RESUMEN
We developed a nanotechnology based-cell mediated drug delivery system by loading myelin antigen-specific T cells with nanoparticles bound to anti-CD20 monoclonal antibody. Anti-CD20 antibody is a current treatment (ocrelizumab) for multiple sclerosis (MS), a chronic, inflammatory and autoimmune disease of the central nervous system (CNS). CD20-depletion has been associated with efficacy in active relapsing and progressive MS, but may not efficiently target inflammatory cells compartmentalized in the CNS. In our work, the intravenous transfer of T cells containing nanoparticle-anti-CD20 complex in mice causes B cell depletion in the spleen and in the brain, whereas the injection of anti-CD20 alone depletes B cells only in the spleen. Testing this system in Experimental Autoimmune Encephalomyelitis (EAE), animal model of MS, we found that spinal cord B cell depletion ameliorates the disease course and pathology. Graphical Abstract.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antígenos CD20 , Linfocitos B , Encefalomielitis Autoinmune Experimental/inmunología , Sistema de Administración de Fármacos con Nanopartículas , Linfocitos T/trasplante , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunología , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunologíaRESUMEN
INTRODUCTION: CT-P10 is the first biosimilar of rituximab (RTX) for the treatment of rheumatoid arthritis (RA). The application of valuable biosimilar for the treatment of RA may decrease economic burden of society, and disease activity of RA. Thus, it is worthwhile to identify the economic advantage and further requirement for the proper use of CT-P10 in real world. AREAS COVERED: Literature searching was performed to identify suitable references written in English for this review article. Rituximab, biosimilar, CT-P10, and rheumatoid arthritis were used as keywords. Current state of RA treatment, position of RTX in the recommendations for the treatment of RA, current status of RTX biosimilar development were assessed before evaluating CT-P10 itself. Physicochemical property, pharmacokinetic profile through phase I to phase III studies, pharmacodynamics, toxicology data, clinical efficacy, and safety were reviewed. EXPERT OPINION: As the first biosimilar to originator RTX, CT-P10 may be a useful alternative for the treatment of RA in all indications for originator RTX. In addition, more studies are required to identify long-term effectiveness and safety of CT-P10 in real world. It is also important to find out new indications of CT-P10 and effective mechanisms to lessen nocebo effect against biosimilar including CT-P10.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Rituximab/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Anticuerpos Monoclonales de Origen Murino/farmacocinética , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Antirreumáticos/farmacocinética , Biosimilares Farmacéuticos/administración & dosificación , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/farmacocinética , Desarrollo de Medicamentos , Humanos , Rituximab/efectos adversos , Rituximab/farmacocinética , Resultado del TratamientoRESUMEN
OBJECTIVE: While the safety and efficacy of convection-enhanced delivery (CED) have been studied in patients receiving single-dose drug infusions, agents for oncological therapy may require repeated or chronic infusions to maintain therapeutic drug concentrations. Repeat and chronic CED infusions have rarely been described for oncological purposes. Currently available CED devices are not approved for extended indwelling use, and the only potential at this time is for sequential treatments through multiple procedures. The authors report on the safety and experience in a group of pediatric patients who received sequential CED into the brainstem for the treatment of diffuse intrinsic pontine glioma. METHODS: Patients in this study were enrolled in a phase I single-center clinical trial using 124I-8H9 monoclonal antibody (124I-omburtamab) administered by CED (clinicaltrials.gov identifier NCT01502917). A retrospective chart and imaging review were used to assess demographic data, CED infusion data, and postoperative neurological and surgical outcomes. MRI scans were analyzed using iPlan Flow software for volumetric measurements. Target and catheter coordinates as well as radial, depth, and absolute error in MRI space were calculated with the ClearPoint imaging software. RESULTS: Seven patients underwent 2 or more sequential CED infusions. No patients experienced Clinical Terminology Criteria for Adverse Events grade 3 or greater deficits. One patient had a persistent grade 2 cranial nerve deficit after a second infusion. No patient experienced hemorrhage or stroke postoperatively. There was a statistically significant decrease in radial error (p = 0.005) and absolute tip error (p = 0.008) for the second infusion compared with the initial infusion. Sequential infusions did not result in significantly different distribution capacities between the first and second infusions (volume of distribution determined by the PET signal/volume of infusion ratio [mean ± SD]: 2.66 ± 0.35 vs 2.42 ± 0.75; p = 0.45). CONCLUSIONS: This series demonstrates the ability to safely perform sequential CED infusions into the pediatric brainstem. Past treatments did not negatively influence the procedural workflow, technical application of the targeting interface, or distribution capacity. This limited experience provides a foundation for using repeat CED for oncological purposes.
