The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Madeleine Duvic - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Denileukin Diftitox retreatment in patients with relapsed cutaneous t cell lymphoma
Leukemia & Lymphoma, 2013Co-Authors: Madeleine Duvic, Ann G Martin, David P Fivenson, Elise A Olsen, Miles H PrinceAbstract:This open-label phase III trial, a companion to an earlier placebo-controlled trial, evaluated safety and efficacy of Denileukin Diftitox (DD) in patients with cutaneous T-cell lymphoma (CTCL) who relapsed after responding to DD primary treatment in the earlier trial. Twenty relapsed patients (stages IA-III) received DD 18 μg/kg/day intravenously on days 1-5 of a 21-day cycle, for ≤ 8 cycles. Efficacy was assessed monthly during the first year then every 3 months. The overall response rate was 40%, mostly partial responses. Nine patients (all baseline stages ≤ IIA) experienced progression. Intent-to-treat median progression-free survival was 205 days, and median duration of response was 274 days. The most common adverse events were nausea, upper respiratory tract infections, fatigue and rigors. Three patients withdrew because of toxicity. This study showed that DD may provide clinically meaningful benefit in patients with CTCL who relapsed after initial response to DD.
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Denileukin Diftitox for the treatment of cd25 low expression mycosis fungoides and sezary syndrome
Leukemia & Lymphoma, 2013Co-Authors: Miles H Prince, Ann G Martin, David P Fivenson, Elise A Olsen, Madeleine DuvicAbstract:In a placebo-controlled study, Denileukin Diftitox (DD) was effective against cutaneous T-cell lymphoma (CTCL) expressing CD25. An open-label companion study examined the efficacy and safety of DD in 36 patients with skin biopsies containing 487 days, and median time to treatment failure was 68.5 days. No difference in PFS by disease stage was observed. The safety profile of DD in CD25 low-expression disease was similar to that in CD25+ disease. These findings suggest that CD25 low expression does not preclude a meaningful clinical response to DD in patients with CTCL.
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pilot study of Denileukin Diftitox alternate dosing regimen in patients with cutaneous peripheral t cell lymphomas
Clinical Lymphoma Myeloma & Leukemia, 2012Co-Authors: Rakhshandra Talpur, Madeleine DuvicAbstract:Abstract 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 Sezary 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.
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predictors of complete responses with Denileukin Diftitox in cutaneous t cell lymphoma
American Journal of Hematology, 2011Co-Authors: Francine M Foss, Madeleine Duvic, Elise A OlsenAbstract:The clinical course of cutaneous T-cell lymphoma (CTCL) is typically chronic, often progressive, and variably response to existing therapeutic interventions. To date, few controlled clinical trials demonstrate durable complete responses (CR) in advanced-stage patients. Denileukin Diftitox (DD) is a recombinant fusion protein targeting the interleukin-2 receptor of malignant cells. Of 263 relapsed and refractory CTCL patients treated with Denileukin Diftitox in three prospective, randomized Phase II and III clinical trials, 24 (9.1%) patients attained a durable complete response lasting beyond 3.6 years. This study evaluated the characteristics of the complete responders in these trials. CR patients had received a mean of 3.6 prior therapies. There was no difference in the frequency of CR based on stage of disease, dose of DD (9 vs. 18 μg/kg/day) (P = 0.646) or between CD25-positive and CD25-negative patients (P = 1.00). Response durations were 57-1,325+ days in the CD25-positive group and 190-400+ days in the CD25-negative group. These studies demonstrate that DD therapy resulted in durable complete responses in a subset of patients with early and advanced CTCL and CD25-positive and CD25-negative disease.
