Tagraxofusp, a first-in-class CD123-targeted agent: Five-year postapproval comprehensive review of the literature.

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.

Blastic Plasmacytoid Dendritic Cell Neoplasm.

OPINION STATEMENT: While there is a high initial response rate with standard chemotherapeutic regimens for blastic plasmacytoid dendritic cell neoplasm (BPDCN), the responses are typically not durable and this remains a very aggressive disease with generally poor outcomes. For this reason, the standard approach for eligible patients has been high-dose induction chemotherapy preferably with acute lymphoblastic leukemia (ALL)-based regimens followed by consolidation with allogeneic hematopoietic stem cell transplantation (alloHSCT). Unfortunately, many patients with this disease are elderly and/or frail and cannot tolerate this therapy, and the low-dose regimens being used in this population are generally not as effective. However, this paradigm may be changing with the advent of newer targeted therapies, particularly the exploitation of CD123. SL-401 has shown very promising results with manageable toxicities and durable responses and appears to be a viable option for elderly or frail patients who are not eligible for transplant. The other CD123-directed therapies, especially chimeric antigen receptor-therapy (CAR-T), may also give promising results in trials that are currently underway. CAR-T has shown promise in a number of other hematologic malignancies, and toxicities have become more manageable as its use is becoming more widespread. While SL-401 has shown potential to provide durable responses even without transplant, we do not yet know whether it will be effective as a means to avoid transplant in patients who are otherwise eligible. All transplant-eligible patients should undergo alloHSCT consolidation given the current available data indicating this is the optimal approach to achieve a long-term remission. Once the CD123-directed therapies are established as standard regimens, future studies may be designed to investigate whether these therapies can be utilized without the use of transplant. Furthermore, combination therapy using anti-CD123 agents with high-dose induction chemotherapy or other low-dose regimens for elderly/frail patients should be investigated. Given the promising results in early clinical trials, it appears CD123 is the most viable target for BPDCN, and future studies should continue to exploit its expression on BPDCN cells.

SL-401 and SL-501, targeted therapeutics directed at the interleukin-3 receptor, inhibit the growth of leukaemic cells and stem cells in advanced phase chronic myeloid leukaemia.

While imatinib and other tyrosine kinase inhibitors (TKIs) are highly efficacious in the treatment of chronic myeloid leukaemia (CML), some patients become refractory to these therapies. After confirming that interleukin-3 receptor (IL3R, CD123) is highly expressed on CD34(+) /CD38(-) BCR-ABL1(+) CML stem cells, we investigated whether targeting IL3R with diphtheria toxin (DT)-IL3 fusion proteins SL-401 (DT388 -IL3) and SL-501 (DT388 -IL3[K116W]) could eradicate these stem cells. SL-401 and SL-501 inhibited cell growth and induced apoptosis in the KBM5 cell line and its TKI-resistant KBM5-STI subline. Combinations of imatinib with these agents increased apoptosis in KBM5 and in primary CML cells. In six primary CML samples, including CML cells harbouring the ABL1 T315I mutation, SL-401 and SL-501 decreased the absolute numbers of viable CD34(+) /CD38(-) /CD123(+) CML progenitor cells by inducing apoptosis. IL3-targeting agents reduced clonogenic growth and diminished the fraction of primitive long-term culture-initiating cells in samples from patients with advanced phase CML that were resistant to TKIs or harboured an ABL1 mutation. Survival was also extended in a mouse model of primary TKI-resistant CML blast crisis. These data suggest that the DT-IL3 fusion proteins, SL-401 and SL-501, deplete CML stem cells and may increase the effectiveness of current CML treatment, which principally targets tumour bulk.

Treatment of patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN): focus on the use of tagraxofusp and clinical considerations.

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.

Evaluating tagraxofusp for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

INTRODUCTION: Unique among hematologic malignancies, blastic plasmacytoid dendritic cell neoplasm (BPDCN) affects multiple compartments including bone marrow, hematologic, lymphatic, dermatologic, and central nervous systems (CNS). Treating BPDCN is challenging, historically, as patients display refractoriness to chemotherapy and absence of long-term remissions in many cases not treated with hematopoietic stem cell transplantation. Discovering the prevalent overexpression of surface receptor CD123 (IL3-Rα) on BPDCN cells led to development of tagraxofusp, a novel anti-CD123 agent for patients with BPDCN. AREAS COVERED: Herein, the authors discuss the preclinical development and phase I/II clinical studies, which led to the approval of tagraxofusp. They discuss the current treatment landscape of BPDCN with tagraxofusp alone or combined with chemotherapy and highlight several ongoing clinical trials involving combinations of tagraxofusp with novel targeted therapeutics for BPDCN. EXPERT OPINION: Tagraxofusp has significantly improved the treatment landscape for patients with newly diagnosed BPDCN and has led to investigative efforts and augmentation of various strategies of targeting CD123, such as antibody-drug conjugates and anti-CD123 chimeric antigen receptor T-cells. However, relapsed/refractory disease and CNS-involvement of BPDCN remain therapeutic challenges. The authors recommend that healthcare providers consider multiple-agent clinical trial approaches and adequate CNS-prophylaxis for all patients with BPDCN.

