5
Facts about BPDCNReferences1. Sullivan JM, Rizzieri DA. Treatment of blastic plasmacytoid dendriticcell neoplasm. Hematology Am Soc Hematol Educ Program.2016;2016(1):16-23. doi: 10.1182/asheducation-2016.1.16.2. Falcone U, Sibai H, Deotare U. A critical review of treatment modalitiesfor blastic plasmacytoid dendritic cell neoplasm. Crit Rev Oncol Hematol.2016;107:156-62.3. Deotare U, Yee KWL, Le LW, et al. Blastic plasmacytoid dendritic cellneoplasm with leukemic presentation: 10-color flow diagnosis andHyperCVAD therapy. Hindawi Case Rep Hematol. 2017; Article ID4984951. https://doi.org/10.1155/2017/4984951.4. Laribi K, Denizon N, Besançon A, et al. Blastic plasmacytoid dendriticcell neoplasm: from origin of the cell to targeted therapies. Biol BloodMarrow Transplant. 2016;22:1357-67.5. Pemmaraju N. Blastic plasmacytoid dendritic cell neoplasm. Clin AdvHematol Oncol. 2016;14:220-2.6. Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of theWorld Health Organization (WHO) classification of myeloidneoplasms and acute leukemia: rationale and important changes. Blood.2009;114:937-51.7. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to theWorld Health Organization classification of myeloid neoplasms andacute leukemia. Blood. 2016;127:2391-2405.8. Shapiro R, Sangle N, Seeney M, et al. Blastic plasmacytoid dendritic cellneoplasm: a review of diagnosis, pathology and therapy. J Cell Sci Ther.2015:S8. doi:10.4172/2157-7013.S8-008.9. Betrian S, Guenounou S, Luqet I, et al. Bendamustine for relapsedblastic plasmacytoid dendritic cell leukaemia. Case report. Hematol Oncol2017;35:252-5. doi: 10.1002/hon.2252.10. Nguyen CM, Stuart L, Skupsky H, et al. Blastic plasmacytoid dendriticcell neoplasm in the pediatric population: a case series and review of theliterature. Am J Dermatopathol. 2015;37:924-8.11. J agalian AG, Buxbaum NP, Facchetti F, et al. Blastic plasmacytoiddendritic cell neoplasm in children: diagnostic features and clinicalimplications. Haematologica. 2010;95:1873-79.12. Sapienza MR, Fuligni F, Agostinelli C, et al. Molecular profiling ofblastic plasmactyoid dendritic cell neoplasm reveals a unique pattern andsuggests selective sensitivity to NF-kB pathway inhibition. Leukemia.2014;28:1606-16.13. Lin C-y, Wu M-Y, Kuo T-t, Lu P-h. Cutaneous blastic p
bone marrow involvement, flow cytometry is appropriate. A recent study has demonstrated that BPDCN can be successfully distinguished from AML, T-cell lymphoblastic leukemia/lymphoma, and NK-cell lymphoma/leukemia using a 10-color AML flow cytometry panel.3 Treatment Prior to the approval of tagraxofusp-erzs in December
The following Fact Fluency Card labels are included in this pack: 1. Plus One Facts 2. Plus Two Facts 3. Plus Three Facts 4. Minus One Facts 5. Minus Two Facts 6. Minus Three Facts 7. Facts of Five 8. Doubles Facts (Addition) 9. Doubles Facts (Subtraction) 10. Near Doubles Facts (e.g. 6 7 6 6 1 12 1 13) 11. Facts of Ten: Addition 12.
doubles-plus-one facts, doubles-plus-two facts, plus-ten facts, plus-nine facts, and then any remaining facts. For multiplication, the suggested sequence is the times-zero principle, times-one principle, times-two and two-times facts, times-five and five-times facts, times-nine and nine-times facts, perfect squares, and then any remaining facts .
Math Bee Practice . 1st Round Mixed Multiplication and Division Facts 2 seconds. Multiplication Facts 6 x 6 _ Multiplication Facts 6 x 6 36. Multiplication Facts 32 8 _ Multiplication Facts 32 8 4. Multiplication Facts 7 x 6 _ Multiplication Facts 7 x 6 42. Multiplication Facts 56 7 _
Reizis et al., 2011). In addition to virus-derived DNA and RNA, pDCs can be activated by self-nucleic acids complexed with antibodies (Båve et al., 2003) or DNA/RNA-binding proteins such as HMGB1 (Tian et al., 2007). In particular, DNA complexes released from activated neutrophils induce
to capture the streams. Dendritic drainage is also common where the rock layers are horizontal. Much of the region of western New York State north of the Pennsylvania border has dendritic drainage because rock layers are flat and there are few faults or folds to divert streams. A radial drainage pattern resembles the spokes of a wheel. Streams .
Spectroelectrochemical Dynamics of Dendritic Poly (Propylene . initial studies also showed that the aptamer used in this study was very selective to, and reproducible for, 17-β-estradiol. Keywords: . [20]or with carbon nanotube and ionic liquid [21]. Since aptamers are known for their ultra-sensitivity
plex interplay of heat/solute diffusion processes and interface curvature effects that are all occurring on dif-ferent length scales. In free growth, the latent heat and the solute (in the case of an alloy) are both rejected into a uniformly undercooled liquid surrounding the growing dendrite. Although free dendritic growth appears to be
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