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Clinical Lymphoma, Myeloma & Leukemia Jun 2012Better treatment and survival outcomes are needed for the rare primary cutaneous peripheral T-cell lymphomas.Five (62.5%) of 8 patients with peripheral T-cell lymphomas... (Clinical Trial)
Clinical Trial
UNLABELLED
Better treatment and survival outcomes are needed for the rare primary cutaneous peripheral T-cell lymphomas.Five (62.5%) of 8 patients with peripheral T-cell lymphomas enrolled in a pilot study of denileukin diftitoxat 18 μg/kg per day for 5 days followed by once weekly for 24 weeks responded, including 2 complete responses, one of which is ongoing at 8 years.
PURPOSE
To evaluate the safety and efficacy of an alternate dosing regimen in rare primary cutaneous peripheral T-cell lymphoma variants.
METHODS
This is a prospective, single center, pilot study of denileukin diftitox (Dd) in patients with persistent or recurrent cutaneous peripheral T-cell lymphomas and mycosis fungoides (MF) variants, excluding Sézary syndrome (SS). Dd was administered at 18 μg/kg per day for 5 days and once weekly for 24 weeks, with response by modified skin weighed assessment tool.
RESULTS
Eight patients, with a median age of 76 years (range, 44-88 years), were treated between December 2003 and July 2008. Five (62.5%) of 8 patients responded, including 3 patients with CD30(+) anaplastic large-cell lymphoma (ALCL) with 2 complete responses, one ongoing at 8 years. One patient with CD8(+) and 1 patient with natural killer T cell lymphoma (NK-T) had partial responses. Progressive disease occurred in 1 patient positive for human T-cell lymphotropic virus and 1 patient with ALCL. Vascular leak syndrome (VLS) occurred in 6 (75%) of 8 patients during or just after cycle 1. Three were grade 3, and 2 of these resulted in study withdrawal. Other adverse effects included nausea or vomiting (n = 3), fatigue (n = 1), back pain (n = 1), transaminase elevations (n = 3), and elevated creatinine (n = 1).
CONCLUSIONS
Dd with an alternate dosing schedule was active in this small study of primary cutaneous T-cell lymphomas.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Pilot Projects; Recombinant Fusion Proteins; Skin Neoplasms; Treatment Outcome
PubMed: 22521504
DOI: 10.1016/j.clml.2012.01.011 -
Journal of Immunology (Baltimore, Md. :... Jun 2012Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating...
Denileukin diftitox (DD), a fusion protein comprising IL-2 and diphtheria toxin, was initially expected to enhance antitumor immunity by selectively eliminating regulatory T cells (Tregs) displaying the high-affinity IL-2R (α-β-γ trimers). Although DD was shown to deplete some Tregs in primates, its effects on NK cells (CD16(+)CD8(+)NKG2A(+)CD3(-)), which constitutively express the intermediate-affinity IL-2R (β-γ dimers) and play a critical role in antitumor immunity, are still unknown. To address this question, cynomolgus monkeys were injected i.v. with two doses of DD (8 or 18 μg/kg). This treatment resulted in a rapid, but short-term, reduction in detectable peripheral blood resting Tregs (CD4(+)CD45RA(+)Foxp3(+)) and a transient increase in the number of activated Tregs (CD4(+)CD45RA(-)Foxp3(high)), followed by their partial depletion (50-60%). In contrast, all NK cells were deleted immediately and durably after DD administration. This difference was not due to a higher binding or internalization of DD by NK cells compared with Tregs. Coadministration of DD with IL-15, which binds to IL-2Rβ-γ, abrogated DD-induced NK cell deletion in vitro and in vivo, whereas it did not affect Treg elimination. Taken together, these results show that DD exerts a potent cytotoxic effect on NK cells, a phenomenon that might impair its antitumoral properties. However, coadministration of IL-15 with DD could alleviate this problem by selectively protecting potentially oncolytic NK cells, while allowing the depletion of immunosuppressive Tregs in cancer patients.
Topics: Animals; Antineoplastic Agents; Diphtheria Toxin; Flow Cytometry; Immunotoxins; Interleukin-15; Interleukin-2; Killer Cells, Natural; Macaca fascicularis; Male; Recombinant Fusion Proteins; T-Lymphocytes, Regulatory
PubMed: 22586034
DOI: 10.4049/jimmunol.1200656 -
JAAD Case Reports Nov 2017
PubMed: 29296637
DOI: 10.1016/j.jdcr.2017.06.031 -
British Journal of Haematology Aug 2007Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were...
