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American Journal of Hematology Jul 2008Denileukin diftitox (Ontak) is an immunotoxin used in the treatment of cutaneous T-cell lymphomas. Vascular leak syndrome is a known complication of this therapy,...
Denileukin diftitox (Ontak) is an immunotoxin used in the treatment of cutaneous T-cell lymphomas. Vascular leak syndrome is a known complication of this therapy, although the syndrome is most often self-limited. We report the case of a patient with cutaneous gamma/delta (gammadelta) T-cell lymphoma and previous undiagnosed liver disease treated with denileukin diftitox. Just 4 days after initiating drug therapy, the patient developed profound vascular leak syndrome characterized by a rapid fall in his previously normal serum albumin to levels below the limit of detection. The patient then quickly deteriorated into rhabdomyolysis and eventual death. To our knowledge, this is the first report of a death directly related to denileukin diftitox therapy. The purpose of this case is to increase awareness and improve management of patients who are treated with denileukin diftitox with resulting vascular leak syndrome leading to hypoalbuminemia.
Topics: Diphtheria Toxin; Fatal Outcome; Fibrosis; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Recombinant Fusion Proteins; Syndrome; Treatment Failure; Vascular Diseases
PubMed: 18335564
DOI: 10.1002/ajh.21180 -
Journal of Clinical Oncology : Official... Apr 2010PURPOSE This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD;... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE This phase III, placebo-controlled, randomized trial was designed to investigate efficacy and safety of two doses of denileukin diftitox (DD; DAB(389)-interleukin-2 [IL-2]), a recombinant fusion protein targeting IL-2 receptor-expressing malignant T lymphocytes, in patients with stage IA to III, CD25 assay-positive cutaneous T-cell lymphoma (CTCL), including the mycosis fungoides and Sézary syndrome forms of the disease, who had received up to three prior therapies. The primary end point was overall response rate (ORR). PATIENTS AND METHODS Patients (N = 144) with biopsy-confirmed, CD25 assay-positive CTCL were randomly assigned to DD 9 microg/kg/d (n = 45), DD 18 microg/kg/d (n = 55), or placebo infusions (n = 44), administered for 5 consecutive days every 3 weeks for up to eight cycles. Patients were monitored for drug efficacy, clinical benefit, and safety of DD. RESULTS ORR was 44% for all participants treated with DD (n = 100; 10% complete response [CR] and 34% partial response [PR]) compared with 15.9% for placebo-treated patients (2% CR and 13.6% PR). ORR was higher in the 18 microg/kg/d group versus the 9 microg/kg/d group (49.1% v 37.8%, respectively), and both doses were significantly superior to placebo. Progression-free survival (PFS) was significantly longer (median, > 2 years) for both DD doses compared with placebo (median, 124 days; P < .001). Rates of moderately severe and severe adverse events (AEs) were slightly higher in the DD groups, whereas moderate and mild AEs were similar to placebo. No statistical differences were observed for drug-related serious AEs. CONCLUSION DD had a significant and durable effect on ORR and PFS with an acceptable safety profile in patients with early- and late-stage CTCL.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Double-Blind Method; Female; Humans; Interleukin-2; International Agencies; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Neoplasm Staging; Placebos; Recombinant Fusion Proteins; Safety; Skin Neoplasms; Survival Rate; Treatment Outcome; Young Adult
PubMed: 20212249
DOI: 10.1200/JCO.2009.26.2386 -
The Journal of Dermatology Feb 2022Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic... (Review)
Review
Cutaneous lymphoma is generally treated with skin-directed therapies (SDT) during the early and localized stages. For the refractory or advanced stages, systemic therapies are used. Previously, retinoids and interferons were used for SDT-resistant cases. Only a few chemotherapy options were available for more advanced disease. In recent years, many novel agents have been introduced and the strategy for systemic therapy has changed, especially for cutaneous T-cell lymphoma (CTCL). For SDT, helical tomotherapy, a new radiation modality, has been drawing attention as an option for radiotherapy. Targeted therapies such as histone deacetylase inhibitors, mogamulizumab, brentuximab vedotin, and denileukin diftitox are new treatment options. Chemotherapy agents such as gemcitabine and pralatrexate have been introduced; they are expected to have meaningful efficacy as monotherapy. Allogeneic hematopoietic stem cell transplantation is still considered for young patients with advanced CTCL as the only potentially curative treatment.
