RESUMEN
Introduction: In the last few years, monoclonal antibodies have rapidly modified the therapeutic strategies for treating patients with multiple myeloma.Areas covered: In this review, the most recent literature data regarding indications for which monoclonal antibodies are currently or will be shortly approved as salvage therapies in relapsed/refractory myeloma are discussed. In particular, updated results until March 22, 2020 of antibodies directed against CD38 (daratumumab and isatuximab), SLAMF7 (elotuzumab), BCMA (GSK2857916/belantamab mafodotin), and PD-1/PD-1 L axis (nivolumab and pembrolizumab) will be analyzed in detail.Expert opinion: Monoclonal antibodies represent a new, very effective approach that will open novel and dynamic treatment scenarios for myeloma patients in the coming years. Optimal positioning and selection of different antibodies that are or will be soon available, appropriate combinations and careful evaluation of possible new toxicities should be considered in the future management of these patients.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Ensayos Clínicos como Asunto , Femenino , Humanos , MasculinoRESUMEN
Advances in our understanding οf tumor immunity have prompted a paradigm shift in oncology, with the emergence of immunotherapy, where therapeutic agents are used to target immune cells rather than cancer cells. A real breakthrough in the field of immunotherapy came with the use of immune checkpoint inhibitors (ICI), namely antagonistic antibodies that block key immune regulatory molecules (checkpoint molecules), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein (PD-1) and its ligand PD-L1, that under physiologic conditions suppress T cell effector function. However, despite the enormous success, a significant proportion of patients do not respond, while responses are frequently accompanied by life-threatening autoimmune related adverse events (irAEs). A major impediment in the effectiveness of ICI immunotherapy is the tumoral resistance, which is dependent on the immunosuppressive nature of tumor microenvironment (TME). Regulatory T cells (Tregs) are among the most abundant suppressive cells in the TME and their presence has been correlated with tumor progression, invasiveness as well as metastasis. Tregs are characterized by the expression of the transcription factor Foxp3 and various mechanisms ranging from cell-to-cell contact to secretion of inhibitory molecules have been implicated in their function. Notably, Tregs amply express most of the checkpoint molecules such as CTLA4, PD1 and LAG3 and therefore represent a direct target of ICI immunotherapy. Taking into consideration the critical role of Tregs in maintenance of immune homeostasis and avoidance of autoimmunity it is plausible that targeting of Tregs by ICI immunotherapy results in the development of irAEs. Since the use of ICI becomes common, and new immune checkpoint molecules are currently under clinical trials for the treatment of cancer, the occurrence of irAEs is expected to dramatically rise. Herein we review the current literature focusing on the role of Tregs in cancer evolution, ICI response and development of irAEs. Unraveling the complex mechanisms that hinder the tumor immune surveillance and in particular how ICI immunotherapy imprint on Treg activities to promote cancer regression while avoid development of irAEs, will empower the design of novel immunotherapeutic modalities in cancer with increased efficacy and diminished adverse events.
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Anticuerpos Antineoplásicos , Enfermedades Autoinmunes , Inmunoterapia/efectos adversos , Neoplasias , Linfocitos T Reguladores/inmunología , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/terapia , Humanos , Proteínas de Neoplasias/inmunología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapia , Linfocitos T Reguladores/patologíaRESUMEN
In 1997, the first monoclonal antibody (MoAb), the chimeric anti-CD20 molecule rituximab, was approved by the US Food and Drug administration for use in cancer patients. Since then, the panel of MoAbs that are approved by international regulatory agencies for the treatment of hematopoietic and solid malignancies has continued to expand, currently encompassing a stunning amount of 20 distinct molecules for 11 targets. We provide a brief scientific background on the use of MoAbs in cancer therapy, review all types of monoclonal antibodies-related adverse events (e.g., allergy, immune-related adverse events, cardiovascular adverse events, and pulmonary adverse events), and discuss the mechanism and treatment of adverse events.