Denileukin diftitox plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma patients. Of the 38 evaluable patients, 30 (80%) were rituximab-refractory. The overall response rate (ORR) was 32%, with six complete responses (CR) and six partial responses (PR). The median time to progression for responders was 8 months (range: 2-36+); two patients with rituximab-refractory follicular lymphoma were in CR at 25 and 36+ months. The ORR was 55% (4 CRs, 2 PRs) in 11/14 patients with rituximab-refractory follicular lymphoma, and 100% in the three patients with rituximab-sensitive tumour. Most toxicities were low grade and transient, and myelotoxicity was uncommon.
Topics: Adult; Aged; Aged, 80 and over; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Combined Chemotherapy Protocols; Diphtheria Toxin; Female; Humans; Interleukin-2; Lymphoma, B-Cell; Lymphoma, Follicular; Male; Middle Aged; Neoplasm Staging; Recombinant Fusion Proteins; Recurrence; Rituximab; Time Factors; Treatment Outcome
PubMed: 17608763
DOI: 10.1111/j.1365-2141.2007.06684.x -
Journal of Pharmaceutical Sciences Jan 2020Immunotoxins (ITs) are attractive anticancer modalities aimed at cancer-specific delivery of highly potent cytotoxic protein toxins. An IT consists of a targeting domain... (Review)
Review
Immunotoxins (ITs) are attractive anticancer modalities aimed at cancer-specific delivery of highly potent cytotoxic protein toxins. An IT consists of a targeting domain (an antibody, cytokine, or another cell-binding protein) chemically conjugated or recombinantly fused to a highly cytotoxic payload (a bacterial and plant toxin or human cytotoxic protein). The mode of action of ITs is killing designated cancer cells through the effector function of toxins in the cytosol after cellular internalization via the targeted cell-specific receptor-mediated endocytosis. Although numerous ITs of diverse structures have been tested in the past decades, only 3 ITs-denileukin diftitox, tagraxofusp, and moxetumomab pasudotox-have been clinically approved for treating hematological cancers. No ITs against solid tumors have been approved for clinical use. In this review, we discuss critical research and development issues associated with ITs that limit their clinical success as well as strategies to overcome these obstacles. The issues include off-target and on-target toxicities, immunogenicity, human cytotoxic proteins, antigen target selection, cytosolic delivery efficacy, solid-tumor targeting, and developability. To realize the therapeutic promise of ITs, novel strategies for safe and effective cytosolic delivery into designated tumors, including solid tumors, are urgently needed.
Topics: Animals; Antineoplastic Agents; Bacterial Toxins; Clinical Trials as Topic; Cytosol; Exotoxins; Humans; Immunotoxins; Neoplasms; Protein Binding; Protein Structure, Secondary
PubMed: 31669121
DOI: 10.1016/j.xphs.2019.10.037 -
Oncology (Williston Park, N.Y.) May 2010Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly... (Review)
Review
Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is a low-grade cutaneous lymphoma characterized by skin-homing CD4+ T cells. It is notable for highly symptomatic progressive skin lesions, including patches, plaques, tumors, and erytheroderma, and has a poorer prognosis at later stages. Diagnosis remains difficult owing to MF's nonspecific skin presentation and identification of the optimal treatment strategy is challenging given the paucity of controlled trials and numerous and emerging treatment options. Management includes topical therapy with the addition of systemic therapy for patients with later-stage disease including tumors; erythroderma; and nodal, visceral, or blood involvement. Topical therapies include mechlorethamine (nitrogen mustard), carmustine (BCNU), steroids, bexarotene gel (Targretin Gel), psoralen plus ultraviolet A (PUVA), ultraviolet B (UVB), and either localized or total skin electron radiotherapy. Systemic therapies include interferon, retinoids, oral bexarotene (Targretin), denileukin diftitox (Ontak), vorinostat (Zolinza), extracorporeal photochemotherapy (photopheresis), and cytotoxic chemotherapy. Herein, we outline clinically relevant aspects of MF, including clinical presentation, pathology, diagnosis, and staging. We describe in detail existing and emerging therapeutics and offer specific recommendations for management of each stage of MF.
Topics: Humans; Mycosis Fungoides; Neoplasm Staging; Skin Neoplasms
PubMed: 20568590
DOI: No ID Found -
Case Reports in Dermatology Jan 2011Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes...
Advanced-stage primary cutaneous T-cell lymphoma has an unfavorable prognosis and low survival rates. Aggressive treatment with chemotherapy is not curative and causes considerable side effects. The combination of bexarotene and denileukin diftitox is associated with an acceptable safety profile and a likely synergistic effect because bexarotene is capable of modulating expression of IL-2 receptor and enhance the susceptibility of T-cell leukemia cells to denileukin diftitox. In the case reported here, the response to this combined treatment was satisfactory and well tolerated. The patient showed a complete regression of pruritus, restlessness, and insomnia. Skin lesions improved partially, and lymphadenopathy was reduced and finally disappeared completely.
PubMed: 21931572
DOI: 10.1159/000324185 -
Leukemia & Lymphoma Jul 2013This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled...