Topics: Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma, T-Cell, Cutaneous; Retinoids; Skin Neoplasms
PubMed: 34958516
DOI: 10.1111/1346-8138.16289 -
Journal of Immunotherapy (Hagerstown,... 2005Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion... (Clinical Trial)
Clinical Trial
Elimination of regulatory T lymphocytes may provide a way to break self-tolerance and unleash the anti-tumor properties of circulating lymphocytes. The use of fusion proteins, which link cytotoxic molecules to receptor targets, provides one approach to this problem. This study examined the ability of a fusion protein of interleukin-2 (IL-2) and diphtheria toxin (Denileukin Diftitox, DAB389IL-2, ONTAK) to eliminate regulatory T lymphocytes based on their expression of high-affinity IL-2 receptors. Thirteen patients (12 with metastatic melanoma, 1 with metastatic renal cell carcinoma) were treated at one of the two Food and Drug Administration-approved doses of Denileukin Diftitox (seven patients at 9 microg/kg, six patients at 18 microg/kg). None of the patients experienced an objective clinical response. Foxp3 expression did not decrease significantly overall, although it did decrease minimally among patients receiving 18 microg/kg (-2.01+/-0.618 copies of Foxp3/10(3) copies of beta-actin; P=0.031). Denileukin Diftitox did not decrease the suppressive ability of CD4CD25 cells as quantified by an in vitro co-culture suppression assay. Furthermore, the increased numbers of lymphocytes in patients resulting from treatment with IL-2 were not susceptible to Denileukin Diftitox. Administration of Denileukin Diftitox does not appear to eliminate regulatory T lymphocytes or cause regression of metastatic melanoma.
Topics: Adult; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Carcinoma, Renal Cell; Cell Line, Tumor; Diphtheria Toxin; Female; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Interleukin-2; Kidney Neoplasms; Male; Melanoma; Middle Aged; Neoplasm Metastasis; RNA, Messenger; Receptors, Interleukin-2; Recombinant Fusion Proteins; Skin Neoplasms; T-Lymphocytes, Regulatory
PubMed: 16224276
DOI: 10.1097/01.cji.0000175468.19742.10 -
Journal of Cutaneous Medicine and... 2006Mycosis fungoides (MF) is the most common clinicopathologic subtype of primary cutaneous T-cell lymphoma. (Review)
Review
BACKGROUND
Mycosis fungoides (MF) is the most common clinicopathologic subtype of primary cutaneous T-cell lymphoma.
OBJECTIVE
The therapy of MF is highlighted in this overview.
RESULTS AND CONCLUSIONS
Skin-directed MF therapies include topical corticosteroids, nitrogen mustard, carmustine (BCNU), topical bexarotene gel, imiquimod cream, radiotherapy, total skin electron beam therapy, and phototherapy. Systemic therapies include extracorporeal photopheresis, interferon, oral bexarotene, denileukin diftitox, monoclonal antibodies and cytokine therapy, and other systemic chemotherapy. Finally, some investigative therapeutic modalities are presented.
Topics: Combined Modality Therapy; Humans; Mycosis Fungoides; Skin Neoplasms
PubMed: 17234106
DOI: 10.2310/7750.2006.00051 -
Expert Review of Anticancer Therapy Apr 2004Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds... (Review)
Review
Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor, Pfizer) or fenofibrate (TriCor, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.
Topics: Anticarcinogenic Agents; Bexarotene; Breast Neoplasms; Clinical Trials as Topic; Humans; Lung Neoplasms; Lymphoma, T-Cell, Cutaneous; Neoplasms; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 15056048
DOI: 10.1586/14737140.4.2.180 -
Leukemia & Lymphoma Dec 2007Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with...
Denileukin diftitox (DD) is approved for treatment of CD-25 expressing cutaneous T-cell lymphomas (CTCL). Initial studies of DD demonstrated responses in patients with B-cell non-Hodgkin lymphoma (NHL). This phase II trial evaluated response rate (RR) and tolerability of DD in this population. Patients were stratified into two arms: those with NHL expressing > or =20% IL-2R (IL-2R+) or <20% IL-2R (IL-2R-). DD was dosed at 18 microg/kg/day for 5 days every 21 days. Corticosteroid pre-medication was not allowed. Thirty-five patients of a planned 77 accrued due to closure for slow accrual. This report is on 29 patients (18 males) with indolent B-cell NHL (11 IL-2R+ and 18 IL-2R-). Histologic subtypes included small lymphocytic (SLL) (8 patients) and follicular grade I/II lymphoma (21 patients). Patients received a median of three prior regimens, including rituximab in 76%. Three partial responses were observed (RR 10%). The RR for the IL-2R- and IL-2R+ patients was 11% and 9%, respectively. Of 8 patients with SLL, 2 responded. Toxicities were generally grade I - II and transient but 1 patient experienced a fatal thrombo-embolism. Therapy with DD is tolerable and modest efficacy was observed in SLL subtype. Measured IL-2R status did not correlate with efficacy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Female; Humans; Interleukin-2; Lymphoma, Non-Hodgkin; Male; Middle Aged; Receptors, Interleukin-2; Recombinant Fusion Proteins
PubMed: 17943599
DOI: 10.1080/10428190701694186 -
Clinical Lymphoma & Myeloma Sep 2007Subcutaneous panniculitis-like lymphomas (SPTCLs) are a heterogeneous group of diseases characterized by pleomorphic lymphocytes infiltrating the subcutis in a lobular...