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efficacy of Denileukin Diftitox retreatment in patients with cutaneous t cell lymphoma who relapsed after initial response
Blood, 2010Co-Authors: Madeleine Duvic, Ann G Martin, David P Fivenson, Elise A Olsen, Miles PrinceAbstract:Abstract Abstract 2863 Introduction: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of non-Hodgkin's lymphomas typically characterized by skin patches, plaques, and tumors. Although CTCL primarily develops in the skin, it may progress to involve lymph nodes, blood, and visceral organs. Denileukin Diftitox (DD) is a recombinant fusion protein that targets the interleukin-2 receptor found on malignant T lymphocytes. In a Phase III trial in DD-naive patients with CD25 assay-positive CTCL (the approved indication for DD), patients treated with DD 9 and 18 μg/kg/day had overall response rates (ORR) of 37% and 46%, respectively, compared with 15% in the placebo arm. Here we analyze results from a multicenter, international, open-label phase 3 study that included a cohort of patients previously treated with DD to determine the benefit of DD retreatment following disease progression. Methods: Study L4389-14 was designed to ascertain the efficacy and safety of DD in patients with stage IA-III CTCL, receipt of ≤3 previous therapies, and life expectancy ≥12 months. The current analysis focuses on the subgroup of CD25-positive patients who experienced response to DD 9 or 18 μg/kg/day in previous clinical trials but who then relapsed. Retreatment consisted of DD 18 μg/kg/day intravenously on Days 1–5 of a 21-day cycle for up to 8 courses. Response assessment was based on the percentage change in tumor burden at each study visit based on a global, weighted score of skin, lymph node, and blood involvement, and responses were confirmed in 3 consecutive DD courses. The primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS), time to treatment failure (TTF), and safety. Results: Twenty patients with CD25-positive CTCL received DD retreatment (4 had complete response to the prior DD treatment, 13 had partial response to prior treatment, 1 had stable disease as prior response, and 2 had unrecorded prior response). At baseline, these patients had a median age of 59.5 years, 70% were male, 80% were white, and 80% had early-stage disease (stage ≤IIA). The 20 patients received a median of 8 courses of DD retreatment. Overall, 40% (8/20) of patients had a secondary response, the majority of which were partial responses (30%; 6/20). Secondary response rates for patients with baseline CTCL stages ≤IIA and ≥IIB were 38% (6/16) and 50% (2/4), respectively. Kaplan-Meier estimated median time to response for the intent-to-treat population was 102 days, and the median duration of response was 274 days. Progression events were observed for 9 patients, all of whom had stage ≤IIA disease at baseline. Kaplan-Meier estimated median PFS for the intent-to-treat population was 205 days (95% CI: 170–429 days), and the median TTF was 189 days (95% CI: 72–429 days). In total, 85% of patients had a treatment-related adverse event (AE), 55% had a treatment-related grade 3/4 AE, and 5% had a treatment-related serious AE. The most common treatment-related AEs were nausea (35%), fatigue (25%), headache (15%), rigors (20%), and pyrexia (10%). The 1 treatment-related serious AE involved pleural effusion. Conclusion: Patients with CD25-positive CTCL who had been treated previously with DD and subsequently relapsed were able to show durable responses upon retreatment. The observed ORR of 40% was similar to that seen with primary treatment with an estimated median duration of response of 9.8 months. Disclosures: Duvic: Eisai: Consultancy, Research Funding, Speakers Bureau. Olsen:Eisai: Research Funding; Merck: Consultancy, Research Funding; Gloucester: Consultancy; Yaupon: Research Funding; Biocryst: Research Funding; Johnson & Johnson : Consultancy, Research Funding. Fivenson:Amgen: Honoraria, Research Funding, Speakers Bureau; Dermik: Research Funding; Centrocor: Honoraria, Research Funding; Abbott: Honoraria, Research Funding, Speakers Bureau; Warner Chilcott: Honoraria, Speakers Bureau; Allergan: Research Funding; Ferndale: Research Funding; Graceway: Research Funding; Biolife: Consultancy, Research Funding; Merck: Honoraria, Research Funding; Pfizer: Research Funding; Galderma: Honoraria, Research Funding; Aspreva: Research Funding; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Perrigo: Research Funding; Organogenesis: Research Funding; Ligand: Research Funding; Connetics: Research Funding; Stiefel/GSK: Honoraria; Clay-Park Labs: Research Funding; Jacobus: Research Funding; Smith and Nephew: Research Funding; Dow Pharma: Research Funding; Therakos: Research Funding; Seragen: Research Funding; Convatec: Research Funding. Prince:Eisai: Consultancy, Honoraria.