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Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Neoplasias del Tronco Encefálico/cirugía , Glioma Pontino Intrínseco Difuso/cirugía , Sistemas de Liberación de Medicamentos/métodos , Radioisótopos de Yodo/uso terapéutico , Procedimientos Neuroquirúrgicos/métodos , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/farmacocinética , Neoplasias del Tronco Encefálico/diagnóstico por imagen , Niño , Preescolar , Convección , Enfermedades de los Nervios Craneales/inducido químicamente , Glioma Pontino Intrínseco Difuso/diagnóstico por imagen , Femenino , Humanos , Infusiones Intravenosas , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/farmacocinética , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Distribución Tisular , Resultado del TratamientoRESUMEN
BACKGROUND: This randomized phase II study tested the hypothesis that schedule dependent chemo-immunotherapy with oregovomab improves progression free survival (PFS) and overall survival (OS) in optimally resected, Stage III/IV ovarian cancer. METHODS: Patients from both academic centers and private practice in the US and Italy with Stage III/IV optimally cytoreduced ovarian cancer were randomized to standard six cycle IV carboplatin-paclitaxel chemotherapy (CP) versus CP plus four immunizations with oregovomab (CPO). A translational assessment of a cellular immune response was the primary endpoint; PFS and OS were measured as secondary endpoints. FINDINGS: 97 patients at thirteen centers were accrued to the protocol, 47 to CPO and 50 to CP. Technical issues led to inconsistent performance of the primary CA125 ELISPOT leading to unevaluable results. At a median follow up of 42 months, PFS and OS outcomes revealed an unexpectedly large treatment effect for CPO relative to CP alone, with median PFS of 41.8 months (95% C.I.: 21.8 - N.E.) for CPO and 12.2 months (10.4-18.6) for CP (p = 0.0027, HR 0.46, CI 0.28-0.7). For OS, the median for CPO has not yet been reached (NE) (45.2-NE) and for CP was 43.2 months (31.8-NE) (p = 0.043, HR 0.35, CI 0.16-0.74). The oregovomab treatment resulted in no change in toxicity profile from CP. INTERPRETATION: The previously identified potential clinical benefit of IV CP when administered with oregovomab was further refined in this randomized phase II study. Increases of PFS and OS of statistically and clinically significant magnitude were evident in this study of a front line chemo-immunotherapy treatment of ovarian cancer.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antineoplásicos Inmunológicos/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/patología , Terapia Combinada , Femenino , Humanos , Inmunoterapia/métodos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Resultado del TratamientoRESUMEN
Rituximab (RTX) is a murine-human chimeric monoclonal antibody against CD20 that has been proven effective for preventing relapse in frequently-relapsing or steroid-dependent nephrotic syndrome (NS). Serum sickness, a type-3 hypersensitivity reaction resulting from injection of foreign proteins, has been reported in patients treated with RTX. Herein, we describe a case of RTX-induced serum sickness (RISS) in a 6-year-old boy with steroid-dependent NS. He presented to the hospital with fever and polyarthralgia at 10 days after his fourth dose of RTX. Although he was started on empiric intravenous antibiotics, there was no evidence of septic arthritis and his symptoms resolved over the course of 4 days. He was diagnosed with RISS based on the chronology of RTX administration and the acute-onset self-limiting course of the polyarthritis. His serum human anti-chimeric antibody (HACA) level on day 53 exceeded the limit of quantification (5000 ng/mL). The pathogenesis of RISS and the role of HACAs remain unclear. It is important for clinicians to recognize RISS, because further infusions of RTX may cause more severe reactions in patients with a history of RISS.
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Anticuerpos Monoclonales de Origen Murino/efectos adversos , Síndrome Nefrótico/tratamiento farmacológico , Rituximab/efectos adversos , Enfermedad del Suero/inducido químicamente , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Artralgia/diagnóstico , Artralgia/etiología , Niño , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Fiebre/diagnóstico , Fiebre/etiología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Infusiones Intravenosas , Masculino , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Enfermedad del Suero/diagnóstico , Enfermedad del Suero/tratamiento farmacológico , Enfermedad del Suero/inmunología , Esteroides/uso terapéutico , Resultado del TratamientoRESUMEN
Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by long-standing inflammation in multiple joints. Rituximab, a monoclonal antibody, which binds to CD20, is effective in suppressing disease activity and preventing joint damage in RA. CT-P10 was developed as a biosimilar of rituximab and approved for use to treat hematologic malignancies and immune diseases including RA. Area covered: This article describes the need for this biosimilar and summarizes the non-clinical studies verifying the physicochemical and biologic similarities and the clinical studies confirming the clinical similarity of CT-P10 to rituximab in patients with RA. Expert opinion: CT-P10 had been evaluated and proven the efficacy and safety in RA in Phase I and III randomized controlled trial with extension studies including a switching regimen. Therefore, CT-P10 is recommended in the treatment of RA.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Antígenos CD20/genética , Antígenos CD20/inmunología , Antirreumáticos/administración & dosificación , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Radiation dose estimations are key for optimizing therapies. We studied the role of 124I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before 131I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Methods: Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for 131I-omburtamab therapy underwent immuno-PET imaging with 124I-8H9 followed by 131I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular 124I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Results: Forty-two patients with complete dosimetry and therapy data were analyzed. 124I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for 131I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on 124I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on 131I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for 124I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for 131I-omburtamab samples. The effective whole-body radiation dose for 124I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. Conclusion: PET imaging with 124I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/farmacocinética , Radioisótopos de Yodo/administración & dosificación , Radioisótopos de Yodo/farmacocinética , Neoplasias Meníngeas/metabolismo , Tomografía de Emisión de Positrones , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Neoplasias Meníngeas/diagnóstico por imagen , Neoplasias Meníngeas/patología , Metástasis de la Neoplasia , Radiometría , Distribución Tisular , Adulto JovenAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Neoplasias Cutáneas , Adenina/análogos & derivados , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Humanos , Pierna/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Piperidinas , Prednisona/administración & dosificación , Rituximab , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Vincristina/administración & dosificaciónRESUMEN
A 67-year-old male was transferred to our hospital with diplopia, decreased deep tendon reflex and ataxia. He had been suspected Fisher syndrome because of previous upper respiratory tract infection. A cerebrospinal fluid examination showed marked hypoglycorrhachia, pleocytosis and elevated protein, and cytological examination suggested malignant lymphoma. Abdominal computed tomography revealed a left adrenal mass. A biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. He was treated with a combination of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, oncovin and prednisolone) and intrathecal administration of methotrexate, cytarabine and prednisolone. Neurological symptoms were gradually improved. Malignancy should be considered in addition to bacterial, fungal or tuberculous meningitis in a case with marked hypoglycorrhachia.
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Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico , Glucosa/líquido cefalorraquídeo , Linfoma de Células B Grandes Difuso/líquido cefalorraquídeo , Linfoma de Células B Grandes Difuso/diagnóstico , Enfermedades del Nervio Oculomotor/etiología , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Sistema Nervioso Central/complicaciones , Neoplasias del Sistema Nervioso Central/patología , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Diagnóstico por Imagen , Doxorrubicina/administración & dosificación , Humanos , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/patología , Masculino , Metotrexato/administración & dosificación , Prednisolona/administración & dosificación , Prednisona/administración & dosificación , Rituximab , Resultado del Tratamiento , Vincristina/administración & dosificaciónAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Retrospectivos , Rituximab , Tasa de Supervivencia , Vincristina/administración & dosificación , Vincristina/efectos adversosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Linfoma de Células B Grandes Difuso , Carga Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Prednisona/efectos adversos , Estudios Retrospectivos , Rituximab , Tasa de Supervivencia , Vincristina/administración & dosificación , Vincristina/efectos adversosAsunto(s)
Arte , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/psicología , Pinturas , Adulto , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Humanos , Masculino , Prednisona/administración & dosificación , Prednisona/efectos adversos , Rituximab , Vincristina/administración & dosificación , Vincristina/efectos adversosAsunto(s)
Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Autoanticuerpos/efectos de los fármacos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Rituximab/efectos adversos , Adulto , Autoanticuerpos/inmunología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hospitales Universitarios , Humanos , Infusiones Intravenosas/efectos adversos , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Medición de Riesgo , Rituximab/uso terapéutico , Resultado del Tratamiento , Reino UnidoRESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC.
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Carcinoma Ductal Pancreático/terapia , Inmunoconjugados/administración & dosificación , Factores Inmunológicos/administración & dosificación , Neoplasias Pancreáticas/terapia , Animales , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/farmacología , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Proliferación Celular/efectos de la radiación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/efectos de la radiación , Quimioradioterapia , Humanos , Inmunoconjugados/química , Inmunoconjugados/farmacología , Factores Inmunológicos/farmacología , Ratones , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacología , Neoplasias Pancreáticas/metabolismo , Fosforilación/efectos de los fármacos , Fosforilación/efectos de la radiación , Factor de Transcripción STAT3/metabolismo , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Follicular lymphoma (FL) is an indolent lymphoma that often transforms into a high-grade lymphoma, mostly diffuse large B-cell lymphoma. A case of FL suggested to transform into plasmablastic lymphoma is presented. A 59-year-old man was admitted to our hospital because of right lower abdominal pain and vomiting. Computed tomography showed a mass in the ileocecum. Colonoscopy showed a mass with an ulcer in the ascending colon, and surgery was performed. Immunohistochemical staining of the biopsied mass showed infiltrated lymphocytes that were positive for CD38, CD45, CD138, and λ chain, and negative for CD4, CD5, CD8, CD10, CD20, CD56, and κ chain. Flow cytometric analysis of the ascites showed similar results. FISH analyses performed using lymph node biopsy specimens, ascite fluid and pleural effusion fluid identified the presence of an IGH/BCL2 translocation. FL was suggested to transform into PBL. Although the patient received three courses of R-CHOP chemotherapy and salvage chemotherapy, the patient died because of lymphoma progression less than 6 months after the diagnosis of PBL. Transformation of FL to PBL is highly unusual. The lack of a standard treatment for PBL results in the poor outcome of this entity. Novel therapeutic approaches are needed.
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Linfoma Folicular/patología , Linfoma Plasmablástico/patología , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antígenos CD , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Ciclofosfamida/administración & dosificación , Progresión de la Enfermedad , Doxorrubicina/administración & dosificación , Resultado Fatal , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/terapia , Masculino , Persona de Mediana Edad , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/genética , Linfoma Plasmablástico/terapia , Prednisona/administración & dosificación , Proteínas Proto-Oncogénicas c-bcl-2/genética , Rituximab , Terapia Recuperativa , Tomografía Computarizada por Rayos X , Translocación Genética , Vincristina/administración & dosificaciónRESUMEN
PURPOSE: We previously reported that â¼30% of patients with localized follicular lymphoma (FL) staged by 18F-fluorodeoxyglucose positron emission tomography-computed tomography receiving primary radiation therapy (RT) will relapse within 5 years. We sought to report outcomes for those who relapsed. METHODS AND MATERIALS: We conducted a multicenter, retrospective study of patients aged ≥18 years who received RT ≥ 24 Gy for stage I to II, grade 1 to 3A FL, staged with 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography. Observation was defined as >6 months without treatment from relapse. Overall survival (OS) and freedom from progression (FFP) were estimated with Kaplan-Meier analysis and univariable and multivariable analyses with Cox regression. RESULTS: Of 512 patients with median follow-up of 52 months, 149 (29.1%) developed recurrent lymphoma at a median of 23 months (range, 1-143) after primary RT. Median follow-up was 33 months after relapse. Three-year OS was 91.4% after recurrence. OS was significantly worse for those with relapse ≤12 months from date of diagnosis versus all others-88.7% versus 97.6%, respectively (P = .01)-and remained significantly worse on multivariable analyses (follicular lymphoma international prognostic index-adjusted hazard ratio, 3.61; P = .009). Histology at relapse included 93 indolent (grade 1-3A), 3 FL grade 3B/not otherwise specified, and 18 diffuse large B-cell lymphoma; 35 patients did not undergo biopsy. Of those with follow-up ≥3 months who underwent biopsy (n = 74) or had presumed (n = 23) indolent recurrence, 58 patients (59.8%) were observed, 19 (19.6%) had systemic therapy, 16 (16.5%) had RT, and 4 (4.1%) had systemic therapy + RT. For patients with indolent recurrences that were observed, 3-year FFP or freedom from treatment was 56.6% (median, 48 months). For all patients with biopsied/presumed indolent recurrence receiving salvage treatment (n = 59, including 20 initially observed) 3-year FFP was 73.9%. CONCLUSIONS: Prognosis for patients with relapsed FL after primary radiation therapy is excellent, supporting the role of primary radiation in the management of early stage disease. Patients with localized FL treated with primary RT who experience early relapse (<12 months) have inferior survival compared with those with longer disease-free interval.
