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

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.

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.

Mechanistically, compound 36 has a high binding affinity for the eEF2K protein and effectively induces its degradation. Additionally, 36 exerts a comparable tumor-suppressive effect to paclitaxel in an MDA-MB-231 cell xenograft mouse model with no obvious toxicity, demonstrating that compound 36 could be developed as a potential novel therapeutic for TNBC treatment.

Moreover, we further discuss the inhibition of eEF2K with small-molecule inhibitors and other new emerging therapeutic strategies in cancer therapy. Taken together, these inspiring findings provide new insights into a promising strategy for inhibiting eEF2K to greatly improve future cancer therapy.

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.

P1/2, N=46, Not yet recruiting, Darell Bigner

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.

Targeted eEF2K blockade may result in cGAS-STING pathway activation, leading to enhanced infiltration and activity of NK cells within HCC tumors. The synergistic effect achieved by combining an eEF2K inhibitor with PD-1 antibody therapy represents a novel and promising approach for the treatment of HCC.

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

P1, N=30, Recruiting, Annick Desjardins, MD | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=18, Active, not recruiting, Annick Desjardins, MD | Trial primary completion date: Dec 2023 --> Dec 2024

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.

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.

Additionally, combination treatment of C1 with paclitaxel, a commonly used chemotherapeutic drug, exhibits synergistic anti-tumor effects against TNBC. This study not only generates a powerful research tool to investigate the therapeutic potential of targeting eEF2K, but also provides a promising lead compound for developing novel drugs for the treatment of TNBC and other cancers.

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.

Eligibility includes adult patients with solitary supratentorial rMG (WHO grade 3/4); ≥ 4weeks after chemotherapy, bevacizumab, or investigational agent; adequate organ function; and KPS ≥70%. The RP2D for intratumoral infusion of D2C7-IT+2141-V11 via CED is identified. The protocol was amended to evaluate the addition of cervical perilymphatic injections of 2141-V11 post CED of D2C7-IT+2141-V11.

Eight (26%) patients received tagraxofusp, matched unrelated donor was the most common donor type (39%), and fludarabine + busulfan-based conditioning was used in 17 (55%) patients. Post-transplant cyclophosphamide (PTCy) was used for GVHD prophylaxis in 23 (74%) patients... These results demonstrate the safety and efficacy of allo-HCT in BPDCN. Patients undergoing allo-HCT in first remission had significantly better outcomes. Prospective studies are needed to better define the role of allo-HCT in BPDCN.

Regarding first-line treatment, 34 patients (50%) received AML-like regimens [19 underwent anthracycline and cytarabine (3+7 regimen), 4 FLAGIDA, 4 received FLUGA (fludarabine plus low-dose cytarabine), 1 cytarabine alone, and 1 azacitidine alone]; 9 (13%) acute lymphoblastic leukemia-like regimens; 8 patients (12%) were treated with lymphoma–like regimens; 6 (9%) received medication within clinical trial; 2 (3%) compassionate use of Tagraxofusp, and 9 (13%) supportive care only. We found large heterogeneity of therapeutic approaches, low complete remission rates and scarce rates of allogeneic transplant in the front-line. Improvement of outcomes through well-defined treatment protocols and innovative agents are needed for this high unmet need disease.

We identified 818 total patients: 36% (292/818) received tagraxofusp, 60% (494/818) received intensive chemotherapy (HyperCVAD, AML and ALL-like, and CHOP), 3% (22/818) received less intensive chemotherapy (azacytidine, venetoclax, or other mild regimes), 1% received pivekimab (10/818). From our analysis, the OR of attaining CR between tagraxofusp and chemotherapy was not significant and did not answer the question of which modality has a higher chance of CR. Although it is not possible to draw a direct comparison between the pooled single arm trials, the trend of proportions favored tagraxofusp for obtaining both CR (71% vs 64%) and PR (17% vs 8%). While the mortality rate was higher for tagraxofusp compared to intensive chemotherapy (43% vs 30%), the NR rate (~21%) and the allo-HSCT rate (~50%) were similar.

Treatment of AML with triplet TAG-AZA-VEN is feasible and shows encouraging activity as up-front therapy in adverse risk AML, including in pts with TP53 mutation. These data (OS 14 mo; TP53 mutant OS 9.5 mo) compare favorably to HMA/VEN in ELN adverse risk (OS 12 mo; Lachowiez, BloodAdv 2023) or TP53 mutant AML with poor risk cytogenetics (OS 5.2 mo; Pollyea, CCR 2022), albeit with some differences between populations. No new safety signals were observed.

Tagraxofusp was able to effectively eliminate pDCs and blasts to a lesser extent as a single agent. High expression of BCL-2 in blasts supports the consideration of tagraxofusp in combination with venetoclax as an effective combination therapy to eradicate both blasts and pDCs in AML-PDC patient samples.