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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 -
Oncology (Williston Park, N.Y.) Feb 2007There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response... (Review)
Review
There are few approved therapies for cutaneous T-cell lymphoma (CTCL). The retinoids are the major biologic response modifiers used in CTCL, producing good response rates but few complete responses. For patients with early-stage disease, the oral retinoids can be combined with other therapies, such as psoralen plus ultraviolet A or interferon alpha, to improve response rates. Combined-modality therapy with oral retinoids, combined chemotherapy, electron-beam therapy, and topical mustargen has also proved effective. For the treatment of advanced-stage disease, the targeted therapy denileukin diftitox (Ontak) provides a nonimmunosuppressive alternative to conventional chemotherapy or radiation therapy. Of the conventional chemotherapies that have been tested in CTCL, gemcitabine (Gemzar) has demonstrated good efficacy in producing responses, particularly in patients with tumors. This agent can be used in combination with a maintenance therapy of bexarotene (Targretin) to manage the plaques and patches of mycosis fungoides. Several other targeted therapies are now also in testing, for example, alemtuzumab (CamPath), HuMax-CD4, several histone deacetylase inhibitors, and the transition-state inhibitor forodesine. These drugs, in combination with currently used therapies, may increase the number and combinations of therapies available for the treatment of this chronic condition to optimize long-lasting responses in CTCL.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Diphtheria Toxin; Dose-Response Relationship, Drug; Humans; Hydroxamic Acids; Immunologic Factors; Interferon-alpha; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Purine Nucleosides; Pyrimidinones; Radiotherapy, Adjuvant; Recombinant Fusion Proteins; Retinoids; Sezary Syndrome; Skin Neoplasms; Vorinostat
PubMed: 17474358
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Feb 2007Cutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages, but survival rates decrease dramatically as the disease progresses. As no curative therapies... (Review)
Review
Cutaneous T-cell lymphoma (CTCL) is relatively benign in its early stages, but survival rates decrease dramatically as the disease progresses. As no curative therapies are currently available, the goal of therapy is preventing or delaying progression from early disease stages while minimizing long-term toxicity. No single agent, including psoralen plus ultraviolet A (PUVA), can control disease progression fully, so combination therapy is needed to improve response rates. In addition, low-dose combination therapy may improve treatment safety and tolerability. A combination of PUVA and interferon (IFN) alpha in early disease has been shown to be effective and well tolerated. Likewise, small studies of PUVA and bexarotene (Targretin) indicate good efficacy for this combination. Reduced doses of these combinations may also be effective as maintenance therapies following complete remission. Other treatment combinations shown to be effective in early disease stages include bexarotene with IFNalpha and bexarotene with denileukin diftitox (Ontak). In advanced stages of CTCL, liposomal-encapsulated doxorubicin or extracorporeal photopheresis may be combined with bexarotene or IFNalpha.
Topics: Antineoplastic Agents; Bexarotene; Clinical Trials as Topic; Combined Modality Therapy; Diphtheria Toxin; Disease Progression; Doxorubicin; Humans; Immunologic Factors; Interferon-alpha; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Neoplasm Staging; PUVA Therapy; Photopheresis; Recombinant Fusion Proteins; Retinoids; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 17474357
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Feb 2007Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients... (Review)
Review
Mycosis fungoides is responsive to treatment in the early stages; patients have a long duration of survival but are rarely cured of the disease. Therefore, patients require long-term, sequential therapies with as little toxicity as possible. In the early stages, skin-directed therapies, such as psoralen plus ultraviolet A in combination with retinoids or interferon, generally produce good, long-term responses. Once the disease progresses, systemic agents such as cytokines and retinoids are introduced. The cytokines provide a rational treatment approach for cutaneous T-cell lymphoma (CTCL) and produce good, long-lasting responses with few immunosuppressant effects. Denileukin diftitox (Ontak) has also been shown to produce good treatment effects, and its toxic effects can usually be controlled using prophylactic therapies. The synthetic retinoid bexarotene (Targretin) is taken orally and produces high response rates in CTCL, with a good long-term tolerability profile. Conventional systemic chemotherapies produce rapid responses and high response rates in CTCL, but these are generally of short duration and accompanied by myelosuppression and immunosuppression. Current treatment strategies therefore consist of the use of initial skin-directed therapies, with the addition of low-toxicity systemic biologic agents as the disease progresses; patients who do not respond to biologic agents should then receive conventional chemotherapies, starting with single agents and progressing to combination therapies.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Cytokines; Diphtheria Toxin; Humans; Immunologic Factors; Interleukin-2; Lymphoma, T-Cell, Cutaneous; Neoplasm Staging; Purines; Recombinant Fusion Proteins; Retinoids; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 17474355
DOI: No ID Found -
British Journal of Haematology Feb 2007This 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...
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.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Diphtheria Toxin; Disease-Free Survival; Drug Administration Schedule; Drug Resistance, Neoplasm; Fatigue; Female; Humans; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Lymphoma, T-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Recombinant Fusion Proteins; Transaminases; Treatment Outcome
PubMed: 17233846
DOI: 10.1111/j.1365-2141.2006.06457.x -
American Journal of Hematology Dec 2006We report here a case of severe steroid-refractory gastrointestinal graft-versus-host disease treated with intra-arterial administration of corticosteroids. A...
We report here a case of severe steroid-refractory gastrointestinal graft-versus-host disease treated with intra-arterial administration of corticosteroids. A 53-year-old female with non-Hodgkin's lymphoma received peripheral blood hematopoietic stem cell transplant from her HLA-matched sibling. She developed grade II skin and grade IV gastrointestinal graft-versus-host disease with no hepatic involvement. Therapy with oral prednisone easily controlled her skin rash but she had profuse diarrhea that did not respond to high dose intravenous corticosteroids and denileukin diftitox. Infusion of methyl-prednisolone into superior and inferior mesenteric arteries produced dramatic improvement of diarrhea, with complete resolution of gastrointestinal graft-versus-host disease.
Topics: Administration, Oral; Antineoplastic Agents; Diarrhea; Diphtheria Toxin; Drug Resistance; Female; Gastrointestinal Diseases; Glucocorticoids; Graft vs Host Disease; Humans; Infusions, Intra-Arterial; Injections, Intravenous; Interleukin-2; Lymphoma, Follicular; Methylprednisolone; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prednisone; Recombinant Fusion Proteins; Skin Diseases
PubMed: 16924649
DOI: 10.1002/ajh.20711 -
Biology of Blood and Marrow... Sep 2006Denileukin diftitox (Ontak) was evaluated in combination with methotrexate (MTX) for preventing acute graft-versus-host disease (GVHD) in dogs given 9.2 Gy of total body...
Denileukin diftitox (Ontak) was evaluated in combination with methotrexate (MTX) for preventing acute graft-versus-host disease (GVHD) in dogs given 9.2 Gy of total body irradiation and DLA-nonidentical hematopoietic cell grafts. Six dogs were given denileukin diftitox 9 ,microg/kg/day intravenously (IV) on days 2, 4, 5, 7, 8, and 10, in combination with MTX 0.4 mg/kg/day IV on days 1, 3, 6, and 11 after transplantation. Median survival of the dogs given MTX in combination with denileukin diftitox was 16 days (range, 13-18 days), similar to that of 35 historical controls given MTX alone (median survival, 20 days). Five of the 6 denileukin diftitox-treated dogs had clinical and pathological evidence of 3-system GVHD; 1 dog died of canine herpes virus infection without evidence of GVHD. In conclusion, denileukin diftitox did not prevent, mitigate, or delay acute GVHD in this stringent and predictive (with respect to outcomes in human patients) hematopoietic cell transplantation model.
Topics: Animals; Antineoplastic Agents; Diphtheria Toxin; Dogs; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesviridae Infections; Immunosuppressive Agents; Interleukin-2; Methotrexate; Models, Animal; Recombinant Fusion Proteins; Time Factors; Whole-Body Irradiation
PubMed: 16920555
DOI: 10.1016/j.bbmt.2006.05.005 -
The British Journal of Ophthalmology Aug 2006
Topics: Antineoplastic Agents; Diphtheria Toxin; Hematologic Neoplasms; Humans; Interleukin-2; Male; Middle Aged; Recombinant Fusion Proteins; Retinal Diseases; Vision Disorders
PubMed: 16854841
DOI: 10.1136/bjo.2006.091165 -
Cancer May 2006The safety and efficacy of the interleukin-2 diphtheria toxin fusion protein (DAB(389)IL2; denileukin diftitox) directed against the IL-2 receptor (IL-2R) was tested in...
BACKGROUND
The safety and efficacy of the interleukin-2 diphtheria toxin fusion protein (DAB(389)IL2; denileukin diftitox) directed against the IL-2 receptor (IL-2R) was tested in patients with recurrent or refractory chronic lymphocytic leukemia (CLL).
METHODS
Denileukin diftitox was administered as 60-minute intravenous infusions for 5 days every 21 days at a dose of 18 mug/kg per day for up to 8 cycles. In total, 28 patients were treated in 2 multiinstitutional studies with similar eligibility criteria and treatment protocols. Twenty-two patients receive > or = 2 cycles of denileukin diftitox and were evaluable for response.
RESULTS
Twelve of 22 patients achieved reductions of peripheral CLL cells, with 5 of 12 patients achieving >80% reductions. Six of 22 patients achieved reductions in the size of lymph node on examination and computed tomography scans, and all 6 of those patients met the criteria for a partial or complete response that lasted > or = 2 months. Bone marrow biopsies before and after treatment confirmed a complete remission that lasted for 1 year in 1 patient. Overall, denileukin diftitox produced complete remission in 1 of 22 patients (4%) and partial remission in 5 of 22 patients (23%) for a total remission rate of 27%. Progression-free intervals in the responders were 2 months in 2 patients and 4 months, 6 months, 7 months, and 12 months in 1 patient each. Toxicities were moderate. No infections associated with immunosuppression were seen. There was no significant correlation of response or toxicities with the numbers of denileukin diftitox cycles received or with CD25 levels.
CONCLUSIONS
Follow-up studies will be required to identify predictors of response that may improve the response rate to denileukin diftitox in patients with CLL.
Topics: Aged; Antineoplastic Agents; Biopsy, Needle; Bone Marrow; Diphtheria Toxin; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunohistochemistry; Infusions, Intravenous; Interleukin-2; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Staging; Probability; Recombinant Fusion Proteins; Risk Assessment; Salvage Therapy; Survival Analysis; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 16586495
DOI: 10.1002/cncr.21851 -
The Journal of Investigative Dermatology Mar 2006Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death....
Denileukin diftitox (Ontak), a recombinant fusion protein of diphtheria toxin and ligand, IL-2, binds to the IL-2 receptor, is internalized, and causes cell death. Denileukin diftitox was approved for the treatment of cutaneous T-cell lymphomas (CTCLs) with CD25+ expression. We prospectively stained lesional skin biopsy specimens from 113 mycosis fungoides and Sézary Syndrome patients for activation markers CD25 and CD30 to correlate expression with clinical tumor-node metastasis (TNM) stage, histologic grade, and response to denileukin diftitox. High expression was defined as positivity of > or =20% of lesional T-cells using immunohistochemistry (IHC). CD25 and CD30 expression was more common in lesions from advanced patients (P = 0.04 and 0.002, respectively). Advanced TNM (T3 or T4) was significantly associated with intermediate-grade (P = 0.002) and large-cell transformation histology (P = 0.04). Of interest, clinical responses were observed in 78.5% of patients with high CD25 expression versus 20% with low to undetectable CD25 expression (P = 0.01) among 24 patients receiving standard 5-day infusions of denileukin diftitox at 18 microg/kg/day. These data suggest that high CD25 expression by IHC is associated with advanced CTCL and with clinical response to denileukin diftitox therapy.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Bexarotene; Diphtheria Toxin; Female; Humans; Interleukin-2; Ki-1 Antigen; L-Lactate Dehydrogenase; Lymphoma, T-Cell, Cutaneous; Male; Middle Aged; Receptors, Interleukin-2; Recombinant Fusion Proteins; Skin; Skin Neoplasms; Tetrahydronaphthalenes
PubMed: 16410787
DOI: 10.1038/sj.jid.5700122