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Linfoma Folicular/mortalidad , Linfoma Folicular/radioterapia , Terapia Recuperativa , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Fluorodesoxiglucosa F18 , Humanos , Estimación de Kaplan-Meier , Linfoma Folicular/diagnóstico por imagen , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Prednisona/administración & dosificación , Supervivencia sin Progresión , Radiofármacos , Recurrencia , Estudios Retrospectivos , Rituximab/uso terapéutico , Factores de Tiempo , Vincristina/administración & dosificación , Espera Vigilante , Adulto JovenRESUMEN
PURPOSE: In patients with gastric extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma, the standard radiation therapy (RT) dose is ≥30 Gy. We report the outcome of patients treated with reduced dose 24 Gy compared with those treated with ≥30 Gy. METHODS AND MATERIALS: We reviewed results from 32 patients who received a diagnosis of gastric MALT lymphoma between 2007 and 2017 who were treated with involved site RT using intensity modulated radiation therapy (IMRT). Response to therapy was based on post-RT endoscopic biopsy. Freedom from local treatment failure (FFLTF), freedom from treatment failure (FFTF), and overall survival (OS) outcomes were determined. RESULTS: The median age of patients at diagnosis was 58 years. Therapy for MALT was given prior to RT in 14 patients with residual biopsy proven disease documented in all cases (anti-microbial, n=11; rituximab, n=2; rituximab, cyclophosphamide, doxorubicin, vincristine, n=1). One patient received RT (36 Gy) and concurrent rituximab. The median RT dose was 30 Gy; it was 30 to 36 Gy in 66% of patients (n = 21) and 24 Gy in 34% of patients (n = 11). Post-RT biopsy documented a complete response in all patients. Failures occurred in the stomach and duodenum, respectively, at 3.6 and 4.5 years, after 30 Gy. At a median follow-up of 55.2 months (73.8 for ≥30 Gy compared with 28.7 for 24 Gy; P < .001), the 2-year FFLTF, FFTF, and OS were 100%, 100%, and 97%, respectively. No association was found between the lower (24-Gy) dose and FFLTF (P = .819), FFTF (P = .819), or OS (P = .469). CONCLUSIONS: Contemporary RT with involved site targeting using IMRT is associated with high complete response rates for patients with gastric MALT lymphoma, even using reduced doses of 24 Gy. Additional follow-up and increased patient numbers are required to confirm equivalent disease control.
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Mucosa Gástrica , Linfoma de Células B de la Zona Marginal/radioterapia , Radioterapia de Intensidad Modulada/métodos , Neoplasias Gástricas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/tratamiento farmacológico , Linfoma de Células B de la Zona Marginal/mortalidad , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Dosificación Radioterapéutica , Estudios Retrospectivos , Rituximab/administración & dosificación , Neoplasias Gástricas/mortalidad , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: CT-P10 is the first biosimilar of the anti-CD20 monoclonal antibody, rituximab. CT-P10 is currently available in over 51 countries worldwide, where it is approved in the same indications as its reference product rituximab. In-use stability studies are conducted for biologics to determine how conditions (e.g., temperature, light, humidity, length of time stored) affect drug quality following dilution and storage in infusion bags. OBJECTIVE: We evaluated the in-use stability of CT-P10 for intravenous infusion stored diluted in infusion bags over longer periods than currently recommended by manufacturer guidelines. METHODS: CT-P10, within the final month of its 36-month shelf life, was diluted to 1.0 or 4.0 mg/mL and stored at 2-8 °C in polyethylene or polyvinylchloride infusion bags for 2, 4, and 6 weeks. CT-P10 infusion bags were incubated at room temperature for 24 h before analysis. Analyses included detection of sub-visible particles, formation of impurities and determination of charge variants, and heavy- and light-chain content. Cell-based CD20 binding affinity and complement-dependent cytotoxicity were also assessed. RESULTS: Diluted CT-P10 solutions remained clear, colorless, and free of visible particles irrespective of type of infusion bag, target concentration, or timepoint. Protein concentrations, sub-visible particles, pH, osmolality, and molecular weight and charge variants were stable across all timepoints and variables. The binding affinity and potency of CT-P10 remained unchanged, indicating that the efficacy of the antibody was maintained following in-use preparation. CONCLUSIONS: We demonstrated that CT-P10 was stable after refrigerated storage for up to 6 weeks followed by incubation at room temperature.
