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Leukemic masses are a known complication in patients with hematologic malignancies. Here we present a case regarding a patient with recently diagnosed B-acute lymphoblastic leukemia (B-ALL) who presented with multiple sites of extramedullary involvement including an anterior mediastinal mass. This mass persisted despite multiple rounds of multiagent cytotoxic therapy. In this report, we summarize the literature regarding mediastinal masses in the setting of B-ALL and illustrate that such masses in patients with leukemias may have surprising etiology, separate from the primary disease.

Background: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases., Methods: For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m 2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m 2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing., Results: Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia., Interpretation: The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted., Funding: Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center., Competing Interests: Declaration of interests NJS has received consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi; research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure; and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene. EJ has received consulting fees and research funding from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, ASTX Pharmaceuticals, AstraZeneca, Autolus, BMS, Genenenctech, Hikma, Kite, Novartis, Pfizer, Takeda Oncology, and Jazz. HA has received consulting fees from Molecular Partners; research funding from Genentech, GlaxoSmithKline, and EBD-300; and honoraria from Illumina. MK has received consulting fees from AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F Hoffman-La Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, and Vincerx; research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, and Stemline; honoraria from AbbVie, Baxk Therapeutics, Genentech, and Stemline Therapeutics; stock options in Reata Pharamceuticals; and holds patents with Novartis, Eli Lilly, and Reata Pharmaceutical. HK has received research funding from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, and Novartis and honoraria from AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda Oncology. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2 -mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%)., (© 2024 Wiley Periodicals LLC.)

Abstract: With emerging new drugs in myelofibrosis (MF), a robust and harmonized framework for defining the severity of anemia and response to treatment will enhance clinical investigation and facilitate interstudy comparisons. Accordingly, the lead authors on the 2013 edition of the International Working Group-European LeukemiaNet (IWG-ELN) response criteria in MF were summoned to revise their document with the intent to (1) account for gender-specific differences in determining hemoglobin levels for eligibility criteria; (2) revise the definition of transfusion-dependent anemia (TDA) based on current restrictive transfusion practices; and (3) provide a structurally simple and easy to apply response criteria that are sensitive enough to detect efficacy signals (minor response) and also account for major responses. The initial draft of the 2024 IWG-ELN proposed criteria was subsequently circulated around a wider group of international experts and their feedback incorporated. The proposed articles include new definitions for TDA (≥3 units in the 12 weeks before study enrollment) and hemoglobin thresholds for eligibility criteria (<10 g/dL for women and <11 g/dL for men). The revised document also provides separate (TDA vs non-TDA) and graded (major vs minor response) response criteria while preserving the requirement for a 12-week period of screening and observation on treatment., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Historically, treatment options for blastic plasmacytoid dendritic cell neoplasm (BPDCN) were limited to conventional chemotherapy, adopted from regimens used to treat acute myeloid or acute lymphoblastic leukemias, or lymphomas. Nowadays, a novel therapy targeting CD123 is available to treat BPDCN. Yet, regardless of treatment choice, achieving a first complete remission (CR1) represents the main goal of therapy, because it represents the best opportunity to prolong survival in BPDCN, if offered an allogeneic hematopoietic cell transplant (allo-HCT) as consolidative therapy. Although no specific conditioning regimen is considered standard-of-care in allo-HCT eligible patients, recent data from two large registries reported a survival advantage when offering total body irradiation-based myeloablative conditioning (MAC) regimens. Unfortunately, applicability of MAC regimens is not feasible in older/unfit patients, which represents a considerable proportion of patients presenting worldwide. In such cases, reduced intensity conditioning regimens represent the next best option. Auto-HCT could be considered in older/unfit patients who did not have BM involvement at initial presentation and at time of the procedure, albeit data supporting this option is less abundant. Future research is needed to decipher the interplay between clinical, genetic, and molecular features of the disease to personalize treatment accordingly, by enhancing efficacy and avoiding unnecessary toxicities., (Copyright © 2024 American Society of Hematology.)