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Anticuerpos Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Rituximab/uso terapéutico , Anticuerpos Antineoplásicos/efectos adversos , Humanos , Rituximab/efectos adversosRESUMEN
Pulmonary delivery of drug-loaded nanoparticles is a novel approach for lung cancer treatment and the conjugation of nanoparticles to a targeting ligand further promotes specificity of the carrier cargo to cancer cells. Notably, the epithelial cell adhesion molecule (EpCAM, CD326) is over expressed in lung cancer. Here, we report the safety and proof-of-concept efficacy of drug-loaded nanoparticles and EpCAM immunonanoparticles in a c-Raf transgenic lung cancer model. PEG-PLA nanoparticles and immunonanoparticles were prepared whereby paclitaxel palmitate (Pcpl) was incorporated as a medication for its common use in lung cancer treatment. Four doses of aerosolized nanoparticle formulations or vehicle were endotracheally administered to mice by consecutive or alternate regimes. Pulmonary delivery of drug loaded nano- and/or immunonanoparticle formulations elicited mild inflammation as evidenced by the slightly increased neutrophil and activated macrophage counts in bronchoalveolar lavage. No evidence for pulmonary toxicity following treatment with either blank or drug-loaded nano- and/or immunonanoparticles was observed. Proof-of-concept efficacy was determined by serial CT scanning and histopathology. Animals treated with either EpCAM antibody or Pcpl solution or drug loaded nano- or immunonanoparticles inhibited disease progression. Conversely, disease progression was noted with vehicle treated animals with nearly 30% loss of their aerated lung volume. Importantly, treatment of mice with either Pcpl or EpCAM antibody solution caused 80% mortality and/or haemorrhage, respectively, thus causing unacceptable toxicity. In contrast, the survival of animals treated with either nano- or immunonanoparticles was 60 and 70%, respectively. Taken collectively, pulmonary delivered drug-loaded nano- and EpCAM immunonanoparticles were well tolerated and can be considered a promising strategy for improving lung cancer treatment.
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Anticuerpos Inmovilizados/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Antineoplásicos Fitogénicos/administración & dosificación , Moléculas de Adhesión Celular/antagonistas & inhibidores , Modelos Animales de Enfermedad , Sistemas de Liberación de Medicamentos , Neoplasias Pulmonares/tratamiento farmacológico , Administración por Inhalación , Animales , Anticuerpos Inmovilizados/efectos adversos , Anticuerpos Inmovilizados/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Antígenos de Neoplasias/metabolismo , Antineoplásicos Fitogénicos/efectos adversos , Antineoplásicos Fitogénicos/uso terapéutico , Moléculas de Adhesión Celular/metabolismo , Sistemas de Liberación de Medicamentos/efectos adversos , Molécula de Adhesión Celular Epitelial , Femenino , Humanos , Pulmón/efectos de los fármacos , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones , Ratones Transgénicos , Nanopartículas/administración & dosificación , Nanopartículas/efectos adversos , Nanopartículas/química , Nanopartículas/uso terapéutico , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Paclitaxel/análogos & derivados , Paclitaxel/uso terapéutico , Palmitatos/administración & dosificación , Palmitatos/efectos adversos , Palmitatos/uso terapéutico , Proteínas Proto-Oncogénicas c-raf/genética , Proteínas Proto-Oncogénicas c-raf/metabolismo , Distribución Aleatoria , Propiedades de Superficie , Análisis de SupervivenciaRESUMEN
The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.
