RESUMEN
We enrolled 25 patients with extensive, steroid-refractory chronic graft-versus-host disease (cGVHD) in a prospective trial evaluating the efficacy of extracorporeal photophoresis (ECP) in both skin and visceral cGVHD. The median time from transplant to initiation of ECP was 790 days. ECP was administered for 2 consecutive days every 2 weeks in 17 patients and once a week in eight patients until best response or stable disease. The median duration of therapy was 9 months (range 3-24 months). In all, 20 patients had improvement in cutaneous GVHD and six had healing of oral ulcerations. Steroid sparing or discontinuation of immunosuppressive medications was possible in 80% of patients. Response rates were similar between patients receiving treatment weekly vs every 2 weeks and in patients commencing ECP less than vs greater than 18 months from transplant (70 vs 66%). When patients were stratified based on the Akpek prognostic score, there was no difference in overall response between the favorable (Akpek score<2.5) and unfavorable risk groups, but patients with progressive onset cGVHD tended to have a higher response than those with de novo onset. In summary, we report improvement in skin and/or visceral cGVHD in 71% overall and 61% of high-risk patients.
Asunto(s)
Enfermedad Injerto contra Huésped/terapia , Fotoféresis/métodos , Terapia Recuperativa/métodos , Adolescente , Adulto , Enfermedad Crónica , Resistencia a Medicamentos , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Humanos , Masculino , Persona de Mediana Edad , Enfermedades de la Boca/etiología , Enfermedades de la Boca/terapia , Pronóstico , Enfermedades de la Piel/etiología , Enfermedades de la Piel/terapia , Esteroides , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
SUMMARY: In all, 55 patients at high risk or ineligible for a conventional allogeneic hematopoietic stem cell transplant (HSCT) received a regimen consisting of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The median age was 49 years (18-70 years); 44 received a sibling and 11 an unrelated HSCT; 44% were over the age of 50 years and 31% had undergone a prior HSCT. Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. Full donor chimerism was documented in 98% by day +100. The 1000-day nonrelapse mortality was 11%. The median follow-up is 502 days (154-1104 days). The 1- and 2-year overall survival (OS) and event-free survival (EFS) are 67, 58 and 55%, and 47%, respectively. Patients who had not received a prior HSCT or had less than three prior chemotherapy regimens had a 71% OS and 67% EFS at 1 year. Greater than grade II aGVHD developed in 9% and chronic GVHD (cGVHD) in 43%, and extensive in 12% and limited in 31%. Of the patients, 86% who engrafted had a disease response, 72% had complete and 14% partial responses. This novel reduced intensity preparative regimen was well tolerated and associated with a low incidence of transplant-related mortality and serious acute and cGVHD.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Quimera por Trasplante , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Anciano , Ciclosporina/farmacología , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Metotrexato/farmacología , Persona de Mediana Edad , Pentostatina/uso terapéutico , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Irradiación Corporal TotalRESUMEN
Despite significant advances in stem cell manipulation and post-transplant immunosuppression, chronic graft-versus-host disease (cGVHD) remains a cause of major long-term morbidity in survivors of allogeneic stem cell transplantation. Extracorporeal photopheresis (ECP) is a novel therapeutic intervention which has demonstrated efficacy in patients with refractory acute and chronic GVHD. Clinical responses have been reported in skin and visceral GVHD. While the long-term immunomodulatory effects of ECP in cGVHD are unknown, recent studies of patients undergoing a 6- to 12-month course of ECP treatment demonstrated an attenuation of Th1-mediated cytokine secretion by activated T-helper cells, a shift in the DC1/DC2 ratio favoring plasmacytoid rather than monocytoid dendritic cell profiles, and a decrease in antigen responsiveness by dendritic cells. The implications of these immunomodulatory effects of ECP on pathogenesis and clinical outcome remains a fertile area for future research.
Asunto(s)
Enfermedad Injerto contra Huésped/terapia , Fotoféresis , Trasplante de Médula Ósea/efectos adversos , Enfermedad Crónica , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Sistema Inmunológico/citología , Sistema Inmunológico/metabolismoRESUMEN
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.
Asunto(s)
Toxina Diftérica/efectos adversos , Hipersensibilidad a las Drogas/prevención & control , Glucocorticoides/uso terapéutico , Inmunosupresores/efectos adversos , Inmunotoxinas/efectos adversos , Interleucina-2/efectos adversos , Linfoma Cutáneo de Células T/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Terapia Combinada , Dexametasona/uso terapéutico , Toxina Diftérica/uso terapéutico , Hipersensibilidad a las Drogas/etiología , Femenino , Humanos , Inmunosupresores/uso terapéutico , Inmunotoxinas/uso terapéutico , Interleucina-2/uso terapéutico , Linfocitos/inmunología , Linfoma Cutáneo de Células T/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Prednisona/uso terapéutico , Premedicación , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias Cutáneas/metabolismo , Síndrome , Resultado del TratamientoRESUMEN
The interleukin (IL)-2 receptor has proved an attractive target for T cell-directed therapies. Agents including monoclonal antibodies, single-chain antibody immunoconjugates, radioimmunoconjugates, and, most recently, ligand fusion toxins have demonstrated activity in vitro and in clinical trials in both hematologic malignancies and diseases characterized by proliferation of activated T cells, such as graft-versus-host disease. DAB389IL-2 (ONTAK) is a ligand fusion toxin consisting of the full-length sequence of the IL-2 gene genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB389IL-2 and its predecessor, DAB486IL-2, have demonstrated activity in a variety of diseases, including cutaneous T cell lymphoma (CTCL), psoriasis, rheumatoid arthritis, and HIV infection. Further clinical development of IL-2 fusion toxins in CTCL and other hematopoietic malignancies is predicated on identification of the high-affinity IL-2 receptor complex on the malignant cells and on a better understanding of the biological determinants of cytotoxicity of these molecules in vivo.
Asunto(s)
Antineoplásicos/uso terapéutico , Toxina Diftérica/uso terapéutico , Inmunotoxinas/uso terapéutico , Interleucina-2/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Ensayos Clínicos Fase III como Asunto , Toxina Diftérica/efectos adversos , Toxina Diftérica/farmacología , Humanos , Inmunotoxinas/efectos adversos , Inmunotoxinas/farmacología , Interleucina-2/efectos adversos , Interleucina-2/farmacología , Linfoma Cutáneo de Células T/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de Interleucina-2/metabolismo , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/farmacología , Neoplasias Cutáneas/metabolismo , Resultado del TratamientoRESUMEN
PURPOSE: To evaluate the role of 9-aminocamptothecin (9-AC), a synthetic camptothecin analog, in advanced cutaneous T-cell lymphoma (CTCL). METHODS: Eligible patients had stage IIB-IV CTCL. 9-AC was infused over 72 h at a dose of 1,100 microg/m2 per day (approximately 46 microg/m2/h) every 2 weeks, with granulocyte-colony stimulating factor (G-CSF) support. RESULTS: Twelve patients received a total of 30 cycles of 9-AC. Nine patients had stage IV disease, 5 patients had circulating Sezary cells, and 2 patients had evidence of tranformation to a large cell lymphoma. Most of the patients were heavily pretreated: 10 had received prior chemotherapy (83%), 5 of whom had received 2 or more prior regimens, including a patient who had received high-dose chemotherapy, and 7 had previously received total-skin electron beam therapy. The study was prematurely terminated due to substantial toxicity. Six patients (50%) developed an indwelling central venous catheter-related infection, 5 during a period of neutropenia. Three patients died due to sepsis 4-8 weeks after their last 9-AC treatment. Two of these patients had a previous history of bacterial sepsis. Four patients (33%) developed grade IV thrombocytopenia. Two partial responses were observed (response rate 17%), but the duration of response was brief, 4-8 weeks. CONCLUSION: 9-AC at this schedule and route of administration had activity but resulted in an unacceptable rate of complicated neutropenia and septic deaths in heavily pretreated patients with advanced CTCL who are susceptible to catheter-related infections.
Asunto(s)
Antineoplásicos/administración & dosificación , Camptotecina/análogos & derivados , Camptotecina/administración & dosificación , Linfoma Cutáneo de Células T/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Antineoplásicos/efectos adversos , Camptotecina/efectos adversos , Progresión de la Enfermedad , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Infusiones Intravenosas , Linfoma Cutáneo de Células T/mortalidad , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/terapia , Neoplasias Cutáneas/mortalidad , Factores de Tiempo , Resultado del TratamientoRESUMEN
Extracorporeal photochemotherapy (ECP) has been associated with clinical improvement in several patients with acute and chronic graft-versus-host disease (cGVHD) after allogeneic bone marrow transplantation, but the mechanism of action is unknown. This study tested the hypothesis that in patients with cGVHD, ECP modulates alloreactivity by affecting activated lymphocyte populations or by altering the interaction between effector lymphocytes and antigen-presenting cells (APCs). Ten patients who had refractory cGVHD were treated with ECP, and the clinical response to and immunologic effects of this therapy were assessed. Seven patients had a response and 3 had no change in clinical manifestations of cGVHD. One patient died from catheter-related sepsis. Immunologic effects observed after ECP included normalization of inverted ratios of CD4 to CD8 cells, an increase in the number of CD3-CD56+ natural killer (NK) cells, and a decrease in CD80+ and CD123+ circulating dendritic cells. The results suggest that ECP modulates both NK cells and APC populations in patients with cGVHD.
Asunto(s)
Circulación Extracorporea , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Terapia PUVA , Adulto , Presentación de Antígeno/efectos de los fármacos , Trasplante de Médula Ósea/efectos adversos , Relación CD4-CD8 , Enfermedad Crónica , Terapia Combinada , Células Dendríticas/efectos de los fármacos , Resistencia a Medicamentos , Femenino , Neoplasias Hematológicas/terapia , Humanos , Inmunosupresores/uso terapéutico , Células Asesinas Naturales/efectos de los fármacos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Linfocitos T Citotóxicos/efectos de los fármacosRESUMEN
Pentostatin (Nipent) has demonstrated significant activity as a single agent in patients with low-grade B- and T-cell lymphomas, but thus far, clinical experience with combinations of pentostatin and other agents is limited. A study of alternating administration of pentostatin and high-dose interferon-alfa-2a (Roferon A) in cutaneous T-cell lymphoma patients has been undertaken and has demonstrated a 41% response rate, with tolerable toxicity. Studies combining pentostatin with alkylating agents, including chlorambucil (Leukeran) and cyclophosphamide (Cytoxan, Neosar) in patients with chronic lymphocytic leukemia (CLL) have reported significant immunosuppression and have required dose modifications of one or both agents. Recently, a clinical trial was initiated to evaluate the combination of pentostatin and cordycepin, a novel purine analog, in patients with terminal deoxynucleotidyl transferase-positive acute lymphocytic leukemia, based on in vitro data demonstrating the significant synergy of this combination.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Pentostatina/uso terapéutico , Nucleósidos de Purina/uso terapéutico , Vidarabina/análogos & derivados , Adulto , Anciano , Antineoplásicos/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Ensayos Clínicos como Asunto , Desoxiadenosinas/uso terapéutico , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Interferones/uso terapéutico , Linfoma de Células B/mortalidad , Linfoma de Células T/mortalidad , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Vidarabina/uso terapéuticoRESUMEN
Cutaneous T-cell lymphoma (CTCL) comprises a constellation of diseases of malignant clonal T lymphocytes that present initially in the skin. Since biochemical studies of pentostatin suggested that T cells are more sensitive to the effects of inhibition of adenosine deaminase by purine analogs, early studies with pentostatin were conducted in patients with refractory T-cell neoplasms. Durable responses were reported in several patients on phase I studies. Of 94 CTCL patients treated on five phase II studies with single-agent pentostatin, the overall response rate was 40%, with a 7% complete response rate; the median time to progression ranged from 1.3 to 8.3 months. There was a trend toward improved response in patients with diffuse erythroderma or plaque disease. A phase II study combining pentostatin with intermittent high-dose interferon-alpha demonstrated a 41% overall response rate, with two complete responses, both in patients with Sézary syndrome and diffuse erythroderma Toxicities have been tolerable at doses of 4 to 5 mg/m2 administered weekly or for 3 consecutive days, with grade 3-4 hematologic toxicity in 31 patients, renal insufficiency in seven, nausea in 17, and conjunctivitis in three. In summary, pentostatin has demonstrated impressive activity in patients with advanced and refractory CTCL. Additional studies using pentostatin in earlier-stage CTCL or in combination with other active agents in advanced disease are warranted.
Asunto(s)
Antibióticos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunosupresores/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Pentostatina/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Inhibidores de la Adenosina Desaminasa , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Progresión de la Enfermedad , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Interferón-alfa/administración & dosificación , Interferón-alfa/uso terapéutico , Pentostatina/administración & dosificación , Pentostatina/efectos adversos , Inducción de Remisión , Síndrome de Sézary/tratamiento farmacológico , Linfocitos T/efectos de los fármacosRESUMEN
Fusion proteins are recombinant molecules that combine a targeting mechanism to a cytocidal moiety. DAB(389)IL-2 (denileukin diftitox; ONTAK), with a unique mechanism of action, is the first genetically constructed fusion protein to reach the clinic. In this molecule, the interleukin-2 (IL-2) gene is genetically fused to the enzymatically active and translocating domains of diphtheria toxin. DAB(389)IL-2 is internalized into IL-2 receptor-bearing cells by endocytosis. The ADP-ribosyltransferase activity of diphtheria toxin is cleaved in the endosome and is translocated into the cytosol where it inhibits protein synthesis, leading to apoptosis. DAB(389)IL-2 and its predecessor, DAB(486)IL-2, have shown clinical activity in a variety of diseases, including B-cell non-Hodgkin's lymphoma, cutaneous T-cell lymphoma (CTCL), Hodgkin's disease, psoriasis, rheumatoid arthritis, and HIV infection. The highest response rates were observed in CTCL, and this became the focus of clinical trials leading to its subsequent approval by the United States Food and Drug Administration for this disease. The potential applications of DAB(389)IL-2 in lymphomas are reviewed.
Asunto(s)
Toxina Diftérica/uso terapéutico , Inmunosupresores/uso terapéutico , Inmunotoxinas/uso terapéutico , Interleucina-2/uso terapéutico , Linfoma/tratamiento farmacológico , Proteínas Recombinantes de Fusión/uso terapéutico , Adulto , Ensayos Clínicos como Asunto , Humanos , Linfoma/metabolismo , Persona de Mediana Edad , Receptores de Interleucina-2/metabolismoRESUMEN
Cutaneous T-cell lymphoma (CTCL) includes a heterogeneous group of diseases manifested in many cases by a prolonged clinical course. Even patients with advanced clinical disease, including erythroderma, adenopathy, and cutaneous tumors, can respond to a number of conservative therapeutic modalities, including radiation, cutaneous and extracorporeal phototherapy, and interferon. More aggressive systemic therapies are generally reserved for patients with visceral involvement or effaced (LN4) lymph node disease or patients refractory to multiple conservative approaches. Since no survival benefit has been demonstrated for multiagent cytotoxic chemotherapy regimens, this therapy is generally reserved for patients whose disease demonstrates an aggressive clinical course requiring immediate palliation. Durable responses (5+ years) have been reported with purine analogues; however, prolonged immunosuppression and increased frequency of opportunistic infections have been demonstrated. Novel therapeutic agents, including interleukin-2, interleukin-12, the phosphorylase inhibitor peldesine (BCX-34), and bexarotene, have demonstrated activity. The interleukin-2 diphtheria toxin fusion protein, DAB(389)IL-2, has demonstrated a 30% response rate in advanced and refractory CTCL patients. The optimal role of targeted biological therapies in advanced patients will likely be in the minimal disease setting following either chemotherapy or radiation.
Asunto(s)
Linfoma Cutáneo de Células T/terapia , Oncología Médica/tendencias , Neoplasias Cutáneas/terapia , Humanos , Linfoma Cutáneo de Células T/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
Genetic engineering has led to the development of fusion protein toxins, which are targeted effector molecules that combine a targeting ligand such as a growth factor with a cytocidal moiety such as a plant or bacterial toxin. The first genetically constructed family of fusion proteins used diphtheria toxin as the toxophore for receptor-binding domain substitution. Diphtheria toxin consists of three domains: an enzymatically active adenosine diphosphate (ADP) ribosyltransferase domain, a hydrophobic transmembrane domain, and a C-terminal receptor-binding domain. Introduction of the enzymatically active domain into the cytosol via receptor-mediated endocytosis results in inhibition of protein synthesis by ADP ribosylation of elongation-factor 2. DAB(486)IL-2, in which the native receptor-binding domain of diphtheria toxin was replaced with the full-length interleukin-2 (IL-2) gene, was capable of intoxicating high-affinity IL-2 receptor-bearing cells in vitro with an IC(50) of 10(-10) M; whereas, cells lacking the full component of the high-affinity IL-2 receptor (p55, p75, p64) were relatively resistant (IC(50) of 10(-8) M). Because of a short in vivo half-life of DAB(486)IL-2, efforts to reengineer the molecule were undertaken, leading to the DAB(389)IL-2 construct, which had a twofold to threefold higher Kd than DAB(486)IL-2 and a longer half-life, resulting in a tenfold increase in potency. Thus far, the clinical activity of both IL-2 chimeric fusion toxins has been similar, with the DAB(389)IL-2 molecule displaying more favorable pharmacokinetics.
Asunto(s)
Toxina Diftérica , Inmunosupresores , Inmunotoxinas , Interleucina-2 , Proteínas Recombinantes de Fusión , Ensayos Clínicos como Asunto , Toxina Diftérica/química , Toxina Diftérica/farmacocinética , Toxina Diftérica/farmacología , Humanos , Inmunosupresores/química , Inmunosupresores/farmacocinética , Inmunosupresores/farmacología , Inmunotoxinas/química , Inmunotoxinas/farmacocinética , Inmunotoxinas/farmacología , Interleucina-2/química , Interleucina-2/farmacocinética , Interleucina-2/farmacología , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/farmacocinética , Proteínas Recombinantes de Fusión/farmacologíaRESUMEN
BACKGROUND: This Phase II study was undertaken to assess the efficacy and toxicity of chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone (EPOCH regimen) in patients with advanced, refractory cutaneous T-cell lymphoma (CTCL). METHODS: Fifteen patients were treated with a 96-hour continuous infusion of etoposide, vincristine, doxorubicin, bolus cyclophosphamide, and oral prednisone, followed by granulocyte-colony stimulating factor support and trimethoprim/sulfamethoxazole prophylaxis. The median age of the patients was 53 years (range, 17-82 years). Six patients had Sézary syndrome (SS), four patients had visceral involvement, and four patients had anaplastic large cell morphology, three with Ki-1 (CD30) positivity. All patients had disease that was refractory to prior chemotherapy or electron beam irradiation and eight of these patients had received cyclophosphamide, doxorubicin, vincristine, and prednisone. Seven patients had received prior interferon therapy and nine patients had received fludarabine and/or 2-CDA. RESULTS: After a median of 5 cycles (range, 1-9 cycles), 4 patients achieved a complete response (27%) and 8 patients achieved a partial response (53%) for an overall response rate of 80% (95% confidence interval, 52-96%). Three patients with visceral involvement, two of three patients with anaplastic large cell morphology, and one patient with human T-cell lymphoma virus leukemia/lymphoma did not respond. All 12 responders had improvement in skin disease; 2 of 6 patients with SS had complete disappearance of circulating Sézary cells. The median progression free survival was 8.0 months (range, 3-22 months). After a median follow-up of 11.4 months (range, 2-56+ months), the median patient survival was 13.5 months. Grade 3 or 4 hematologic toxicity occurred in 8 patients (61%); 5 of these 8 patients had febrile neutropenia. Six patients developed staphylococcal bacteremia, two patients had disseminated herpes infection, and one patient had Pneumocystis carinii pneumonia. Grade 3 neurotoxicity occurred in one patient. Two patients had a significant decrease in left ventricular ejection fraction and one patient had supraventricular tachycardia. CONCLUSIONS: EPOCH chemotherapy has a high response rate with acceptable toxicity in patients with advanced and refractory CTCL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma Cutáneo de Células T/tratamiento farmacológico , Administración Oral , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidad , Ciclofosfamida/administración & dosificación , Ciclofosfamida/toxicidad , Doxorrubicina/administración & dosificación , Doxorrubicina/toxicidad , Etopósido/administración & dosificación , Etopósido/toxicidad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/toxicidad , Inducción de Remisión , Síndrome de Sézary/complicaciones , Vincristina/administración & dosificación , Vincristina/toxicidadRESUMEN
Cutaneous lymphomas comprise a spectrum of diseases characterized by infiltration of the skin by malignant lymphocytes. The clinical manifestations of cutaneous lymphomas vary, and they can mimic benign dermatoses, as well as nodal or visceral malignancies with cutaneous spread. Cutaneous lymphomas are divided into T-cell lymphomas and B-cell lymphomas. Cutaneous T-cell lymphomas include mycosis fungoides, Sézary syndrome, lymphomatoid papulosis, CD30+ large cell lymphoma, and adult T-cell leukemia/lymphoma. The extent and severity of skin manifestations in cutaneous T-cell lymphomas are prognostic indicators of extracutaneous involvement. Primary cutaneous B-cell lymphomas comprise 10% to 25% of all primary cutaneous non-Hodgkin's lymphomas and are classified according to their cell of origin. Most cutaneous B-cell lymphomas have an indolent course and excellent prognosis when compared to their nodal counterparts. Many factors have been implicated in the etiology of cutaneous lymphomas, including chemical and drug exposures, as well as microbial agents, such as the Epstein-Barr virus (EBV), human T-lymphocyte virus-1 (HTLV-1), and Borrelia burgdorferi. Immunohistochemistry and lymphocyte-receptor gene rearrangement studies are useful in distinguishing malignant from benign conditions.
Asunto(s)
Linfoma de Células B/diagnóstico , Linfoma Cutáneo de Células T/diagnóstico , Neoplasias Cutáneas/diagnóstico , Diagnóstico Diferencial , Humanos , Linfoma de Células B/etiología , Linfoma de Células B/patología , Linfoma Cutáneo de Células T/etiología , Linfoma Cutáneo de Células T/patología , Estadificación de Neoplasias , Neoplasias Cutáneas/etiología , Neoplasias Cutáneas/patologíaRESUMEN
Ten patients with advanced or refractory CD5-expressing hematologic neoplasms [two with chronic lymphocytic leukemia and eight with cutaneous T-cell lymphoma (CTCL)] were treated in a Phase I study with the radioimmunoconjugate 90Y-T101, which targets CD5+ lymphocytes. Prior imaging studies using 111In-T101 demonstrated uptake in involved lymph nodes and skin in patients with CTCL, and Phase I studies with unmodified T101 demonstrated transient responses. In this study, patients were treated with 5 or 10 mCi of 90Y chelated to T101 via isothiocyanatobenzyl diethylenetriamine pentaacetic acid, along with tracer doses of 111In-T101 for imaging. The biodistribution of the radioimmunoconjugate was determined by measuring 90Y and 111In blood clearance, urine excretion, and accumulation in bone marrow and in involved skin lesions. The intravascular pharmacokinetics of 90Y were predicted by 111In-labeled T101. The greatest differences in biodistribution between 111In and 90Y were in the higher bone accumulation of 90Y and its lower urinary excretion. Imaging studies demonstrated targeting of skin lesions and involved lymph nodes in CTCL patients. The predominant toxicity was bone marrow suppression. Rapid antigenic modulation of CD5 on circulating T and B cells was observed. Recovery of T-cell populations occurred within 2-3 weeks; however, suppression of B-cell populations persisted after 5+ weeks. All CTCL patients developed human antimouse antibody after one cycle and thus were not retreated; one patient with chronic lymphocytic leukemia received a second cycle of therapy. Partial responses occurred in five patients, two with chronic lymphocytic leukemia and three with CTCL. The median response duration was 23 weeks. One CTCL patient who subsequently received electron beam irradiation to a residual lesion is disease-free after 6 years.