Introduction: JAK inhibitors (JAKi) have changed the treatment paradigm of myelofibrosis (MF). Currently, 4 JAKis are approved in the US as monotherapy (mono) to treat patients with MF. JAKis are also being studied in combination (combo) with novel agents. Herein, we review some of the key studies that evaluated JAKi as mono and combo in MF., Areas Covered: We performed a Pubmed search for 'JAK inhibitors' and 'myelofibrosis' from 1/2010 to 12/2023. For mono, we included only the unique phase II/III studies of the approved JAKi. Selective studies that evaluated JAKi in combo with the novel agents were also included., Expert Opinion: JAKis aim to provide clinical benefit to patients via spleen size reduction and MPN symptom improvement. In order to potentially increase clinical benefit for patients with MF, several novel agents are being partnered with ruxolitinib (RUX) with the ongoing hypothesis to augment greater measures of MF disease modification. The novel agents are either 'added-on' to RUX or as a combo in JAKi naïve patients. Also, the mutant-targeting era of therapies is now beginning with novel CALR-mutated, novel JAK2 V617F mutation-specific and type II JAK2i in the initial stages of drug development, representing a new approach to treatment.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Competing Interests: Disclosures Dr C.D.D. declares research support (to institution): Abbvie, Astex, Beigene, Calithera, BMS, Cleave, ImmuneOnc, and Loxo; consultant/advisory boards: Abbvie, Astellas, BMS, Daiichi-Sankyo, GenMab, GSK, Immunogen, Notable Labs, Servier, and Stemline. Dr. T.K. reports grant or research support from BMS, Celgene, Pfizer, Amgen, Jazz, AstraZeneca, and Genetech; consultant fees from Agios, Jazz, Genetech, and Novartis. Dr. F.R. reports research funding from BMS, Amgen, Xencor, Macrogenics, Orsenix, Abbvie, Prelude, Astex; consultancy and honoraria from Celgene, BMS, Amgen, Astellas, Xencor, Agios, AstraZeneca, and Orsenix. Dr N.P reports research contributions from Affymetrix, Stemline Therapeutics, AbbVie, Daiichi Sankyo, Plexxikon, Cellectis, Novartis, Samus Therapeutics; grant support from Affymetrix, SagerStrong; and honoraria from Stemline Therapeutics, LFB Biotechnologies, MustangBio, Incyte Corporation, Celgene, DAVA Oncology, Blueprint Medicines, Novartis, and Roche Diagnostics. The other authors have no conflict of interest.

VEXAS syndrome is a recently described entity characterized by systemic inflammatory and hematologic manifestations. The disease was first characterized by Beck et al. in 2020 in a study characterizing 25 patients with undiagnosed adult-onset inflammatory syndromes. While the literature regarding VEXAS syndrome has grown exponentially since 2020, there is still much to be understood. This lack of information leads to challenges in both the diagnosis and treatment of patients with VEXAS syndrome. Patients will often have a variety of clinical symptoms that can lead to missed or delayed diagnoses. Additionally, awareness of VEXAS syndrome is still developing among clinicians. In this comprehensive review, we summarize the current literature regarding VEXAS syndrome, and explore clinical updates of this emerging disease state. Our aim of this review is to increase awareness regarding this new disease state and identify research areas to better understand future treatment approaches for patients with VEXAS syndrome.