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Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Antineoplásicos/administración & dosificación , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Linfoma de Células B/tratamiento farmacológico , Linfoma Folicular/tratamiento farmacológico , Lectina 2 Similar a Ig de Unión al Ácido Siálico , Adulto , Anciano , Animales , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/inmunología , Antineoplásicos/efectos adversos , Antineoplásicos/inmunología , China , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfoma de Células B/inmunología , Linfoma de Células B/patología , Linfoma Folicular/inmunología , Linfoma Folicular/patología , Masculino , Ratones , Persona de Mediana EdadAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Citomegalovirus/fisiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Paraproteinemias/etiología , Acondicionamiento Pretrasplante/efectos adversos , Femenino , Humanos , MasculinoRESUMEN
Two cases are reported of rare digestive opportunistic parasites in patients being treated with alemtuzumab for lymphoid haematological malignancies. In both patients, classical biological examinations were insufficient to reach the diagnosis. Only specific parasitological techniques enabled diagnoses of cryptosporidiosis and microsporidiosis, respectively. In both cases, cellular immune reconstitution was sufficient to eradicate these opportunistic infections. In this context, parasitological diagnosis is often underestimated by medical practitioners, so immunologists and oncohaematologists need to be aware of this kind of opportunistic pathogen.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Antineoplásicos/efectos adversos , Criptosporidiosis/inducido químicamente , Cryptosporidium/aislamiento & purificación , Enterocytozoon/aislamiento & purificación , Microsporidiosis/inducido químicamente , Infecciones Oportunistas/inducido químicamente , Anciano , Alemtuzumab , Criptosporidiosis/diagnóstico , Criptosporidiosis/inmunología , Criptosporidiosis/parasitología , Cryptosporidium/genética , Cryptosporidium/inmunología , Enterocytozoon/inmunología , Femenino , Humanos , Inmunidad Celular , Masculino , Técnicas Microbiológicas , Microsporidiosis/diagnóstico , Microsporidiosis/inmunología , Microsporidiosis/microbiología , Infecciones Oportunistas/diagnóstico , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/microbiología , Infecciones Oportunistas/parasitologíaRESUMEN
BACKGROUND: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon ß-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined. METHODS: The lymphocyte reconstitution (n=36; 384 person years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis. RESULTS: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10(9) cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person years of follow-up. CONCLUSIONS: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Linfopenia/inducido químicamente , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Femenino , Humanos , Recuento de Linfocitos , Subgrupos Linfocitarios/efectos de los fármacos , Subgrupos Linfocitarios/inmunología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/inmunología , Factores de Tiempo , Adulto JovenAsunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Factores Inmunológicos/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Alemtuzumab , Femenino , Humanos , MasculinoRESUMEN
The introduction of monoclonal antibodies has been a milestone in the treatment of hematologic neoplasms. The CD20 antibody rituximab has been a trailblazer and represents meanwhile a fixed combination partner of different first- and second-line chemotherapies in CD20-positive B-cell-non-Hodgkin's lymphoma (NHL). Rituximab maintenance is established in follicular lymphoma. The drug is also used for the treatment of non-malignant hematologic diseases (i.e. immunthrombocytopenia). Rituximab was followed by the CD52 antibody alemtuzumab and recently by the CD20 antibody ofatumumab for the therapy of CLL and the radioimmunconjugate ibritumomab-tiuxetan indicated for the treatment of refractory or relapsed CD20-positive follicular lymphoma or as consolidation after induction chemotherapy. In the near future, approval of several new antibodies is expected. For the treatment of refractory or relapsed Hodgkin's lymphoma and relapsed systemic anaplastic large cell lymphoma, the CD30 antibody brentuximab vedotin has been shown to be a highly active new treatment option.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia/tratamiento farmacológico , Linfoma/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Brentuximab Vedotina , Humanos , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , RituximabRESUMEN
OBJECTIVES: This prospective study was designed to develop a steroid and calcineurin inhibitor-free regimen for kidney transplants using alemtuzumab. MATERIALS AND METHODS: A single dose of alemtuzumab (30 mg) was given preoperatively. Phase 1: Twenty-one patients were randomized into 2 groups; the tacrolimus (n=11) and the sirolimus groups (n=10). Steroids were given for 5 days. Azathioprine (1 mg/kg) was added when white blood cells ≥ 4000 cells/cm(3). Mean follow-up was 48 ± 2.8 and 48.2 ± 1.6 months for the tacrolimus and sirolimus groups. Phase 2: Twenty patients were included and the study design was modified. Tacrolimus was given for 2 months, and was replaced by sirolimus thereafter. The mean follow-up was 28.3 ± 2.1 months. RESULTS: Phase 1: Acute rejection episodes were encountered in 5 patients of the tacrolimus versus 2 cases in the sirolimus group (P = .44). Antibody-mediated rejection was diagnosed in 2 recipients in each group. Four patients were switched from sirolimus to tacrolimus owing to resistant rejection, significant proteinuria, persistent thrombocytopenia, lymphocele, and urinary leakage. One patient was shifted from tacrolimus to sirolimus owing to Kaposi sarcoma. Glomerular filtration rate was significantly higher in the sirolimus group. Currently, 14 patients (8 tacrolimus, and 6 sirolimus) are steroid-free. One patient died from the tacrolimus group owing to fulminant hepatitis. Two grafts were lost in the sirolimus group versus 1 graft in the tacrolimus group. Phase 2: Five patients developed successfully treated borderline changes with no antibody-mediated rejection. Mean serum creatinine was 114.9 ± 17.7 µmol/L. Currently, 17 patients are steroid free and 15 of them are calcineurin inhibitor-free as well. In this phase, only 1 patient died with a functioning graft. CONCLUSIONS: This clinical trial provides a good insight into a potentially effective steroid and calcineurin inhibitor-free protocol with the use of alemtuzumab induction in combination with sirolimus.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/administración & dosificación , Trasplante de Riñón , Donadores Vivos , Acondicionamiento Pretrasplante/métodos , Adolescente , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Azatioprina/administración & dosificación , Inhibidores de la Calcineurina , Esquema de Medicación , Sustitución de Medicamentos , Quimioterapia Combinada , Egipto , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/mortalidad , Humanos , Inmunosupresores/efectos adversos , Trasplante de Riñón/inmunología , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/análogos & derivados , Estudios Prospectivos , Sirolimus/administración & dosificación , Esteroides/administración & dosificación , Tacrolimus/administración & dosificación , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
In a phase 2 clinical trial of annual alemtuzumab for treatment of relapsing-remitting multiple sclerosis, 6 of 216 patients (2.8%) developed immune thrombocytopenia (ITP). Over mean follow-up of 4.5 years, the incidence rate of ITP was 6.2 (95% confidence interval, 2.3-13.3) per 1000 person-years. Median times from initial and last alemtuzumab exposure to ITP diagnosis were 24.5 and 10.5 months, respectively. Five patients developed severe thrombocytopenia. Four were symptomatic, including fatal intracranial hemorrhage in the index case. Four patients received standard first-line ITP therapy, all of whom responded to treatment within 1 week. All 5 surviving patients achieved complete remission and remained in complete remission without need for ongoing ITP therapy for a median duration of 34 months at last follow-up. A monitoring plan for the early detection of ITP, implemented after presentation of the index case, identified all 5 subsequent cases before serious hemorrhagic morbidity or mortality occurred. In conclusion, we describe a distinctive form of ITP associated with alemtuzumab treatment characterized by delayed presentation after drug exposure, responsiveness to conventional ITP therapies, and prolonged remission. Clinicians should maintain a high level of vigilance and consider routine monitoring for ITP in patients treated with this agent. This trial was registered at www.clinicaltrials.gov as #NCT00050778.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Factores Inmunológicos/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Púrpura Trombocitopénica Idiopática/inmunología , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/uso terapéutico , Antígenos CD , Antígenos de Neoplasias , Antígeno CD52 , Estudios de Cohortes , Monitoreo de Drogas , Terminación Anticipada de los Ensayos Clínicos , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Glicoproteínas/antagonistas & inhibidores , Humanos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/uso terapéutico , Incidencia , Masculino , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/prevención & control , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/inducido químicamente , Púrpura Trombocitopénica Idiopática/epidemiología , Púrpura Trombocitopénica Idiopática/terapia , Inducción de Remisión , Prevención Secundaria , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiologíaRESUMEN
Unlike cytotoxic agents that indiscriminately affect rapidly dividing cells, newer antineoplastic agents such as targeted therapies and immunotherapies are associated with thyroid dysfunction. These include tyrosine kinase inhibitors, bexarotene, radioiodine-based cancer therapies, denileukin diftitox, alemtuzumab, interferon-α, interleukin-2, ipilimumab, tremelimumab, thalidomide, and lenalidomide. Primary hypothyroidism is the most common side effect, although thyrotoxicosis and effects on thyroid-stimulating hormone secretion and thyroid hormone metabolism have also been described. Most agents cause thyroid dysfunction in 20%-50% of patients, although some have even higher rates. Despite this, physicians may overlook drug-induced thyroid dysfunction because of the complexity of the clinical picture in the cancer patient. Symptoms of hypothyroidism, such as fatigue, weakness, depression, memory loss, cold intolerance, and cardiovascular effects, may be incorrectly attributed to the primary disease or to the antineoplastic agent. Underdiagnosis of thyroid dysfunction can have important consequences for cancer patient management. At a minimum, the symptoms will adversely affect the patient's quality of life. Alternatively, such symptoms can lead to dose reductions of potentially life-saving therapies. Hypothyroidism can also alter the kinetics and clearance of medications, which may lead to undesirable side effects. Thyrotoxicosis can be mistaken for sepsis or a nonendocrinologic drug side effect. In some patients, thyroid disease may indicate a higher likelihood of tumor response to the agent. Both hypothyroidism and thyrotoxicosis are easily diagnosed with inexpensive and specific tests. In many patients, particularly those with hypothyroidism, the treatment is straightforward. We therefore recommend routine testing for thyroid abnormalities in patients receiving these antineoplastic agents.