Subcutaneous panniculitis-like lymphomas (SPTCLs) are a heterogeneous group of diseases characterized by pleomorphic lymphocytes infiltrating the subcutis in a lobular panniculitis-like pattern. Characterization of SPTCL based on T-cell phenotype has prognostic significance in that most patients with the alpha/beta T-cell phenotype of SPTCL demonstrate clinically indolent behavior, whereas those with gamma/delta variant typically manifest more aggressive disease. In the past, traditional therapies have included single-agent or systemic multi-agent chemotherapy with or without radiation therapy, immunosuppressive therapies, or, in refractory patients, bone marrow transplantation. We describe complete clinical regression of disease and a median response duration of > 6 months in 2 patients with SPTCL treated with corticosteroids and denileukin diftitox. Furthermore, the addition of bexarotene to denileukin diftitox restored a clinical response in 1 of the patients after disease progression, suggesting the activity of this combination in patients with SPTCL.
Topics: Adrenal Cortex Hormones; Adult; Antineoplastic Agents; Diphtheria Toxin; Humans; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Panniculitis; Radiography; Recombinant Fusion Proteins; Tomography, Emission-Computed; Treatment Outcome
PubMed: 18021473
DOI: 10.3816/clm.2007.n.040 -
Journal of Immunotherapy (Hagerstown,... Sep 2010High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2... (Clinical Trial)
Clinical Trial
High-dose (HD) IL-2 is approved to treat renal cell carcinoma (RCC) with modest response rates and significant toxicity. Enhancement of cytotoxic T-cell activity by IL-2 is 1 mechanism of action. IL-2 also stimulates regulatory T lymphocytes (Tregs), which are associated with poor prognosis. Favorable outcomes are associated with greater rebound absolute lymphocyte count (Fumagalli 2003). DD depletes IL-2 receptor (CD25 component) expressing cells. We hypothesized that sequential therapy could complement each other; DD would deplete Tregs so IL-2 could more effectively stimulate proliferation and activity of cytotoxic T lymphocytes. Patients (n=18) received standard HD IL-2 and 1 dose of DD daily for 3 days; periodic flow cytometry and complete blood counts were performed. Group A included 3 patients to assess safety only with DD 6 μg/kg between the IL-2 courses. Group B included 9 patients at 9 μg/kg DD before the IL-2 courses. Group C included 6 patients at 9 μg/kg DD between the IL-2 courses. Efficacy using the RECIST criteria was assessed after the treatment. Fifteen patients from a study of IL-2 without DD served as controls for toxicity comparison and 13 of these for flow cytometry comparisons. No unusual toxicity was noted. For group B/C patients receiving DD, the median decline in Tregs was 56.3% from pre-DD to post-DD (P=0.013). Peak absolute lymphocyte count change from baseline was +9980/μL for group B, +4470/μL for group C, and +4720/μL for the controls (P=0.005 B vs. C). The overall response rate was 5 of 15 (33%); 3 of 9 (33%) and 2 of 6 (33%) for groups B and C, respectively, including 2 patients with sarcomatoid RCC and 1 with earlier sunitinib therapy.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cell Count; Cell Proliferation; Cell Separation; Diphtheria Toxin; Female; Flow Cytometry; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Kidney Neoplasms; Lymphocyte Depletion; Male; Middle Aged; Neoplasm Metastasis; Recombinant Fusion Proteins; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory
PubMed: 20664355
DOI: 10.1097/CJI.0b013e3181e4752e -
The British Journal of Dermatology May 2006Denileukin diftitox (Ontak) is a fusion protein comprising a diphtheria toxin and an interleukin (IL)-2 moiety that specifically targets CD25 (IL-2 receptor)-positive...
Denileukin diftitox (Ontak) is a fusion protein comprising a diphtheria toxin and an interleukin (IL)-2 moiety that specifically targets CD25 (IL-2 receptor)-positive tumour cells. We report a patient with rapidly progressive Epstein-Barr virus-positive nasal type extranodal natural killer/T-cell lymphoma (extranodal NKTCL), treated with a combination of denileukin diftitox (Ontak) and oral bexarotene (Targretin). A significant regression of the cutaneous tumours was observed already after the first cycle of denileukin diftitox and was maintained for a period of 5 months with monthly cycles of denileukin diftitox. The treatment was well tolerated. Following this response the patient decided to stop the treatment. He was then followed by his oncologist and lost from dermatological follow-up. Shortly after treatment withdrawal the disease progressed and the patient received one cycle of doxorubicin (Caelyx). He died from septic shock syndrome 2 months later. To our knowledge this is the first case of extranodal NKTCL treated with denileukin diftitox and bexarotene. A striking, albeit transient, response occurred with this therapy. Combination treatment with denileukin diftitox and bexarotene should be further assessed in this aggressive type of cutaneous lymphoma.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Diphtheria Toxin; Fatal Outcome; Humans; Interleukin-2; Killer Cells, Natural; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Recombinant Fusion Proteins; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 16634908
DOI: 10.1111/j.1365-2133.2006.07151.x