The presence of BRAF mutation in hematological malignancies, excluding Hairy cell leukemia, and its significance as a driver mutation in myeloid neoplasms (MNs) remains largely understudied. This research aims to evaluate patient characteristics and outcomes of BRAF -mutated MNs. Among a cohort of 6667 patients, 48 (0.7%) had BRAF -mutated MNs. Notably, three patients exhibited sole BRAF mutation, providing evidence supporting the hypothesis of BRAF 's role as a driver mutation in MNs. In acute myeloid leukemia, the majority of patients had secondary acute myeloid leukemia, accompanied by poor-risk cytogenic and RAS pathway mutations. Although the acquisition of BRAF mutation during disease progression did not correlate with unfavorable outcomes, its clearance through chemotherapy or stem cell transplant exhibited favorable outcomes (median overall survival of 34.8 months versus 10.4 months, p  = 0.047). Furthermore, G469A was the most frequently observed BRAF mutation, differing from solid tumors and hairy cell leukemia, where V600E mutations were predominant.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and clinically aggressive hematologic malignancy with limited treatment options. Currently, standard treatment strategies include clinical trials; chemotherapy regimens such as hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD); and tagraxofusp-erzs (TAG, previously SL-401) which is the first-in-class targeted therapy against CD123. TAG received Food and Drug Administration approval for frontline BPDCN treatment in December 2018 and has increasingly become an alternative to chemotherapy, offering potentially more effective and less toxic options. However, despite promising results, there are still patients who may be resistant to TAG monotherapy and/or who respond but eventually relapse. Herein, we discuss an important patient case of BPDCN treated with TAG and review BPDCN treatment strategies., Competing Interests: Source of Support: None. Conflict of Interest: None.

Background: The dual inhibition of the BCR::ABL1 tyrosine kinase and BCL-2 could potentially deepen the response rates of chronic myeloid leukemia in chronic phase (CML-CP). This study evaluated the safety and efficacy of the combination of dasatinib and venetoclax., Methods: In this phase 2 trial, patients with CML-CP or accelerated phase (clonal evolution) received dasatinib 50 mg/day for three courses; venetoclax was added in course 4 for 3 years. The initial venetoclax dose was 200 mg/day continuously but reduced later to 200 mg/day for 14 days, and to 100 mg/day for 7 days per course once a molecular response (MR)4.5 was achieved. After 3 years of combination, patients were maintained on single-agent dasatinib. The primary end point was the rate of major molecular response (MMR) by 12 months of combination., Results: Sixty-five patients were treated. Their median age was 46 years (range, 23-73). By 12 months of combination, the MMR, MR4, and MR4.5 rates were 86%, 53%, and 45%, respectively. After a median follow-up of 42 months, the 4-year event-free and overall survival rates were 96% and 100%, respectively. Outcomes with the combination were comparable to historical outcomes with single-agent dasatinib (cumulative 12-months MMR rate of 79% with both strategies). The incidence of grade 3-4 neutropenia was 22% with the combination and 11% with single-agent dasatinib (p < .001)., Conclusions: Treatment with dasatinib and venetoclax was safe and effective in CML-CP. The cumulative response rates with the combination were similar to those with single-agent dasatinib. Further follow-up is needed to evaluate the rates of durable deep molecular response and treatment-free remission., (© 2024 American Cancer Society.)

Purpose: AML presenting with hyperleukocytosis is associated with poor outcomes. We aim to understand the factors associated with early mortality and overall survival (OS) to help guide management and improve early mortality., Methods: We retrospectively reviewed data from 129 consecutive patients with newly diagnosed AML and a WBC count ≥100 × 10 9 /L between January 2010 and April 2020. Logistic regression models estimated odds ratios for 4-week mortality. Cox proportional hazard models estimated hazard ratios for OS., Results: The median age was 65 years (range, 23-86); the median WBC was 146 × 10 9 /L (range, 100-687). Seventy-five (58%) patients had clinical leukostasis (CL). FLT3 , NPM1 , and RAS pathway mutations were detected in 63%, 45%, and 27% of patients, respectively. Cytoreduction consisted of hydroxyurea in 124 (96%) patients, cytarabine in 69 (54%), and leukapheresis in 31 (24%). The cumulative 4-week and 8-week mortality rates were 9% and 13%, respectively, all in patients age 65 years and older. By multivariate analysis, older age, CL, and thrombocytopenia <40 × 10 9 /L were independently associated with a higher 4-week mortality rate. After a median follow-up of 49.4 months, the median OS was 14.3 months (95% CI, 7 to 21.6), with 4-year OS of 29%. Age 65 years and older, CL, tumor lysis syndrome, elevated LDH ≥2,000 U/L, elevated lactate ≥2.2 mmol/L, and poor-risk cytogenetics were independent factors associated with worse OS., Conclusion: Hyperleukocytosis is a life-threatening hematologic emergency. Early recognition and intervention including cytoreduction, blood product support, antibiotics, and renal replacement therapy may help mitigate the risk of morbidity and early mortality.