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Antineoplásicos/efectos adversos , Hipertiroidismo/inducido químicamente , Hipotiroidismo/inducido químicamente , Neoplasias/tratamiento farmacológico , Glándula Tiroides/efectos de los fármacos , Hormonas Tiroideas/sangre , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Anticarcinógenos/efectos adversos , Antineoplásicos/administración & dosificación , Bexaroteno , Toxina Diftérica/efectos adversos , Humanos , Hipertiroidismo/sangre , Hipertiroidismo/diagnóstico , Hipopituitarismo/complicaciones , Hipopituitarismo/etiología , Hipotiroidismo/sangre , Hipotiroidismo/diagnóstico , Hipotiroidismo/tratamiento farmacológico , Hipotiroidismo/etiología , Interferón-alfa/efectos adversos , Interleucina-2/efectos adversos , Interleucina-2/análogos & derivados , Radioisótopos de Yodo/administración & dosificación , Ipilimumab , Lenalidomida , Terapia Molecular Dirigida/métodos , Neoplasias/inmunología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Calidad de Vida , Radioinmunoterapia , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes/efectos adversos , Tetrahidronaftalenos/efectos adversos , Talidomida/efectos adversos , Talidomida/análogos & derivados , Pruebas de Función de la Tiroides , Glándula Tiroides/metabolismo , Tiroiditis Autoinmune/inducido químicamenteRESUMEN
Hypomethylating agents such as 5-azacytidine or decitabine have been a major breakthrough in the treatment of patients with myelodysplastic syndromes (MDS). They have been shown to improve transfusion requirements and to change the natural history of the disease. However, with increasing cumulative clinical experience, it has become apparent that these agents are not curative and have their own shortcomings. There is a subgroup of patients who do not respond to frontline therapy and a large, growing cohort of patients that lose response or progress while on hypomethylating agent-based therapy. There are no standard treatment options in this arena and it is therefore a focus of significant research interest. Since the mechanisms of resistance to hypomethylating agents are not known, selection of therapy is largely empiric but must take into account the age, comorbidities, and performance status of the patient, as well as the characteristics of the disease at the time of treatment failure. Higher intensity approaches and allogeneic stem cell transplant can yield improved response rates and long-term disease control but should be limited to a selected cohort of patients who can tolerate the treatment-related morbidities. For the majority of patients who likely will be better candidates for lower intensity therapy, several novel, investigational approaches are becoming available. Among these are newer nucleoside analogues, inhibitors of protein tyrosine kinases, molecules that interact with redox signaling within the cell, immunotherapy approaches, and others. Patients with MDS whose disease has failed to respond to hypomethylating agent therapy should be referred for clinical trials when available. As we learn more about the patterns and mechanisms of failure, the next challenge will be to determine which therapies are suitable for each individual patient.
