P1, N=43, Recruiting, City of Hope Medical Center | Trial completion date: Jan 2027 --> Apr 2027 | Trial primary completion date: Jan 2027 --> Apr 2027

In conclusion, this large-scale, retrospective database analysis suggests that VEN + HMA is an effective therapeutic alternative to tagraxofusp in older patients for the management of BPDCN. Future studies are needed to prospectively validate these findings.

P1/2, N=20, Recruiting, Stanford University | Not yet recruiting --> Recruiting | Trial primary completion date: Oct 2026 --> Oct 2027

P2, N=25, Terminated, Gruppo Italiano Malattie EMatologiche dell'Adulto | N=50 --> 25 | Recruiting --> Terminated; poor enrollment

Our study confirms that BPDCN is a very rare and difficult-to-treat disease. Underdiagnosis and underreporting in the literature pose further challenges. Symptoms at presentation seem to differ slightly between sexes and reaching a complete remission after first-line treatment remains crucial for a prolonged overall survival. Effective treatment protocols in first line include transplantation regimens (mainly allogenic, potentially also autologous) as well as ALL protocols. In order to understand the significance of tagraxofusp as a bridge to transplant or as a continuous monotherapy in elderly patients, further evaluation with longer follow-up periods is required. In general, analysis of the Swiss patients confirmed the results from the worldwide cohort.

BPDCN is frequently misidentified, but early, accurate diagnosis is critical to extending patient survival using tagraxofusp, a first-in-class CD123-targeted therapy, and increasing their chances of receiving a potentially curative stem cell transplantation. Cases of BPDCN in countries of the Gulf Cooperation Council are lower than the extrapolated incidence from other geographic locations due to lack of awareness of key diagnostic features, lack of consensus on the minimal phenotype for diagnosis, and lack of local immunohistochemistry testing facilities, contributing to underdiagnosis in this region. Practical recommendations, a streamlined diagnostic panel, and suggested multidisciplinary approaches based on expert experience regarding diagnostic and clinical challenges specific to this region, and a review of the literature are presented here to facilitate diagnosis of BPDCN in this region by primary care physicians, dermatologists, and hematologists.

P1/2, N=64, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

P1/2, N=82, Completed, Stemline Therapeutics, Inc. | Phase classification: P2 --> P1/2

P2, N=76, Recruiting, Stemline Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1, N=44, Recruiting, Karen Ballen, MD | Trial primary completion date: Jul 2024 --> Jul 2026

Now, with over 5 years since the first commercially approved targeted agent specifically dedicated for BPDCN, the CD123-targeted agent tagraxofusp, improvements have been demonstrated particularly in the frontline setting for patients with BPDCN. The field is abundant with hope, as it has experienced advancements including greater molecular characterization, expanded identification of potential targets for therapy beyond CD123, advent of combination therapies, improving parameters for stem cell transplantation, and novel clinical trials specifically available for patients with BPDCN.

P1/2, N=20, Not yet recruiting, Stanford University | Initiation date: Oct 2024 --> Jan 2025

Misdiagnosis or late diagnosis of this clinically heterogeneous BPDCN may lead to systemic spread and poor outcomes. Hence, prompt diagnosis and treatment are essential, with a multidisciplinary approach.

P1, N=43, Recruiting, City of Hope Medical Center | Not yet recruiting --> Recruiting

P2, N=76, Not yet recruiting, Stemline Therapeutics, Inc. | Initiation date: Aug 2024 --> Nov 2024

Mechanistically, TBK1 deletion or inhibition by amlexanox or GSK8612 reduced the expression of the transcription factor interferon-regulatory factor (IRF)4 and increased the level of IRF5 activation in macrophages stimulated with M-CSF, leading to an M1-like profile with highly proinflammatory factors. IRF5 deletion reversed the effect of TBK1 inhibition on M-CSF-mediated macrophage polarization. Our findings suggest that TBK1 contributes to the regulation of macrophage polarization in response to M-CSF stimulation partly through the IRF5/IRF4 axis.

This case emphasizes the challenges of diagnosing and treating BPDCN, noting its rarity and absence of standard therapy. Tagraxofusp has shown promising results but presents safety concerns like capillary leak syndrome, particularly in elderly patients with comorbidities.

In conclusion, our study demonstrates that simply inhibiting TBK1 in all immune cells is not effective for the treatment of colitis. Further investigation the anti-inflammatory mechanism of ALX on dendritic cells and macrophages may provide a new strategy for the treatment of IBD.

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...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.

P1/2, N=20, Not yet recruiting, Stanford University

P2, N=3, Terminated, M.D. Anderson Cancer Center | Completed --> Terminated; The protocol was terminated early due to slow participant accrual and the sponsor not willing to provide the study drug.

P1/2, N=4, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | N=40 --> 4

P1, N=43, Not yet recruiting, City of Hope Medical Center

P2, N=76, Not yet recruiting, Stemline Therapeutics, Inc.

P1, N=72, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: May 2024 --> May 2025

P1, N=20, Not yet recruiting, University of Kansas Medical Center

In line with results from 13 published cases outside clinical trials in the literature, sustained responses were associated with CR after tagraxofusp treatment and subsequent alloHCT. Our results provide real-world evidence for safety and efficacy of tagraxofusp as first-line treatment for BPDCN.

P2, N=53, Recruiting, Joshua Zeidner | Not yet recruiting --> Recruiting

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.

No abstract available

P1, N=0, Withdrawn, Jonsson Comprehensive Cancer Center | N=29 --> 0 | Not yet recruiting --> Withdrawn

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.

Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

P1, N=36, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting | Phase classification: P1a/1b --> P1

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.

P2, N=7, Terminated, University of Michigan | N=15 --> 7 | Suspended --> Terminated; Due to limited funding, trial was suspended, intending to restart with additional funds; then preliminary results were obtained, and research moved on to placebo controlled trial. Results for both have been published.

The patient showed resistance to Tagraxofusp and Venetoclax, and he died about 16 months after diagnosis. Considering the predicted effect of the AFF4::IRF1 fusion on IRF1's antitumor effects and immune regulation, and the possibility of its relevance to the aggressive course observed in this case, we propose further evaluation of the clinical significance of this fusion in BPDCN in future cooperative group studies and the consideration of therapeutic strategies aimed at restoring IRF1-dependent antineoplastic effects in such cases.

BPDCN is a rare and challenging entity sharing various typical characteristics of other hematological diseases. Comprehensive diagnostics should be initiated timely to ensure appropriate treatment strategies.

P2, N=53, Not yet recruiting, Joshua Zeidner

Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations.

Therapy prior to allo-HCT included hydroxyurea and TAG + venetoclax + mini-HyperCVAD for 5 cycles. This case report demonstrates a patient experiencing a clinically meaningful benefit with TAG maintenance therapy after allo-HCT. Both prolonged survival and manageable safety, in this case, highlight the feasibility of long-term TAG maintenance post-allo-HCT to control BPDCN.

The role of the JAK/Signal transducer and activator of transcriptions (STAT) pathway in MF has led to the recent approval of three different JAK2 inhibitors (ruxolitinib, pacritinib, and fedratinib) for MF treatment. Our studies showed high sensitivity of MF cell lines to tagraxofusp as a single agent, which is expected given phase 2 results demonstrated clinical efficacy of single-agent tagraxofusp in R/R MF (Yacoub et al. ASH 2021). In addition, synergism was observed in combination with JAK inhibitors.