Asunto(s)
Anticuerpos Monoclonales/farmacocinética , Antígenos CD5/inmunología , Inmunoconjugados/farmacocinética , Leucemia Linfocítica Crónica de Células B/metabolismo , Linfoma Cutáneo de Células T/metabolismo , Radioisótopos de Itrio/farmacocinética , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/inmunología , Inmunoconjugados/uso terapéutico , Radioisótopos de Indio/farmacocinética , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/radioterapia , Leucemia Linfocítica Crónica de Células B/terapia , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/radioterapia , Linfoma Cutáneo de Células T/terapia , Persona de Mediana Edad , Radioinmunoterapia , Distribución Tisular , Resultado del Tratamiento , Radioisótopos de Itrio/efectos adversos , Radioisótopos de Itrio/uso terapéuticoAsunto(s)
Toxina Diftérica/uso terapéutico , Interleucina-2/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Toxina Diftérica/química , Humanos , Interleucina-2/química , Linfoma no Hodgkin/terapia , Linfoma de Células T/terapia , Linfoma Cutáneo de Células T/terapia , Psoriasis/terapia , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
Downregulation of bcr-abl expression in the chronic myelogenous leukemia cell line K562 using antisense oligonucleotides has been shown to enhance the sensitivity of the cells to apoptotic stimuli, suggesting that p210 bcr-abl, like bcl-2 functions as an anti-apoptosis factor (McGahon A et al, Blood 1994, 83: 1179). In these experiments, the inhibition of p210 bcr-abl expression alone was not sufficient to induce apoptosis. We demonstrated that exposure to low doses (0.5 mM) of a butyric acid analog, arginine butyrate, was capable of inducing apoptosis in selected leukemia cell lines, including K562 cells, and in fresh leukemia cells from patients with chronic myelogenous leukemia. To further explore the mechanisms of this effect, we examined expression of p210 bcr-abl after butyrate exposure and found a dose-related inhibition of p210 bcr-abl protein without concordant change in other phosphoproteins, including the JAK-1 kinase. Further analysis revealed that the inhibition of bcr-abl expression occurs due to transcriptional regulation of the bcr-abl gene by arginine butyrate. These results suggest that arginine butyrate and other butyrate analogs alone or in combination may be useful in the therapy of patients with chronic myelogenous leukemia or bcr-abl expressing acute leukemias.
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Arginina/análogos & derivados , Butiratos/farmacología , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Arginina/farmacología , Regulación hacia Abajo , Humanos , Janus Quinasa 1 , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Células Tumorales CultivadasRESUMEN
Interleukin 7 (IL-7) induces the proliferation of B cell progenitors in long-term bone marrow cultures, promotes the growth of resting fetal and adult thymocytes, and costimulates mature human T cell proliferation. IL-7 also induces cell growth in hematologic malignancies such as acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, and Sezary syndrome. We have constructed a recombinant fusion protein, DAB389 IL-7, composed of the catalytic and transmembrane domains of diphtheria toxin (DT), fused to IL-7. We demonstrate that DAB389 IL-7 is selectively cytotoxic for only those cells bearing the IL-7 receptor and that entry into target cells is mediated through the receptor. The nontoxic mutant, DA(E149S)B389 IL-7, was constructed and used to demonstrate that the catalytic domain of DT is responsible for the ADP ribosylation of elongation factor 2 that results in cytotoxicity. Finally, we demonstrate that DA(E149S)B389 IL-7 induces the growth of IL-7-dependent cells, verifying the bioactivity of the IL-7 binding domain of DAB389 IL-7. We propose that DAB389 IL-7 may be an important reagent in studying the IL-7--IL-7 receptor complex and may possess potential as a therapeutic agent against IL-7 receptor-bearing hematologic malignancies.
Asunto(s)
Antígenos CD/fisiología , Antineoplásicos/farmacología , Muerte Celular , Toxina Diftérica/farmacología , Interleucina-7/farmacología , Receptores de Interleucina/fisiología , Adenosina Difosfato Ribosa/metabolismo , Animales , Antígenos CD/análisis , Linfocitos B/patología , Escherichia coli/genética , Humanos , Inmunotoxinas , Leucemia de Células T/patología , Ratones , Factor 2 de Elongación Peptídica , Factores de Elongación de Péptidos/metabolismo , Ratas , Receptores de Interleucina/análisis , Receptores de Interleucina-7 , Proteínas Recombinantes de Fusión , Células Tumorales CultivadasRESUMEN
Strontium-89 is routinely used for pain control in advanced skeletal metastatic disease. A common side effect of Sr-89 therapy is a mild to moderate bone marrow suppression. To avoid complications from marrow suppression, a pretreatment platelet count of > 60,000/mm3 and a WBC count of > 2,400/mm3 are suggested. The authors present two patients who, despite satisfying these criteria, developed profound and prolonged bone marrow suppression after therapy. The severity of this response was most likely caused by pre-existing extensive bone marrow replacement with tumor. The contribution of local radiation therapy to bone marrow suppression is presumed to be minimal. The authors recommend that pretreatment criteria for determination of eligibility for Sr-89 therapy in selected patients be expanded to include steadily decreasing blood counts, and evaluation of extent of marrow involvement by biopsy or MR imaging.