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Antineoplásicos/uso terapéutico , Azacitidina/farmacología , Resistencia a Medicamentos , Inhibidores Enzimáticos/farmacología , Síndromes Mielodisplásicos/tratamiento farmacológico , Nucleótidos de Adenina/efectos adversos , Nucleótidos de Adenina/uso terapéutico , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/uso terapéutico , Azacitidina/análogos & derivados , Clofarabina , Citosina/efectos adversos , Citosina/análogos & derivados , Citosina/uso terapéutico , Decitabina , Sustitución de Medicamentos , Glutatión/efectos adversos , Glutatión/análogos & derivados , Glutatión/uso terapéutico , Glicina/efectos adversos , Glicina/análogos & derivados , Glicina/uso terapéutico , Humanos , Síndromes Mielodisplásicos/terapia , Trasplante de Células Madre , Sulfonas/efectos adversos , Sulfonas/uso terapéutico , Insuficiencia del TratamientoRESUMEN
Posterior reversible encephalopathy syndrome (PRES) is a combined clinical and radiological syndrome characterised by headaches, encephalopathy, seizures and visual loss. We present the case of a 55-year-old male who developed this condition following treatment with deoxycoformycin and alemtuzumab. We review the literature considering diagnosis, pathophysiology and optimal strategies for treatment of this condition.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pentostatina/efectos adversos , Síndrome de Leucoencefalopatía Posterior/inducido químicamente , Alemtuzumab , Humanos , MasculinoRESUMEN
Intravenous alemtuzumab is an effective and well-tolerated treatment for T-cell prolymphocytic leukemia (T-PLL). Alemtuzumab given intravenously as first-line treatment in 32 patients resulted in an overall response rate of 91% with 81% complete responses. Studies in B-cell chronic lymphocytic leukemia have shown subcutaneous alemtuzumab to be equally as effective as intravenous alemtuzumab. The UKCLL05 pilot study examined the efficacy and toxicity of this more convenient method of administration in 9 previously untreated patients with T-PLL. Only 3 of 9 patients (33%) responded to treatment. Furthermore, 2 of 9 patients (22%) died while on treatment. Recruitment was terminated because of these poor results. After rescue therapy with intravenous alemtuzumab and/or pentostatin, median progression-free survival and overall survival were similar to the intravenous group. Alemtuzumab delivered intravenously, but not subcutaneously, remains the treatment of choice for previously untreated T-PLL.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Antineoplásicos/administración & dosificación , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Alemtuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Inyecciones Intravenosas , Inyecciones Subcutáneas , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Proyectos Piloto , Resultado del TratamientoRESUMEN
BACKGROUND: Immunosuppressive regimens for kidney transplantation which reduce the long-term burden of immunosuppression are attractive, but little data are available to judge the safety and efficacy of the different strategies used. We tested the hypothesis that the simple, cheap, regimen of alemtuzumab induction combined with tacrolimus monotherapy maintenance provided equivalent outcomes to the more commonly used combination of interleukin-2 receptor monoclonal antibody induction with tacrolimus and mycophenolate mofetil combination maintenance, both regimens using steroid withdrawal after 7 days. METHODS: One hundred twenty-three live or deceased donor renal transplant recipients were randomized 2:1 to receive alemtuzumab/tacrolimus or daclizumab/tacrolimus/mycophenolate. The primary endpoint was survival with a functioning graft at 1 year. RESULTS: Both regimens produced equivalent, excellent outcomes with the primary outcome measure of 97.6% in the alemtuzumab arm and 95.1% in the daclizumab arm at 1 year (95% confidence interval of difference 6.9% to -1.7%) and at 2 years 92.6% and 95.1%. Rejection was less frequent in the alemtuzumab arm with 1- and 2-year rejection-free survival of 91.2% and 89.9% compared with 82.3% and 82.3% in the daclizumab arm. There were no significant differences in terms of the occurrence of opportunistic infections. CONCLUSION: Alemtuzumab induction with tacrolimus maintenance monotherapy and short-course steroid use provides a simple, safe, and effective immunosuppressive regimen for renal transplantation.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Inmunosupresores/uso terapéutico , Trasplante de Riñón/inmunología , Tacrolimus/uso terapéutico , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Antineoplásicos/efectos adversos , Daclizumab , Quimioterapia Combinada , Femenino , Supervivencia de Injerto/inmunología , Supervivencia de Injerto/fisiología , Humanos , Inmunoglobulina G/efectos adversos , Inmunoglobulina G/uso terapéutico , Inmunosupresores/efectos adversos , Trasplante de Riñón/fisiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapéutico , Estudios Prospectivos , Tacrolimus/efectos adversos , Resultado del TratamientoRESUMEN
Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is associated with superior overall survival (OS) for patients with chronic lymphocytic leukemia (CLL). Alemtuzumab (A) was added to FCR (CFAR) in a phase 2 trial for high-risk untreated patients < 70 years with serum ß-2 microglobulin (ß2M) ≥ 4 mg/L. Sixty patients were enrolled; median age was 59 years (range, 42-69); 75% were male; median ß2M was 5.1 mg/L (range, 4-11.6); and 51% were Rai III-IV. Complete remission (CR) was achieved in 70%, partial remission (PR) in 18%, nodular PR in 3%, for an overall response of 92%. Of 14 patients with 17p deletion, CR was achieved by 8 (57%). Of 57 BM samples evaluated by 3-color flow cytometry at the end of treatment, 41 (72%) were negative for residual disease. Grade 3-4 neutropenia and thrombocytopenia occurred with 33% and 13% courses, respectively. The median progression-free survival was 38 months and median OS was not reached. In conclusion, CFAR is an active frontline regimen for high-risk CLL. Response rates and survival are comparable with historic high-risk FCR-treated patients. CFAR may be a useful frontline regimen to achieve CR in patients with 17p deletion before allogeneic stem cell transplantation.