Tagraxofusp is a first-in-class CD123-directed conjugate of an amended diphtheria toxin platform and recombinant interleukin 3. Binding and subsequent internalization of the drug result in cell death via disruption of intracellular protein synthesis. CD123 is a surface marker that is expressed in several hematological malignancies, especially blastic plasmacytoid dendritic cell neoplasm (BPDCN), where its expression is ubiquitous. A pivotal study of tagraxofusp in BPDCN resulted in its approval for the treatment of BPDCN, the first treatment approved for this indication. Since the introduction of tagraxofusp, research has focused on the management of adverse effects, combination therapy to improve outcomes in fit patients, and dosing and combination strategies to mitigate toxicities while preserving efficacy, especially among older patients. The successful targeting of CD123 in BPDCN has also encouraged research into a variety of other CD123-positive hematological neoplasms, including acute myeloid leukemia (AML), and informed the development of other novel agents targeting CD123. This review examines the clinical data leading to the development and approval of tagraxofusp in BPDCN, how it is being used in combination to improve outcomes in BPDCN and AML, and its developing role in other hematological malignancies., (© 2024 American Cancer Society.)

Myeloproliferative neoplasms (MPN) are characterized by a clonal proliferation of myeloid lineage cells within the bone marrow. The classical BCR-ABL negative MPNs are comprised of polycythaemia vera, essential thrombocythaemia and primary myelofibrosis. Historically, the majority of MPNs are diagnosed in adults older than 60 years of age; however, in recent years, there has been recognition of MPNs in the adolescent and young adult (AYA) population. AYAs with MPN, typically defined as between the ages of 15 and 39 years old, may comprise up to 20% of patients diagnosed with MPN. They demonstrate unique patterns of driver mutations and thrombotic events and remain at risk for progression to more aggressive disease states. Given the likely long length of time they will live with their disease, there is a significant unmet need in identifying well-tolerated and effective treatment options for these patients, particularly with the advent of disease modification. In this review, we provide a comprehensive overview of the clinical features, disease course and management of AYA patients with MPN and, in doing so, highlight key characteristics that distinguish them from their older counterparts., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Background: An inflammatory bone marrow microenvironment contributes to acquired bone marrow failure syndromes. CK0801, an allogeneic T regulatory (Treg) cell therapy product, can potentially interrupt this continuous loop of inflammation and restore hematopoiesis., Methods: In this phase 1 dose-escalation study of CK0801 Treg cells, we enrolled patients with bone marrow failure syndromes with suboptimal response to their prior therapy to determine the safety and efficacy of this treatment for bone marrow failure syndromes., Results: We enrolled nine patients with a median age of 57 years (range, 19 to 74) with an underlying diagnosis of aplastic anemia (n=4), myelofibrosis (n=4), or hypoplastic myelodysplasia (n=1). Patients had a median of three prior therapies for a bone marrow failure syndrome. Starting dose levels of CK0801 were 1 × 10 6 (n=3), 3 × 10 6 (n=3), and 10 × 10 6 (n=3) cells per kg of ideal body weight. No lymphodepletion was administered. CK0801 was administered in the outpatient setting with no infusion reactions, no grade 3 or 4 severe adverse reactions, and no dose-limiting toxicity. At 12 months, CK0801 induced objective responses in three of four patients with myelofibrosis (two had symptom response, one had anemia response, and one had stable disease) and three of four patients with aplastic anemia (three had partial response). Three of four transfusion-dependent patients at baseline achieved transfusion independence. Although the duration of observation was limited at 0.9 to 12 months, there were no observed increases in infections, no transformations to leukemia, and no deaths., Conclusions: In previously treated patients, CK0801 demonstrated no dose-limiting toxicity and showed evidence of efficacy, providing proof of concept for targeting inflammation as a therapy for bone marrow failure. (Funded by Cellenkos Inc.; Clinicaltrials.gov number, NCT03773393.).