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Anticuerpos Monoclonales de Origen Murino/química , Biosimilares Farmacéuticos/química , Rituximab/química , Animales , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Biosimilares Farmacéuticos/administración & dosificación , Células CHO , Cricetulus , Estabilidad de Medicamentos , Almacenaje de Medicamentos , Infusiones Intravenosas , Rituximab/administración & dosificación , Temperatura , Pruebas de ToxicidadRESUMEN
OBJECTIVE: The aim of this study was to investigate long-term clinical outcomes of extended treatment with CT-P10, a rituximab biosimilar, compared with rituximab reference products sourced from the USA and the EU (US-RTX and EU-RTX) in rheumatoid arthritis (RA) for up to 48 weeks. METHODS: In this multinational, randomized, double-blind trial, adults with active RA received up to two courses of CT-P10, US-RTX, or EU-RTX alongside methotrexate. Efficacy endpoints included Disease Activity Score 28-joint count (DAS28) and American College of Rheumatology (ACR) response rates. Pharmacokinetics, pharmacodynamics, immunogenicity, and safety were also assessed. RESULTS: Of 372 patients randomized to the study drug, 330 (88.7%) completed the second treatment course. Mean change from baseline to week 48 in DAS28-C-reactive protein was comparable in the CT-P10 and combined rituximab (US-RTX and EU-RTX) groups (- 2.7 and - 2.6, respectively). ACR20, ACR50, and ACR70 response rates at week 48 indicated no differences between groups (80.6%, 55.4%, and 31.7% vs. 79.8%, 53.9%, and 33.7% in the CT-P10 and combined rituximab groups, respectively). Similar improvements in the Health Assessment Questionnaire Disability Index and all medical outcomes in the Short Form 36-Item Health Survey, including physical and mental health, were seen in all groups. At week 48, antidrug antibodies were detected in 4.9%, 9.4%, and 8.6% of patients in the CT-P10, US-RTX, and EU-RTX groups, respectively. CT-P10 and rituximab displayed similar pharmacokinetic, pharmacodynamic, and safety profiles. CONCLUSION: CT-P10 was similar to EU-RTX and US-RTX in terms of efficacy, pharmacokinetics, pharmacodynamics, immunogenicity, and safety up to week 48. CLINICALTRIALS. GOV IDENTIFIER: NCT02149121.
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Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Biosimilares Farmacéuticos/administración & dosificación , Rituximab/administración & dosificación , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Biosimilares Farmacéuticos/efectos adversos , Sedimentación Sanguínea/efectos de los fármacos , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Masculino , Metotrexato/administración & dosificación , Persona de Mediana Edad , Medición de Resultados Informados por el Paciente , Rituximab/efectos adversos , Adulto JovenRESUMEN
PF-06647263, a novel antibody-drug conjugate consisting of an anti-EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple-negative breast cancer (TNBC). In the dose-escalation part 1 of this multicenter, open-label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF-06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose-expansion cohort), 12 patients with pretreated, metastatic TNBC received PF-06647263 at the RP2D to further evaluate tumor response and overall safety. PF-06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thrombocytopenia). The most common AEs with the QW regimen (fatigue, nausea, vomiting, mucosal inflammation, thrombocytopenia, and diarrhea) were mostly mild to moderate in severity. The MTD was not estimated. PF-06647263 exposures increased in a dose-related manner across the doses evaluated. The RP2D was determined to be 0.015 mg/kg QW. Six (10%) patients achieved a confirmed partial response and 22 (36.7%) patients had stable disease. No correlations were observed between tumor responses and EFNA4 expression levels. Study findings showed manageable safety and favorable PK for PF-06647263 administered QW at the RP2D, with preliminary evidence of limited antitumor activity in patients with TNBC and ovarian cancer.