A multicenter phase II trial to determine the safety and efficacy of combination therapy with denileukin diftitox and cyclophosphamide, doxorubicin, vincristine and prednisone in untreated peripheral T-cell lymphoma: the CONCEPT study.
This phase II study to determine the safety and efficacy of denileukin diftitox (DD) and cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) enrolled patients with newly diagnosed peripheral T-cell lymphoma (PTCL). Forty-nine received DD 18 μg/kg/day (days 1, 2) with CHOP (day 3) every 21 days for ≤ 6-8 cycles. Intent-to-treat (ITT) and safety populations comprised all patients. In the ITT population, the overall response rate was 65%, median duration of response was 30 months and median progression-free survival was 12 months. Median overall survival was not attained at the end of the study, and the overall survival rate was 63.3%. The two most frequent treatment-related adverse events (AEs) were fatigue and nausea. Most frequent AEs ≥ grade 3 within the hematologic system were lymphopenia (24.5%), neutropenia (20.4%) and leukopenia (18.4%). Three treatment-related deaths occurred. DD plus CHOP was well tolerated, and progression-free and overall survival improved versus historical comparison with CHOP alone. Confirmation in larger trials is warranted.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Diphtheria Toxin; Doxorubicin; Female; Humans; Interleukin-2; Lymphoma, T-Cell, Peripheral; Male; Middle Aged; Prednisone; Recombinant Fusion Proteins; Treatment Outcome; Vincristine; Young Adult
PubMed: 23278639
DOI: 10.3109/10428194.2012.742521 -
BMC Cancer Dec 2011We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted...
BACKGROUND
We previously found that administration of an interleukin 2/diphtheria toxin conjugate (DAB/IL2; Denileukin Diftitox; ONTAK) to stage IV melanoma patients depleted CD4(+)CD25(HI)Foxp3(+) regulatory T cells and expanded melanoma-specific CD8(+) T cells. The goal of this study was to assess the clinical efficacy of DAB/IL2 in an expanded cohort of stage IV melanoma patients.
METHODS
In a single-center, phase II trial, DAB/IL2 (12 μg/kg; 4 daily doses; 21 day cycles) was administered to 60 unresectable stage IV melanoma patients and response rates were assessed using a combination of 2-[(18)F]-fluoro-2-deoxy-glucose (FDG)-positron emission tomography (PET) and computed tomography (CT) imaging.
RESULTS
After DAB/IL2 administration, 16.7% of the 60 patients had partial responses, 5% stable disease and 15% mixed responses. Importantly, 45.5% of the chemo/immuno-naïve sub-population (11/60 patients) experienced partial responses. One year survival was markedly higher in partial responders (80 ± 11.9%) relative to patients with progressive disease (23.7 ± 6.5%; p value < 0.001) and 40 ± 6.2% of the total DAB/IL2-treated population were alive at 1 year.
CONCLUSIONS
These data support the development of multi-center, randomized trials of DAB/IL2 as a monotherapy and in combination with other immunotherapeutic agents for the treatment of stage IV melanoma.
TRIAL REGISTRATION
NCT00299689.
Topics: Aged; Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Kentucky; Male; Melanoma; Middle Aged; Positron-Emission Tomography; Recombinant Fusion Proteins; Skin Neoplasms; Survival Analysis; T-Lymphocytes; Tomography, X-Ray Computed
PubMed: 22165955
DOI: 10.1186/1471-2407-11-515 -
The Australasian Journal of Dermatology Nov 2003Cutaneous lymphomas are rare and, although some are a manifestation of systemic lymphoma, the majority arise primarily from the skin. These primary cutaneous lymphomas... (Review)
Review
Cutaneous lymphomas are rare and, although some are a manifestation of systemic lymphoma, the majority arise primarily from the skin. These primary cutaneous lymphomas comprise both T- and B-cell subtypes and represent a wide spectrum of disorders, which at times can be difficult to diagnose and classify. Classical therapeutic strategies include topical corticosteroids, phototherapy, radiotherapy, retinoids, extracorporeal photopheresis, topical chemotherapy, systemic chemotherapy and biological response modifiers. Newer therapies include the synthetic retinoid bexarotene, the immunotoxin conjugate denileukin diftitox, interleukin-12 and monoclonal antibodies such as alemtuzumab and rituximab.
Topics: Administration, Topical; Adrenal Cortex Hormones; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Combined Modality Therapy; Education, Medical, Continuing; Female; Humans; Immunohistochemistry; Immunologic Factors; Lymphoma, T-Cell, Cutaneous; Male; Mycosis Fungoides; Neoplasm Staging; Phototherapy; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Sezary Syndrome; Skin Neoplasms; Survival Analysis; Treatment Outcome
PubMed: 14616487
DOI: 10.1046/j.1440-0960.2003..x