Francine M Foss - One of the best experts on this subject based on the ideXlab platform.
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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
Leukemia & Lymphoma, 2013Co-Authors: Francine M Foss, Andre Goy, N N Sjakshie, Ranjana H Advani, Eric D Jacobsen, Mitchell R Smith, Rami S Komrokji, Kelly Pendergrass, Vanessa BolejackAbstract: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 peri...
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predictors of complete responses with Denileukin Diftitox in cutaneous t cell lymphoma
American Journal of Hematology, 2011Co-Authors: Francine M Foss, Madeleine Duvic, Elise A OlsenAbstract:The clinical course of cutaneous T-cell lymphoma (CTCL) is typically chronic, often progressive, and variably response to existing therapeutic interventions. To date, few controlled clinical trials demonstrate durable complete responses (CR) in advanced-stage patients. Denileukin Diftitox (DD) is a recombinant fusion protein targeting the interleukin-2 receptor of malignant cells. Of 263 relapsed and refractory CTCL patients treated with Denileukin Diftitox in three prospective, randomized Phase II and III clinical trials, 24 (9.1%) patients attained a durable complete response lasting beyond 3.6 years. This study evaluated the characteristics of the complete responders in these trials. CR patients had received a mean of 3.6 prior therapies. There was no difference in the frequency of CR based on stage of disease, dose of DD (9 vs. 18 μg/kg/day) (P = 0.646) or between CD25-positive and CD25-negative patients (P = 1.00). Response durations were 57-1,325+ days in the CD25-positive group and 190-400+ days in the CD25-negative group. These studies demonstrate that DD therapy resulted in durable complete responses in a subset of patients with early and advanced CTCL and CD25-positive and CD25-negative disease.
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phase ii study of Denileukin Diftitox with chop chemotherapy in newly diagnosed ptcl concept trial
Journal of Clinical Oncology, 2010Co-Authors: Francine M Foss, Andre Goy, N N Sjakshie, Ranjana H Advani, Eric D JacobsenAbstract:8045 Background: Denileukin Diftitox (DD), a genetically engineered fusion protein, targets malignancies expressing the IL-2 receptor and has demonstrated a 48% objective response rate in relapsed/...
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role of Denileukin Diftitox in the treatment of persistent or recurrent cutaneous t cell lymphoma
Cancer management and research, 2010Co-Authors: Frederick Lansigan, Diane M Stearns, Francine M FossAbstract:Denileukin Diftitox (Ontak®) is indicated for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL), a rare lymphoproliferative disorder of the skin. Denileukin Diftitox was the first fusion protein toxin approved for the treatment of a human disease. This fusion protein toxin combines the IL2 protein with diphtheria toxin, and targets the CD25 subunit of the IL2 receptor, resulting in the unique delivery of a cytocidal agent to CD-25 bearing T-cells. Historically, immunotherapy targeting malignant T-cells including monoclonal antibodies has been largely ineffective as cytocidal agents compared to immunotherapy directed against B-cells such as rituximab. This review will summarize the development of Denileukin Diftitox, its proposed mechanism of action, the pivotal clinical trials that led to its FDA approval, the improvements in quality of life, and the common toxicities experienced during the treatment of patients with CTCL. CTCL is often a chronic progressive lymphoma requiring the sequential use of treatments such as retinoids, traditional chemotherapy, or biological response modifiers. The incorporation of the immunotoxin Denileukin Diftitox into the sequential or combinatorial treatment of CTCL will also be addressed.
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complete responses with Denileukin Diftitox in cutaneous t cell lymphoma studies
Blood, 2009Co-Authors: Francine M Foss, Madeleine Duvic, Elise A Olsen, Anna KozlovskiAbstract:Abstract Abstract 3745 Poster Board III-681 Cutaneous T-cell lymphoma (CTCL) is a disorder of CD4+ helper T-cells with manifestations in the skin, nodes, and, in advanced stages, blood and visceral sites. For many patients, the clinical course of the disease is chronic and progressive, despite multiple therapeutic interventions. To date, are few controlled clinical trials which demonstrate durable complete responses (CR) in advanced stage patients. Denileukin Diftitox (DD) is a recombinant fusion protein targeting interleukin-2 receptor which has demonstrated efficacy in early and advanced stage CTCL with response rates of 30% and 44% in two clinical trials of CTCL pts with Stage Ib-IVA relapsed and refractory CTCL or Stage I-III disease, ≤3 prior therapies respectively. In these trials, patients (pts) were randomized to receive DD at a dose of either 9 or 18 ug/kg/d daily x 5 every 21 days. Another rollover trial enrolled pts who had progressed after prior response with DD (N=29) or were CD25- (N=36); all pts in the rollover trial were treated with DD at 18ug/kg dose. Of 263 intent-to-treat pts in these trials, 227 had CD25+ skin infiltrates by immunohistochemistry (IHC) confirmed by a reference pathologist and 36 were CD25-. Overall, 24 (9.1%) pts attained durable complete response (CR). The median age of the responders was 59, and 12 CR pts were over age 60. Of the CR group, 15 pts had early stage (I-IIa) disease and 9 had advanced stage (IIb-IV) CTCL. The mean prior therapies was 3.6 with 37% of patients having received >3 therapies. Of the 24 CR pts, 21 were CD25+ and 3 were CD25-. Two CR were pts who had previously responded to DD in an earlier clinical trial. Of all pts receiving 9 ug/kg dose (N=80), there were 6 (7.5%) CR; for all pts receiving 18 ug/kg dose (N=183), there were 18 (9.8%) CR. There was no significant difference frequency of CR between the 9 and 18 ug/kg groups (P=0.56) or between the CD25+ (N=118) and CD25- (N=36) pts treated at 18 ug/kg dose (P=0.64). CR rate was similar between the early and advanced stage patients (10.7% vs 8.9% respectively). The median time to response was 53.5 vs 41days for CD25+ pts treated in the 9 and 18 ug/kg groups respectively, and 43 days for the CD25- group. The response durations ranged from 57 days to >1325 days in the CD25+ and 190-400 days in the CD25- groups. Of the 24 CR, 7 have progressed as of the time of the analysis and 17 remain in CR. The overall median PFS at the time of analysis has not been reached (range 169-1388+ days). Of the 24 CR, 3 pts had hypersensitivity reactions and 3 had capillary leak syndrome associated with DD treatment. In summary, these studies demonstrate clinical benefit of DD with CR in both early and advanced CTCL at both 9 and 18 ug/kg doses and with durable responses in a small number of pts whose malignant lymphocytes were CD25- by ICH. Disclosures: Foss: Eisai : Speakers Bureau. Olsen: Eisai: Research Funding. Kozlovski: Eisai Pharm: Employment.
Timothy M Kuzel - One of the best experts on this subject based on the ideXlab platform.
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phase ii study of Denileukin Diftitox for previously treated indolent non hodgkin lymphoma final results of e1497
Leukemia & Lymphoma, 2007Co-Authors: Timothy M Kuzel, Francine M Foss, John W Eklund, Edie Weller, R D Gascoyne, N Abramson, J F Schwerkoske, S J HorningAbstract: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.
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phase ii study of Denileukin Diftitox for previously treated low grade non hodgkin s lymphoma e1497 final report
Journal of Clinical Oncology, 2005Co-Authors: John W Eklund, Francine M Foss, Timothy M Kuzel, Edie Weller, R D Gascoyne, N Abramson, J F Schwerkoske, S J HorningAbstract:6684 Background: Denileukin Diftitox (DD), a recombinant fusion protein of diphtheria toxin linked to interleukin-2, is FDA approved for the tx of cutaneous T-cell NHL. Initial studies of DD included several heavily pretreated pts with B-cell NHL, and objective responses were observed. This phase II trial was designed to evaluate the response rate (RR) and toxicity of DD in pts with relapsed low grade B-cell NHL, and to evaluate RR by tumor interleukin-2 receptor (IL-2R) expression. Methods: Eligible patients were stratified into two arms: pts with >20% IL-2R expression (IL-2R+) or patients with <20% IL-2R expression (IL-2R-) with independent response assessment for each group. DD was dosed at 18μg/kg/d for 5 days every 21 days for 2 cycles. Responders continued therapy for up to six cycles. Steroid premedication was not allowed. Results: The study closed prematurely due to slow accrual. Thirty of 35 pts entered were eligible and underwent treatment (18 M, 12 F; 12 IL-2R+ and 18 IL-2R-). The median pt age...
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Denileukin Diftitox a concise clinical review
Expert Review of Anticancer Therapy, 2005Co-Authors: John W Eklund, Timothy M KuzelAbstract:Denileukin Diftitox (DAB389IL-2; Ontak®) is a novel recombinant fusion protein approved by the US Food and Drug Administration for the treatment of relapsed or refractory cutaneous T-cell lymphoma. It consists of fragments of diphtheria toxin linked to human interleukin-2 and works by targeting the high-affinity interleukin-2 receptor expressed on malignant cells. This article will review the clinical trials leading to the approval of Denileukin Diftitox for cutaneous T-cell lymphoma, and discuss the potential future role of this novel drug in patients with both malignant and nonmalignant diseases, including non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, solid tumors, psoriasis and graft-versus-host disease.
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quality of life improvements in cutaneous t cell lymphoma patients treated with Denileukin Diftitox ontak
Clinical Lymphoma Myeloma & Leukemia, 2002Co-Authors: Madeleine Duvic, Youn H. Kim, Francine M Foss, Patricia Bacha, Timothy M Kuzel, Ann G Martin, Elise A Olsen, Peter Heald, Jean Nichols, Astra LiepaAbstract:Cutaneous T-cell lymphoma (CTCL) can be associated with painful, pruritic, disfiguring lesions. As part of a multicenter, randomized phase III trial in patients with heavily pretreated advanced and/or recurrent CTCL, the effects of an interleukin-2 receptor-targeted fusion protein, Denileukin Diftitox (DAB389IL-2, ONTAK), on patient-rated overall quality of life (QOL), skin appearance, and pruritus severity were evaluated. A total of 71 patients with stage IB-IVA CTCL received intravenous Denileukin Diftitox 9 microg/kg/day or 18 microg/kg/day over 15-60 minutes for 5 consecutive days on an outpatient basis; cycles were planned for every 21 days for a total of 8 cycles over 6 months. Prior to each treatment cycle, patients were evaluated for disease response and were asked to self-rate their overall QOL via the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire, skin appearance (7-point scale), and pruritus severity (10-cm visual analogue scale). Composite FACT-G and most individual subscale scores (physical, social/family, emotional, and functional well being) in documented responders (n = 21) gradually increased during the study period, generally reaching statistical significance (P < 0.05) by cycle 3, and were significantly (P < or = 0.041) higher than the scores of nonresponders at endpoint. Additionally for responders, assessments of skin severity and pruritus severity showed significant (P < or = 0.05) improvements at study endpoint compared with baseline. Adverse transfusion-related events (eg, hypersensitivity reactions, flu-like syndrome) were common during cycles 1 and 2, and vascular-leak syndrome occurred in 25% of patients. Denileukin Diftitox was not associated with any clinically significant myelosuppression. Heavily pretreated patients with advanced and/or recurrent CTCL who responded to Denileukin Diftitox therapy showed significant improvements in self-rated overall QOL, skin appearance, and pruritus severity.
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biological correlates of acute hypersensitivity events with dab389il 2 Denileukin Diftitox ontak in cutaneous t cell lymphoma decreased frequency and severity with steroid premedication
Clinical Lymphoma Myeloma & Leukemia, 2001Co-Authors: Francine M Foss, Patricia Bacha, Kathryn Osann, Tracy Bell, Timothy M KuzelAbstract: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.
Nam H Dang - One of the best experts on this subject based on the ideXlab platform.
