P1, N=13, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: May 2026 --> Aug 2025 | Trial primary completion date: May 2026 --> Aug 2025

P1, N=16, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2025 --> Mar 2026

P1/2, N=64, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Jan 2027 | Trial primary completion date: Jan 2026 --> Jan 2027

To our knowledge, this is the first reported case demonstrating the use of tagraxofusp in a patient with BPDCN and advanced chronic kidney disease, showing that even a minimum of tolerated treatment dose can induce a sustained response. Despite the risk of adverse events, tagraxofusp should be considered a viable treatment option for elderly patients with poor performance status and significant comorbidities who are ineligible for intensive chemotherapy or stem cell transplantation, as even limited exposure may achieve meaningful clinical responses.

Common adverse events included increased alanine aminotransferase (81.8%) and aspartate aminotransferase (72.7%), hypoalbuminemia, hypokalemia, and capillary leak syndrome (54.5%). The results indicate that TAG was effective and had a manageable safety profile in Japanese BPDCN patients.

These findings demonstrate the on-target effect and unique BM-sparing profile of tagraxofusp, which are paramount when treating myelosuppressive, CD123-positive hematologic diseases. The results support single-agent tagraxofusp as standard-of-care, nonmyelosuppressive first-line treatment for BPDCN and as a potential combination partner for other CD123-positive hematologic malignancies.

The approval of tagraxofusp established a foundation for targeted therapy in BPDCN and demonstrated high response rates, leading to the development of additional antibody - drug conjugates and cellular therapies targeting CD123. Other promising targeted approaches include BCL2 inhibitors, proteasome inhibitors, and therapies directed against surface antigens such as CD38 and CD303, as well as bromodomain and extraterminal (BET) inhibitors. Collectively, these strategies represent important advances that may significantly improve the historically poor outcomes associated with BPDCN.

In this trial, tagraxofusp monotherapy in MF was well tolerated, without cumulative myelotoxicity, and with symptom score improvements, warranting further investigation in combination therapy. This trial was registered at www.clincaltrials.gov as #NCT02268253.

During tagraxofusp treatment, strict monitoring for early recognition of CLS symptoms and directed intervention is essential for managing CLS; with this approach CLS is typically mild and occurs mostly in cycle 1, without recurrence. We discuss patient selection and optimization, monitoring, and early intervention for successful identification and optimized management of CLS in real-world practice.

Given the poor prognosis associated with this subtype, CD123-targeted therapy, such as tagraxofusp-erzs, alone or in combination with agents like azacitidine and venetoclax, may represent a rational therapeutic approach. To our knowledge, this represents the third case report of RUNX1 rearrangement in pDC-AML and may provide valuable insights for future research.

P1, N=50, Terminated, LAVA Therapeutics N.V. | Recruiting --> Terminated

In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4+ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect.