Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DAB(389)IL-2 (denileukin diftitox, ONTAK) is a cytokine-targeted fusion protein that delivers the catalytic domain of diphtheria toxin to lymphoma cells expressing the interleukin-2 receptor (IL-2R). In phase I and phase III studies of DAB(389)IL-2 in patients with cutaneous T-cell lymphoma (CTCL), non-Hodgkin's lymphoma, and Hodgkin's disease in which premedications were limited to diphenhydramine and acetaminophen, acute infusion-related hypersensitivity reactions occurred in 70% of patients and vascular leak syndrome (VLS) in 27%, resulting in discontinuation of therapy in 29% of patients. There was no correlation between the dose or half-life of DAB(389)IL-2 and the occurrence of hypersensitivity events or VLS. To explore whether steroid premedication would improve the tolerability of DAB(389)IL-2, we treated 15 patients with CTCL with either dexamethasone or prednisone prior to each dose of DAB(389)IL-2. The incidence of acute infusion events was significantly decreased, with only three patients experiencing acute infusion events (one grade 4) and only two patients developing clinically apparent VLS. Grade 3 skin rash occurred in two patients and moderately severe asthenia in nine patients. A significantly improved response rate of 60% was noted with the use of steroid premedication compared to prior studies in which steroids were prohibited. We conclude that steroid premedication significantly improves the tolerability of DAB(389)IL-2 without compromising the clinical response.
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PMID:Biological correlates of acute hypersensitivity events with DAB(389)IL-2 (denileukin diftitox, ONTAK) in cutaneous T-cell lymphoma: decreased frequency and severity with steroid premedication. 1170 45

DAB(389)IL-2 (ONTAK) is a fusion protein consisting of the ADP-ribosyltransferase and membrane translocating domains of native diphtheria toxin and the full-length sequence for interleukin-2 (IL-2) gene. In vitro data demonstrates that DAB(389)IL-2 is cytotoxic to cells expressing the high affinity IL-2 receptor (IL-2R). In Phases I and II clinical trials of patients whose tumor cells express a component of the IL-2R, the response rates were 18% for B-cell non-Hodgkin lymphoma (NHL) and 30% for cutaneous T-cell lymphoma (CTCL). In this study, we examined the effects of arginine butyrate on IL-2R expression and susceptibility of leukemia cells to intoxication by DAB(389)IL-2. We demonstrate that the p75 subunit of the IL-2R (IL-2Rbeta) is upregulated in the presence of low concentrations of arginine butyrate (0.06mM) which had no direct growth inhibitory effect on the cells. To explore mechanisms of this upregulation, we examined the effect of 0.06mM arginine butyrate on relevant transcriptional elements and on histone deacetylase and found activation of cAMP response element (CRE) but not NFAT or NFKB, as well as inhibition of histone deacetylase (HDAC). Our results suggest that the effects of physiologically achievable concentrations of butyrate on IL-2R expression could be exploited to enhance the susceptibility of intermediate and low-affinity IL-2R expressing leukemia cells to DAB(389)IL-2.
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PMID:Arginine butyrate increases the cytotoxicity of DAB(389)IL-2 in leukemia and lymphoma cells by upregulation of IL-2Rbeta gene. 1244 77

This phase II study evaluated the safety and efficacy of denileukin diftitox, an interleukin-2-diphtheria toxin fusion protein, in relapsed/refractory T-cell non-Hodgkin lymphoma (T-NHL), excluding cutaneous T-cell lymphoma. Eligible patients received denileukin diftitox 18 microg/kg/d x 5 d every 3 weeks for up to eight cycles. Tumour staging was performed every two cycles and the primary endpoint was the objective response rate [complete response (CR) + partial response (PR)]. For 27 patients enrolled, median age: 55 years (range 26-80 years), 70.4% male, and mean prior therapies: 2.5 (range 1-6). Objective responses (six CRs, seven PRs) were achieved in 13 patients (48.1%), stable disease in eight (29.6%) and six (22.2%) had progressive disease. An objective response was achieved in eight of 13 patients (61.5%) with CD25(+) tumours (four CR/four PR) and five of 11 patients (45.5%) with CD25(-) tumours (two CR/three PR). Median progression-free survival was 6 months (range, 1-38+ months). Most adverse reactions were grade 1/2 and transient. No grade 4-5 toxicities were reported. Denileukin diftitox had significant activity and was well tolerated in relapsed/refractory T-NHL, with responses observed in both CD25(+) and CD25(-) tumours. Further studies of denileukin diftitox in combination with other agents are warranted in previously untreated and relapsed/refractory T-NHL.
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PMID:Phase II trial of denileukin diftitox for relapsed/refractory T-cell non-Hodgkin lymphoma. 1723 46

Peripheral T-cell lymphoma (PTCL) is an aggressive form of non-Hodgkin's lymphoma (NHL), associated with poor prognosis and without standard approach to treatment. Denileukin diftitox (Ontak) is a synthetic fusion protein combining the receptor-binding domain of interleukin-2 to the enzymatically active portion of diphtheria toxin. While approved for the treatment of cutaneous T-cell lymphoma, it has demonstrated activity in non-Hodgkin's lymphomas of both T-cell and B-cell origin. This report documents the first case of de novo maintenance therapy with denileukin diftitox sustaining an ongoing complete response at the molecular level for 2 years in a patient with PTCL.
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PMID:De novo maintenance therapy with denileukin diftitox (Ontak) in a patient with peripheral T-cell lymphoma is associated with prolonged remission. 1838 17

Denileukin diftitox (Ontak) is a novel recombinant fusion protein consisting of peptide sequences for the enzymatically active and membrane translocation domain of diphtheria toxin linked to human IL-2. Denileukin diftitox specifically binds to IL-2 receptors on the cell membrane, is internalized via receptor-mediated endocytosis and inhibits protein synthesis by ADP ribosylation of elongation factor 2, resulting in cell death. This article focuses on the clinical trial that led to the US FDA approval of the drug for cutaneous T-cell lymphoma in 1999, and other investigational studies for hematologic malignancies, recurrent and refractory chronic lymphocytic leukemia, non-Hodgkin B-cell lymphoma, graft-versus-host disease and autoimmune disease, demonstrating the activity and adverse effects of the drug.
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PMID:Optimizing denileukin diftitox (Ontak) therapy. 1868 57

Recombinant immunotoxins are proteins composed of fragments of monoclonal antibodies fused to truncated protein toxins. No agents of this class are approved yet for medical use, although a related molecule, denileukin diftitox, composed of interleukin-2 fused to truncated diphtheria toxin, is approved for relapsed/refractory cutaneous T-cell lymphoma. Recombinant immunotoxins which have been tested in patients with chemotherapy-pretreated hematologic malignancies include LMB-2 (anti-CD25), BL22 (CAT-3888, anti-CD22) and HA22 (CAT-8015, anti-CD22), each containing an Fv fragment fused to truncated Pseudomonas exotoxin. Major responses were observed with LMB-2 in adult T-cell leukemia, chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma, Hodgkin's disease, and hairy cell leukemia (HCL). BL22 resulted in a high complete remission rate in patients with HCL, particularly those without excessive tumor burden. HA22, an improved version of BL22 with higher affinity to CD22, is now undergoing phase I testing in HCL, CLL, non-Hodgkin's lymphoma, and pediatric acute lymphoblastic leukemia.
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PMID:Recombinant immunotoxins for the treatment of chemoresistant hematologic malignancies. 1968 36

Cutaneous T-cell lymphoma (CTCL) is a rare non-Hodgkin lymphoma with predominant skin manifestations and a relatively indolent course at early stages, but it can be fatal in advanced settings. In the absence of cure, the goal of therapy for CTCL is to induce long-term remissions without further compromising a patient's immune system or quality of life. Denileukin diftitox (DD) is a fusion protein chemotherapeutic agent used for the treatment of persistent or recurrent CTCL. It binds selectively to the high- and intermediate-affinity interleukin-2 receptor (CD25+) on lymphocytes and is internalized by these cells. Inside the cells, the diphtheria toxin portion of fusion protein is cleaved by proteolytic enzymes, causing cell death. DD produces durable responses and may forestall disease progression. This article reviews DD phase III clinical trial data and summarizes one institution's clinical experience in the management of the most frequent and clinically significant adverse effects of DD (e.g., acute infusion reactions, capillary leak syndrome, hypoalbuminemia, visual changes, constitutional symptoms, rash, hepatobiliary disorders). Many DD-associated adverse effects can be managed effectively without dose reduction or interruption of treatment with prudent use of supportive care measures.
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PMID:Adverse effects of denileukin diftitox and their management in patients with cutaneous T-cell lymphoma. 2302 42

T-cell lymphomas (TCLs) are a heterogenous group of diseases that show histologic and immunophenotypic features overlapping with reactive lymphoid proliferations and often require the use of ancillary testing for accurate diagnosis. The oncoprotein, bcl-2, is expressed in various types of lymphoma. At present, expression of this protein is useful for distinguishing several B-cell lymphomas. Although there are some anecdotal reports that the lack of bcl-2 expression by T cells might also be a useful marker for the diagnosis of TCL, there are no focused studies to address this hypothesis. Another antigen with value in TCL diagnosis is programmed death-1 (PD-1), a marker of follicular helper T cells, which has been reported to be sensitive in the detection of angioimmunoblastic TCL and peripheral T-cell lymphoma, unclassified. However, several reports have also shown that PD-1-positive cells may be increased in a number of settings other than TCL, including reactive and atypical lymphadenopathies. Finally, lymphoma cells express a variety of cytokine receptors and signaling molecules that are current or potential targets for immunomodulatory therapy. One such target is the interleukin (IL)-2 receptor (CD25), which is acted on by denileukin diftitox/ONTAK, a recombinant diphtheria toxin-IL-2 fusion protein. Selection of suitable patients for therapy often includes pretreatment assessment of CD25 expression in tumor cells. In order to further assess the diagnostic and therapeutic utility of these antigens, we compared the expression of the CD25, PD-1, and bcl-2 in 119 cases of T-cell non-Hodgkin lymphoma using immunohistochemical techniques applied to routinely processed and paraffin-embedded tissues. We show that lack of expression of bcl-2 was observed in 52% cases of TCL and may aid in identification of neoplastic T-cell populations. In combination, bcl-2, CD25, and PD-1 provide diagnostic utility and may aid in selecting appropriate patients for immunomodulatory therapy.
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PMID:Utility of BCL2, PD1, and CD25 immunohistochemical expression in the diagnosis of T-cell lymphomas. 2370 49

The interleukin-3 receptor alpha chain (IL-3R), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.
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PMID:CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies. 3154 72


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