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Denileukin Diftitox ontak as maintenance therapy for peripheral t cell lymphomas three cases with sustained remission
Case reports in oncological medicine, 2015Co-Authors: Alejandra Fuentes, Ellen Szwed, Cathy D Spears, Sandeep Thaper, Long H Dang, Nam H DangAbstract:Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin Diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where Denileukin Diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.
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de novo maintenance therapy with Denileukin Diftitox ontak in a patient with peripheral t cell lymphoma is associated with prolonged remission
American Journal of Hematology, 2008Co-Authors: Bryan Y Wong, Robert Fitzwilson, Nam H DangAbstract: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. Am. J. Hematol. 2008. © 2008 Wiley-Liss, Inc.
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Denileukin Diftitox as novel targeted therapy for lymphoid malignancies
Cancer Investigation, 2007Co-Authors: Bryan Y Wong, Stephanie A Gregory, Nam H DangAbstract:Denileukin Diftitox (DAB389IL-2; Ontak) is a cytotoxic fusion protein designed to target cells expressing the receptor for interleukin-2 (IL-2). It has been approved for treatment of patients with persistent or recurrent cutaneous T-cell lymphoma (CTCL) whose malignant cells express the CD25 component of the IL-2 receptor, but more recent data indicate activity in the setting of not only T-cell but also B-cell malignancies. This review will update the experience to date of Denileukin Diftitox in T- and B-cell malignancies.
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phase ii trial of the combination of Denileukin Diftitox and rituximab for relapsed refractory b cell non hodgkin lymphoma
British Journal of Haematology, 2007Co-Authors: Nam H Dang, Pamela L Walker, Fredrick B Hagemeister, Felipe Samaniego, Andre Goy, Peter Mclaughlin, Luis Fayad, Jorge E Romaguara, Sattva S Neelapu, Michael WangAbstract: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.
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phase ii trial of Denileukin Diftitox for relapsed refractory t cell non hodgkin lymphoma
British Journal of Haematology, 2007Co-Authors: Nam H Dang, Dan Jones, Barbara Pro, Fredrick B Hagemeister, Felipe Samaniego, Barry I Samuels, Maria A Rodriguez, Andre Goy, Jorge E Romaguera, Peter MclaughlinAbstract: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.
Tyler J Curiel - One of the best experts on this subject based on the ideXlab platform.
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Denileukin Diftitox reduces el4 lymphoma growth by depleting regulatory t cells which can be improved by αicos vac12p 1116
Journal of Immunology, 2015Co-Authors: Justin M Drerup, Vincent Hurez, Vinh Dao, Yang Liu, Alvaro Padron, Aijie Liu, Tyler J CurielAbstract:Immunotherapy shows promise in carcinoma treatments. As less is known about effects on lymphomas, we tested EL4 T cell lymphoma. We found that EL4 cells were CD25 - CTLA4 - B7H1 lo PD1 hi by flow cytometry. Immune checkpoint blockade with αCTLA4, αB7H1, or αPD1 antibodies had no effect on tumor growth in EL4-challenged mice. αCD25 worked as prophylaxis (before EL4 challenge) but not therapy, despite depleting regulatory T cells (Tregs). In Foxp3 DTR mice, specific Treg depletion reduced EL4 tumor growth, suggesting Treg depletion as a good treatment strategy. Denileukin Diftitox (DD) is a relatively-specific Treg depletion drug with clinical benefits in mouse and human cancer. DD (5 μg/4 days starting 4 days after EL4 challenge) significantly delayed EL4 tumor growth and increased survival (P=.002) in WT mice. DD protection was lost in βδ TCR KO mice lacking all T cells, suggesting a T cell dependent treatment mechanism. In EL4-challenged WT, DD depleted Tregs > αCD25 but significantly increased ICOS by 2-fold on remaining Tregs > than on CD4 + or CD8 + T cells in tumor draining lymph nodes. Nearly all Tregs within tumors were ICOS + . ICOS + Tregs were mostly CD44 + with hi Ki-67, suggesting activation that reduced DD treatment effects. In support, αICOS (100 μg/4 days starting 1 day after DD) enhanced DD-mediated EL4 tumor growth inhibition, but did not improve overall survival. DD-mediated Treg depletion plus αICOS and/or other adjuncts could lead to effective lymphoma immunotherapy.