BPDCN is an aggressive myeloid malignancy with a poor prognosis. It derives from the precursors of plasmacytoid dendritic cells and is characterized by CD123 overexpression, which is seen in all patients with BPDCN. The CD123-directed therapy tagraxofusp is the only approved treatment for BPDCN; it was approved in the US as monotherapy for the treatment of patients aged ≥2 years with treatment-naive or relapsed/refractory BPDCN. Herein, we review the available data supporting the utility of tagraxofusp in treating patients with BPDCN. In addition, we present best practices and real-world insights from clinicians in academic and community settings in the US on how they use tagraxofusp to treat BPDCN. Several case studies illustrate the efficacy of tagraxofusp and discuss its safety profile, as well as the prevention, mitigation, and management of anticipated adverse events.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases., Competing Interests: Disclosures Naveen Pemmaraju: Pacylex Pharmaceuticals, Astellas Pharma US, ImmunoGen, Inc, Bristol-Myers Squibb Co., Cimeio Therapeutics AG, EUSA Pharma, Menarini Group, Blueprint Medicines, CTI BioPharma, ClearView Healthcare Partners, Novartis Pharmaceutical, Neopharm, Celgene Corporation, AbbVie Pharmaceuticals, Pharma Essentia, Curio Science, DAVA Oncology, Imedex, Intellisphere, CancerNet, Harborside Press, Aptitude Health, Medscape, Magdalen Medical Publishing, OncLive, CareDx, Patient Power, Physician Education Resource (PER): Consultancy/Scientific Advisory Board/Speaking; United States Department of Defense, National Institute of Health/National Cancer Institute (NIH/NCI): Research (Grant); Affymetrix: Research Funding; Dan's House of Hope: Membership on an entity's Board of Directors/Management; ASH Committee on Communications, ASCO Cancer.Net Editorial Board: Leadership; Karger Publishers: Licences; HemOnc Times/Oncology Times: Uncompensated. Eric Deconinck: Stemline Therapeutics: Consultancy, honoraria; ImmunoGen: Consultancy, honoraria; Chugai: Research funding; Novartis: Research funding. Priyanka Mehta: Pfizer, AbbVie, Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Stemline Therapeutics: Advisory board/honoraria. Irwin Walker: Sanofi: Research funding. Marco Herling: AbbVie, BeiGene, Jazz, Janssen, Stemline Therapeutics, Takeda: Consultancy; Mundipharma EDO, Janpix, Novartis, Roche: Funding of preclinical research. Francine Garnache-Ottou: Stemline Therapeutics, LFB: Consultancy. Nadia Gabarin: Declarations of interest: none. Clinton Campbell: Declarations of interest: none. Johannes Duell: Stemline: Lecturing Yakir Moshe: AbbVie: Advisory board, research funding, speaker; Astellas, Medison: Advisory board, speaker; Gilead, Novartis, Stemline: Advisory board Tariq Mughal: Informa Publishing, Oxford University Press: Royalties. Consultant: Stemline Therapeutics Inc, New York, NY, USA. Mohamad Mohty: Jazz Pharmaceuticals: Research funding, honoraria. Emanuele Angelucci: Menarini/Stemline, Novartis: Honoraria; bluebird bio, Glaxo, Gilead, Roche: Board of Directors or advisory committees; Vifor Pharma, BMS, Vertex Inc.: Participation DMC., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)