Relapse of tagraxofusp treated blastic plasmacytoid dendritic cell neoplasm with loss of CD123 expression.

Tagraxofusp, a CD123-based-targeted immunotherapy, was recently approved to treat blastic plasmacytoid dendritic cell neoplasm (BPDCN) with excellent response. Also, a subset of BPDCN shows resistance to tagraxofusp. These resistant cases continue to express CD123, which forms the basis of the continued utility of tagraxofusp in newer combination chemotherapies to overcome resistance in BPDCN. Herein, we report a case of an elderly male with BPDCN that achieved complete remission on initial primary treatment with tagraxofusp. However, BPDCN relapsed after 1.5 years while on treatment, with loss of CD123 expression. At relapse, the neoplasm was comprehensively immunophenotyped by flow cytometry (performed on both peripheral blood and bone marrow specimen) and by immunohistochemical evaluation of the bone marrow clot section. The neoplasm at relapse was diagnostic of BPDCN with a lack of CD123 expression. This case highlights a potential limitation of current and upcoming tagraxofusp-based multidrug therapies, at least in a subset of refractory BPDCN. We believe our report will serve as a sentinel to incite future investigations involving alternate resistance mechanisms in BDPCN.

Targeting CD123 in BPDCN: an emerging field.

INTRODUCTION: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with historically poor outcomes for patients, often refractory to traditional chemotherapy. Recent research has focused on targeted therapy to improve responses and limit potential toxicity. AREAS COVERED: CD123 (also known as IL-3 Rα) is a cell surface marker and attractive therapeutic target for many myeloid malignancies, particularly BPDCN, whose cells ubiquitously overexpress CD123. We review the history of CD123 research regarding BPDCN, recent advances including FDA approval of tagraxofusp (formerly SL-401) for BPDCN, and ongoing clinical studies utilizing novel therapeutic strategies to target CD123. EXPERT OPINION: The approval of tagraxofusp for the treatment of BPDCN in December 2018 drastically changed the treatment landscape for patients with this rare neoplasm. While tagraxofusp is better tolerated than traditional multi-agent chemotherapy regimens, it requires close monitoring and sound clinical judgment by providers to prevent and mitigate severe treatment-related complications with special attention to the recognition and management of capillary leak syndrome (CLS). Several other promising strategies for targeting CD123 in BPDCN are currently under investigation, including antibody-drug conjugates, T-cell engagers, and CAR-T cellular therapeutics. These CD123 targeted approaches may soon become standard of care for patients with this difficult to treat malignancy.

Role of tagraxofusp in treating blastic plasmacytoid dendritic cell neoplasm (BPDCN).

Introduction: Advances and drug development in rare diseases, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), has historically been limited by small numbers of patients in the target population. In recent years, the development of tagraxofusp (SL-401) (ELZONRIS, Stemline Therapeutics) for the treatment of adult and pediatric BPDCN has been a successful story that led to US FDA approval in December 2018.Areas covered: In this evaluation of tagraxofusp, we briefly review chemistry; pharmacokinetics and pharmacodynamics, as we focus on the clinical experience and future directions.Expert Opinion: Tagraxofusp has been a welcome new addition and a successful initial development step in the targeted treatment of BPDCN. In phase I/II clinical trial, major responses were observed in 90% of treatment-naïve patients, with 72% of the responses observed as complete remissions. Limitations on the usage of tagraxofusp and strategies to handle those limitations were further explored in this review.

Tagraxofusp as treatment for patients with blastic plasmacytoid dendritic cell neoplasm.

INTRODUCTION: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, aggressive hematologic malignancy that previously lacked standardized therapeutic approaches. CD123 (interleukin-3 receptor alpha unit) is highly expressed in many hematologic malignancies, including BPDCN. Tagraxofusp-ezrs (tagraxofusp from herein) is an agent that consists of interleukin-3 fused to a truncated diphtheria toxin, targeting CD123. The Food and Drug Administration recently approved tagraxofusp as therapy for BPDCN for adults and children aged 2 years and older. AREAS COVERED: We discuss the history and clinical background of BPDCN along with tagraxofusp as its first-line therapy. We review the clinical efficacy and safety profile of tagraxofusp in adults including proposed sensitivity and resistance. Finally, we summarize tagraxofusp use in the pediatric population. EXPERT OPINION: Tagraxofusp is a newly approved therapy for BPDCN, a hematologic malignancy that has overall historically poor outcomes. With its significant efficacy, many patients were successfully bridged to stem cell transplantation in the clinical trial leading to its ultimate approval. Clinical awareness for major toxicities, including capillary leak syndrome will be a critical aspect of using this novel agent. In the future, investigation of its use in other hematologic malignancies and expansion of clinical trials in pediatric populations with BPDCN are warranted.