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anti cd25 antibody and Denileukin Diftitox deplete regulatory t cells in id8 ovarian cancer equally but αcd25 promotes more t cell cytotoxicity that correlates with better survival vac12p 1112
Journal of Immunology, 2015Co-Authors: Justin M Drerup, Vincent Hurez, Aijie Liu, Tyler J CurielAbstract:In ovarian cancer (OC) regulatory T cells (Tregs) block anticancer immunity, suggesting Treg depletion could be beneficial. In our phase 2 Denileukin Diftitox (DDT) trial we found no clinical efficacy in 19 OC patients despite Treg depletion. αCD25 depletes Tregs but reportedly only works as cancer prophylaxis. We found that αCD25 did not treat subcutaneous B16 mouse melanoma whereas DDT did, and both reduced Tregs equally. We further show that in intraperitoneal ID8 challenge, αCD25 depletes Tregs in ascites and strikingly extends survival better than DDT, the first demonstration that αCD25 is effective cancer treatment (vs prophylaxis). Treg suppression of T cell proliferation in vitro from ID8-bearing mice was equal after DDT or αCD25. DDT and αCD25 could thus target or modulate Treg subsets or other immune cells differentially, as neither is Treg-specific. Despite reduced clinical efficacy, DDT increased beneficial IFN-γ+CD4+ and ID8-specific CD8+ T cells and NK cells in ascites better than αCD25, but also increased pro-tumorigenic IL-17+ and TNF-α+ CD4+ T cells, whereas αCD25 did not. αCD25 increased numbers of ascites GzB+CD107a+CD8+ T cells whereas DDT did not, suggesting increased cytotoxicity that could explain better clinical efficacy. These observations show that Treg depletion agents available for clinical use have distinct effects on antitumor immunity, help define clinical indications for αCD25 versus DDT and identify responsive cancers or anatomic compartments.
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Denileukin Diftitox depletes regulatory t cells without clinical benefit in advanced stage epithelial ovarian carcinoma vac3p 945
Journal of Immunology, 2014Co-Authors: Tyler J Curiel, Ilona Kryczek, Weiping Zou, Suzanne Thibodeaux, Shawna Wall, Srilakshmi Pandeswara, Benjamin J Daniel, Justin M Drerup, Kruthi Murthy, Brian BarnettAbstract:Denileukin Diftitox (DT) depletes regulatory T cells (Treg) that correlates with immune and clinical benefits in metastatic human melanoma and improved clinical outcomes in a renal cancer vaccine trial. We tested immune and clinical effects of Treg depletion using DT in a phase 0/I cancer trial and a phase II ovarian cancer trial. In our phase 0/I trial, we noted reductions in blood Treg prevalence and concentration (median ~18% and ~50%, respectively) 3-7 days after one intravenous DT infusion at 9 or 12 μg/kg, in 6 of 7 evaluable patients with breast, lung, and ovarian cancers, and melanoma, and increased blood IFN-γ+ and Ki-67+ T cells. Weekly DT significantly reduced metastatic tumors in one ovarian cancer patient prompting a small phase II trial in epithelial ovarian cancers. 28 patients received DT once every 3-4 weeks which significantly depleted functional Tregs from blood and the tumor microenvironment, but with variable immune outcomes and no significant clinical efficacy. Weekly DT eventually reduced effector T cells. In mouse ovarian cancer models we found that: i) DT efficacy depended on adaptive immunity, ii) its IL-2 moiety did not mediate clinical effects, and iii) its treatment mechanism appeared distinct from anti-CD25 antibody, which depleted Tregs in a human breast cancer trial. DT depletes Tregs in various carcinomas but requires more dosing and schedule studies. Treg-specific agents and combination treatments could also improve Treg depletion efficacy.
