The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy.

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.

Tagraxofusp, a first-in-class CD123-directed antibody conjugate comprising human interleukin-3 and truncated diphtheria toxin, represents a welcome addition to the treatment armamentarium for BPDCN...Several questions remain unanswered-namely, the potential benefit of post-transplant consolidation or maintenance strategies to mitigate the risk of relapse or progression, and the role of next-generation sequencing as a prognostic tool and for better defining depth of remission and measurable residual disease, among others. We believe that further improvement in the prognosis of BPDCN will require large collaborative efforts, considering the rarity of this disease.

In this case series, we describe our institutional experience treating BPDCN both pre- and post-tagraxofusp approval. We summarize six cases, the majority of which occurred in elderly patients, and highlight unique challenges of treating BPDCN at a center that serves a large rural/frontier area with variable access to specialty care.