Tagraxofusp for the Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A Brief Report on Emerging Data.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy, for which conventional chemotherapy has poor outcomes. CD123, the α-subunit of interleukin (IL)-3 receptor, is constantly overexpressed at the surface of tumoral cells. Tagraxofusp (or SL-401) is a recombinant cytotoxin which consists of human interleukin-3 fused to a truncated diphtheria toxin. It is currently the only novel therapy with a prospective evaluation of efficacy and safety in the treatment of BPDCN and is also the only one to achieve FDA approval. In this short review, the results of tagraxofusp are summarized and perspectives of its use in BPDCN and in other malignancies are discussed. The safety profile is also summarized, since capillary leak syndrome is the main toxic effect of the drug, along with more common toxicities including an increase in transaminases and thrombocytopenia.

Blastic Plasmacytoid Dendritic Cell Neoplasm-Current Insights.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare clonal hematologic malignancy of plasmacytoid dendritic cell precursors. The presentation and clinical course of BPDCN is widely heterogeneous and was most recently categorized as a distinct clinical entity by the World Health Organization in 2016. The expanded understanding of the pathobiology of BPDCN has improved diagnostic accuracy and informed novel targeted therapeutic options. The United States Food and Drug Administration-approval of tagraxofusp (SL-401) in December 2018 has focused attention on this leukemia frequently associated with skin involvement. Herein, we aim to: (1) review etiology; (2) summarize diagnostic criteria; and (3) discuss historic treatments and novel therapies for BPDCN.

Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies.

Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

Tagraxofusp, a novel CD123-directed cytotoxin to treat blastic plasmacytoid dendritic cell neoplasm.

Tagraxofusp is a toxin-cytokine fusion protein consisting of engineered diphtheria toxin (DT) and interleukin-3 (IL-3). The IL-3 domain binds to the cluster of differentiation 123 (CD123) and translocates DT into the cytosol, which leads to cell death. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematologic malignancy with a strong expression of CD123. Historical data show that the prognosis of BPDCN is poor, with a median overall survival of 9 to 13 months. On December 21, 2018, the United States Food and Drug Administration (FDA) approved tagraxofusp for the treatment of adults and children with newly diagnosed or relapsed/refractory BPDCN, becoming the first FDA-approved drug for this disease. In this review, we examine the preclinical studies and phase I/II clinical studies that led to FDA approval of tagraxofusp, focusing on its molecular pharmacology, pharmacokinetics, efficacy and safety profile. We also discuss future directions regarding BPDCN management.

First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases.

BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematological malignancy with extremely poor outcome. The median overall survival for adult patients is 9-13 months. Pediatric patients are exceedingly rare with an unclear clinical course. Currently, no standardized therapy has been established, although an acute lymphoblastic leukemia type of treatment appears to be more effective in those patients who are able to tolerate aggressive chemotherapy. SL-401 is a targeted therapy directed to CD123, a protein ubiquitously expressed at high level on the surface of BPDCN blasts. In adult phase 2 trials, it has demonstrated efficacy with 90% overall response rate. No pediatric patients with BPDCN using SL-401 have been reported. CASE PRESENTATION: Here, we report the first pediatric experience of three children with BPDCN treated with SL-401 at our institution. All patients tolerated SL-401 without significant toxicities. One patient with multiply relapsed and refractory disease had no response. The other two cases had significant and rapid clinical improvement after the two courses of treatment. However, the response was transient, and growth of soft tissue mass was observed in-between cycles in both patients with large tumor burden. CONCLUSIONS: This is the first report of SL-401 in pediatric patients with BPDCN. Sl-401 was well tolerated and can produce a promising response. Further testing this agent in children is warranted.

The advances in therapy of blastic plasmacytoid dendritic cell neoplasm.

INTRODUCTION: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy that contributes to <1% of all hematologic neoplasms. Before the introduction of various targeted agents, the therapeutic approach was based on regimens used for acute lymphoblastic or myeloid leukemia and non-Hodgkin's lymphoma (e.g. hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) -based regimens) followed by allogeneic stem cell transplantation for eligible patients. Given that this disease primarily affects older patients, there is a significant barrier to using these highly toxic regimens, even though these regimens are usually associated with the most durable response. AREAS COVERED: In this review, we briefly discuss outcomes with the use of leukemia-based induction regimens as well as the use of stem cell transplant. We also review low-intensity chemotherapeutic regimens. Finally, we will describe both preclinical and early clinical data regarding novel targeted strategies for treating BPDCN without the use of cytotoxic chemotherapy, with a focus on the use of CD123 directed therapy. EXPERT OPINION: While the current standard treatment for BPDCN is acute leukemia-based regimen followed by hematopoietic stem cell transplantation for transplant-eligible patients, there are very promising results for CD123 directed therapies. The future of BPDCN treatment may include targeted therapies without the need for cytotoxic chemotherapy.