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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tagraxofusp (Elzonris™) is a fusion protein consisting of interleukin 3 (IL-3) fused to diphtheria toxin that is used for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It gained FDA approval in 2018 and it is considered to be a first-in-class medication. Elzonris™ is a novel targeted therapy directed to CD123 of the tumor cells. The IL-3 binds to the CD123-expressing tumor cells and delivers the cytotoxic diphtheria toxin to the cells. This causes the blockage of protein synthesis in the cell and causing cell death. The approval of Elzonris™ was based on the positive results of two multi-center, open-label, single-arm clinical trials, which were performed in two groups of patients. The rate of complete response was the primary endpoint of the trial. The primary endpoint was reached by approximately 54% of the patients. One of the patients achieved a complete response and one clinical complete response in the study. Most common adverse events include capillary leak syndrome, nausea, weight gain, fatigue, peripheral edema, and an increase in body temperature.
Leukemias
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
At present, in addition to IFNα being tested as a monotherapy and in combination, many drugs including the next-generation JAK inhibitors are in clinical trials, principally for the treatment of patients with MF.115 The clinical development of next-generation JAK2 inhibitors has been difficult, with many studies discontinued due to the emergence of serious toxicity (e.g. Wernicke’s encephalopathy). Fedratinib’s development in MF was discontinued in 2013, then re-evaluated in 2017, and licensed in 2019.113 Another JAK2 inhibitor, pacritinib, previously shown to be active in the PERSIST-1 and PERSIST-2 studies, is undergoing further development with refinement of optimal dosage. Recently, the Phase III study results show pacritinib 200 mg twice daily to be significantly better than the best available therapy, including ruxolitinib, for reducing splenomegaly and clinical symptoms in patients with MF and thrombocytopenia, both previously untreated patients and those who had received prior ruxolitinib. Momelotinib, a JAK2 inhibitor, was tested in the SIMPLIFY-1 and -2 studies in 2017, in first- and second-line settings, respectively, but trials failed to meet their primary endpoint. In addition to JAK inhibition and interferons, many other investigational agents, either alone or in combination with ruxolitinib, are being tested. These include hedgehog, aurora kinase, SMAC, HDAC, and MDM2 inhibitors, in addition to the JAK2-allosteric inhibitors, such as LS104 and ON044580, which have a greater specificity for JAK2V617F and are inhibitory in a non-ATP competitive manner. A novel agent, tagraxofusp, which targets CD123 and plasmacytoid dendritic cells, observed in MF patients, is currently being tested in a Phase II study.
Evaluating tagraxofusp for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN)
Published in Expert Opinion on Pharmacotherapy, 2022
Nathaniel R. Wilson, Naveen Pemmaraju
Tagraxofusp has been instrumental in improving outcomes and adding another key therapeutic option for the overall approach for the historically difficult-to-treat malignancy that is BPDCN. Targeting aberrant overexpression of CD123 has changed the treatment landscape in frontline presentation; however, relapsed and refractory BPDCN remains an aggressive disease with poor prognosis and limited treatment options with less-than-optimal outcomes. Furthermore, the ability of tagraxofusp to cross the blood–brain barrier is unknown, which may have treatment implications as we are beginning to understand the significant rate of CNS involvement of BPDCN. As above, tagraxofusp has been incorporated into several various clinical trials for both frontline and relapsed/refractory treatment situations.
Targeting CD123 in BPDCN: an emerging field
Published in Expert Review of Hematology, 2021
Adam J DiPippo, Nathaniel R Wilson, Naveen Pemmaraju
Treatment with tagraxofusp overall was well-tolerated with the most common adverse effects including increased liver enzymes, thrombocytopenia, and hypoalbuminemia, along with adverse symptoms of fever, nausea, chills, and edema [63]. Onset of increased liver enzymes was between 5–10 days and typically resolved within 15–21 days [63]. All adverse events were reported as transient and the suspected result of direct injury to affected organ/organ systems from nonspecific tagraxofusp uptake from IL3R located on other cells (i.e. vascular endothelium, reticular endothelial cells, hepatocytes, and megakaryocytes). It was believed that the infusion-related adverse events were likely due to cytokine release from either macrophages sent in response to cellular damage by tagraxofusp or by apoptosis of BPDCN cells themselves [63].
Tagraxofusp as treatment for patients with blastic plasmacytoid dendritic cell neoplasm
Published in Expert Review of Anticancer Therapy, 2020
Sophia S. Lee, Deborah McCue, Naveen Pemmaraju
Tagraxofusp, recently approved by the FDA for the treatment of BPDCN patients who are 2 years and older, is an anti-CD123 targeted therapy. This agent has shown overall clinical benefits that outweigh the expected risks; careful monitoring of the reported adverse events is required. Upon initiation, the physician should monitor for hypersensitivity reactions, monitor for hepatotoxicity, thrombocytopenia, and CLS, particularly in the first cycle of administration. CLS patients may present with mild hypotension, hypoalbuminemia, and weight gain with edema. These adverse events may require delaying or withholding additional tagraxofusp doses. Although a decrease in albumin has been suggested as the predictor of CLS, further exploration of albumin level in correlation to CLS is to be done in future studies. Following closely with package insert/label directions is of utmost importance, especially guidance on when to hold further drug doses in cases of hypoalbuminemia, elevated liver function tests, or weight gain.