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il 2 immunotoxin Denileukin Diftitox reduces regulatory t cells and enhances vaccine mediated t cell immunity
Blood, 2007Co-Authors: Mary T Litzinger, Romaine I Fernando, Tyler J Curiel, Douglas W Grosenbach, Jeffrey Schlom, Claudia PalenaAbstract:CD4+CD25+Foxp3+ regulatory T (Treg) cells have been implicated in the lack of effective antitumor immunity. Denileukin Diftitox (DAB389IL-2), a fusion protein of interleukin 2 (IL-2) and diphtheria toxin, provides a means of targeting Treg cells. In this study, we examined (1) the effect of Denileukin Diftitox on the deletion of Treg cells in various lymphoid compartments and (2) the dose scheduling of Denileukin Diftitox in combination with a recombinant poxviral vaccine to enhance antigen-specific immune responses. Treg cells in spleen, peripheral blood, and bone marrow of normal C57BL/6 mice were variously reduced after a single intraperitoneal injection of Denileukin Diftitox; the reduction was evident within 24 hours and lasted approximately 10 days. Injection of Denileukin Diftitox 1 day before vaccination enhanced antigen-specific T-cell responses above levels induced by vaccination alone. These studies show for the first time in a murine model (1) the differential effects of Denileukin Diftitox on Treg cells in different cellular compartments, (2) the advantage of combining Denileukin Diftitox with a vaccine to enhance antigen-specific T-cell immune responses, (3) the lack of inhibition by Denileukin Diftitox of host immune responses directed against a live viral vector, and (4) the importance of dose scheduling of Denileukin Diftitox when used in combination with a vaccine.
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importance of dose scheduling of Denileukin Diftitox vaccine combination therapy to reduce t regs and to enhance immune responses
Cancer Research, 2007Co-Authors: Mary T Litzinger, Romaine I Fernando, Tyler J Curiel, Jeffrey Schlom, Claudia PalenaAbstract:220 Regulatory T cells (T regs) play a crucial role in the maintenance of immunological self-tolerance and therefore in the prevention of autoimmune disease. In the context of cancer, recent findings suggest that T regs are in part responsible for lack of effective anti-tumor immunity. In fact, it has been shown that cancer patients have a high number of T regs circulating in peripheral blood as well as at the tumor site. The constitutively high expression of the IL-2R α subunit (CD25) on the surface of T regs allows for strategies aimed at depleting this T-cell population by targeting of the IL-2R. Denileukin Diftitox, a fusion protein of IL-2 and diphtheria toxin, provides one such means of targeting this population. However, because Denileukin Diftitox can potentially deplete activated T cells as well as T regs, the scheduling of Denileukin Diftitox in combination with vaccine becomes an important consideration. In this study, we examined (a) the effect of Denileukin Diftitox on depletion of Tregs in various cellular compartments and (b) the dose scheduling of Denileukin Diftitox in combination with vaccine to enhance antigen-specific immune responses. A single injection of Denileukin Diftitox in mice (0.75 μg, i.p.) resulted in a reduction in the percentage of CD4+CD25+Foxp3+ T cells in spleen, peripheral blood, and bone marrow at day 1 post-administration. The depletion of T regs in spleen and blood was transient, normalizing by day 10 post-administration, whereas the level of T regs in bone marrow remained depressed at day 10. In subsequent experiments, we examined the use of Denileukin Diftitox in combination with recombinant poxvirus vaccines encoding for a specific antigen and a triad of costimulatory molecules (TRICOM: B7-1, ICAM-1, and LFA-3), in the induction of antigen-specific immune responses in mice (to CEA or NP34). Various schedules of Denileukin Diftitox/vaccine combination therapy were evaluated, with Denileukin Diftitox being administered on days -7, -3, -1, 0, and +3 relative to vaccine. Injection of Denileukin Diftitox one day prior to vaccine was the most efficient in enhancing antigen-specific immune responses above that induced by vaccination alone. In contrast, Denileukin Diftitox administration three days after vaccine showed a negative impact on the development of an antigen-specific immune response. These studies indicate the potential utility of combination immune therapies designed to (a) reduce immune suppressive factors and (b) enhance activation of T-cell responses.