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Anticuerpos Monoclonales/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/terapia , Adulto , Anciano , Alemtuzumab , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Antineoplásicos/administración & dosificación , Anticuerpos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Deleción Cromosómica , Cromosomas Humanos Par 17 , Terapia Combinada , Ciclofosfamida/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Neutropenia/etiología , Inducción de Remisión , Factores de Riesgo , Rituximab , Síndrome de Smith-Magenis , Trombocitopenia/etiología , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
OBJECTIVE: To define the rate, timing, and clinical risk factors for the development of autoimmune disease (AID) after alemtuzumab treatment for multiple sclerosis (MS). METHODS: We analyzed prospective clinical and serologic data from 248 patients with MS treated with alemtuzumab, with median follow-up of 34.3 months (range 6.7-107.3). RESULTS: Novel AID developed in 22.2%. Thyroid AID was most frequent (15.7%). A range of hematologic, renal, and dermatologic AID were also observed as was asymptomatic development of novel autoantibodies. AID was seen from 2 weeks after initial treatment and was most frequent 12-18 months after first treatment. No new cases of AID were identified 60 months or more after initial treatment and risk of AID was independent of total alemtuzumab dose or interval of dosage. While established risk factors for AID including sex and age had no impact on AID frequency, both family history (odds ratio = 7.31, 95% confidence interval 3.02-17.68) of AID and a personal smoking history (odds ratio = 3.05, 95% confidence interval 1.50-6.19) were predictive of AID expression. CONCLUSIONS: Cumulative risk for AID in MS following alemtuzumab is 22.2%, most frequent between 12 and 18 months following first dose and evident for up to 5 years. Individual risk is modified by smoking and family history, which should be incorporated within the counseling process prior to treatment. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that the risk of AID after alemtuzumab treatment for MS is time-limited and modified by external factors.
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Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/efectos adversos , Anticuerpos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedades Autoinmunes/inducido químicamente , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/tratamiento farmacológico , Adolescente , Adulto , Anciano , Alemtuzumab , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados , Autoanticuerpos/análisis , Enfermedades Autoinmunes/genética , Estudios de Cohortes , Consejo , Femenino , Estudios de Seguimiento , Humanos , Masculino , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Estudios Prospectivos , Factores de Riesgo , Fumar , Enfermedades de la Tiroides/inducido químicamente , Enfermedades de la Tiroides/inmunología , Resultado del Tratamiento , Adulto JovenRESUMEN
Although combination regimens have improved outcomes over monotherapy in chronic lymphocytic leukemia (CLL), patients eventually relapse. Combined fludarabine, cyclophosphamide, and monoclonal anti-CD52 antibody alemtuzumab (FCC) provided synergistic cytotoxicity with effective clearing of minimal residual disease. This phase 2 study determined FCC efficacy and safety in relapsed/refractory CD52(+) B-CLL after ≥ 1 line of treatment. From January 2005 through June 2008, up to 6 courses of oral fludarabine 40 mg/m² per day, oral cyclophosphamide 250 mg/m² per day, and subcutaneous alemtuzumab (Mab-Campath) 10 mg (increased to 20 mg after first 10-patient cohort) were administered days 1 to 3 every 28 days. The primary objective was overall response rate (ORR); secondary objectives included response duration, time to disease progression, and safety and tolerability. ORR was 67% in 43 patients; 30% achieved complete response. ORR significantly improved with 1 versus ≥ 2 prior therapies (P = .018), and without versus with previous monoclonal antibody treatment (P = .003). Median progression-free survival was 24.4 months, not reached in patients achieving complete response. Median overall survival was 33.6 months. Myelosuppression was the most common adverse event, with a low percentage of cytomegalovirus reactivations and manageable infections. However, close vigilance of opportunistic infections is warranted. FCC provides effective immunotherapy in relapsed/refractory CLL, including in patients with poor-risk prognostic factors.