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1.
Medicine (Baltimore) ; 98(44): e17769, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689840

RESUMO

RATIONALE: The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies. Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone. To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients. Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations. PATIENT CONCERNS AND DIAGNOSIS: We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I. INTERVENTIONS: She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy. OUTCOMES: Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction. Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression. LESSONS: Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population. Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations. This novel combination can cause additional toxicities which seem to be overall manageable.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mesilato de Imatinib/administração & dosagem , Melanoma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/tratamento farmacológico , Idoso de 80 Anos ou mais , Feminino , Humanos , Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica/tratamento farmacológico , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Resultado do Tratamento
2.
Medicine (Baltimore) ; 98(46): e17681, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725610

RESUMO

RATIONALE: Castleman's disease (CD) is a rare lymphoproliferative disease. Compared to unicentric CD, multicentric Castleman disease (MCD) displays poorer prognosis and great variance to different therapies. Though chemotherapy, immunization therapy, and glucocorticoids have been used in the treatment of MCD, its optimal treatment is still controversial. PATIENT CONCERNS: A 47-year-old woman was admitted due to poor appetite, general fatigue, puffiness of face, systemic rash, and abdominal distension. On physical examination, the patient displayed as general lymphadenopathy, splenomegaly, hepatomegaly, and shifting dullness. DIAGNOSES: After biopsy of her swollen lymph node and laboratory tests, her initial diagnosis was hyaline vascular-CD. INTERVENTIONS: She was treated with combination of tocilizumab, lenalidomide, and glucocorticoids. OUTCOMES: This patient achieved complete remission (CR) with all her indexes returned to be normal. Her blood routines and biochemical examinations were still normal during the following period. LESSONS: We reported a case with multicentric Castleman's disease (MCD) which acquired quite good remission after combination treatment with tocilizumab, lenalidomide, and glucocorticoids. Our report provided powerful evidence for displaying the efficiency and safety of target therapy against unicentric Castleman disease.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Glucocorticoides/administração & dosagem , Fatores Imunológicos/administração & dosagem , Lenalidomida/administração & dosagem , Quimioterapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Medicine (Baltimore) ; 98(38): e17262, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31568001

RESUMO

BACKGROUND: This study will systematically investigate the efficacy and safety of the combination of pertuzumab, trastuzumab, and docetaxel (PTD) for treatment of patients with HER2-positive breast cancer (HER2-PBC). METHODS: A comprehensive literature search for this study will consist of 2 parts: electronic database records and gray literature. The electronic database literatures are searched from PubMed, EMBASE, Cochrane Library, Web of Science, Google Scholar, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All databases will be searched from inception up to the present. In addition, gray literatures, such as dissertations, ongoing trials, and so on, will also be searched. Two authors will independently read the records, extract data collection, and evaluate the risk of bias. RevMan V.5.3 software will be applied for statistical analysis. RESULTS: This study will summarize up-to-date evidence of PTD for patients with HER2-PBC via overall survival, complete response, cancer-specific survival, recurrence-free survival, disease-free survival, quality of life, and toxicities. CONCLUSION: This study will provide efficacy and safety of PTD for HER2-PBC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Docetaxel/uso terapêutico , Genes erbB-2 , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Docetaxel/administração & dosagem , Feminino , Humanos , Trastuzumab/administração & dosagem , Resultado do Tratamento
4.
N Engl J Med ; 381(14): 1321-1332, 2019 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-31577874

RESUMO

BACKGROUND: In the majority of patients with chronic spontaneous urticaria, most currently available therapies do not result in complete symptom control. Ligelizumab is a next-generation high-affinity humanized monoclonal anti-IgE antibody. Data are limited regarding the dose-response relationship of ligelizumab and the efficacy and safety of ligelizumab as compared with omalizumab and placebo in patients who have moderate-to-severe chronic spontaneous urticaria that is inadequately controlled with H1-antihistamines at approved or increased doses, alone or in combination with H2-antihistamines or leukotriene-receptor antagonists. METHODS: In a phase 2b dose-finding trial, we randomly assigned patients to receive ligelizumab at a dose of 24 mg, 72 mg, or 240 mg, omalizumab at a dose of 300 mg, or placebo, administered subcutaneously every 4 weeks for a period of 20 weeks, or a single 120-mg dose of ligelizumab. Disease symptoms of hives, itch, and angioedema were monitored by means of weekly activity scores. The main objective was to determine a dose-response relationship for the complete control of hives (indicated by a weekly hives-severity score of 0, on a scale from 0 to 21, with higher scores indicating greater severity); the primary end point of this response was assessed at week 12. Complete symptom control was indicated by a weekly urticaria activity score of 0 (on a scale from 0 to 42, with higher scores indicating greater severity). Safety was analyzed throughout the trial. RESULTS: A total of 382 patients underwent randomization. At week 12, a total of 30%, 51%, and 42% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of hives, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. A dose-response relationship was established. At week 12, a total of 30%, 44%, and 40% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of symptoms, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. In this small and short trial, no safety concerns regarding ligelizumab or omalizumab emerged. CONCLUSIONS: A higher percentage of patients had complete control of symptoms of chronic spontaneous urticaria with ligelizumab therapy of 72 mg or 240 mg than with omalizumab or placebo. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT02477332.).


Assuntos
Antialérgicos/administração & dosagem , Anticorpos Anti-Idiotípicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Omalizumab/administração & dosagem , Urticária/tratamento farmacológico , Adulto , Idoso , Antialérgicos/efeitos adversos , Anticorpos Anti-Idiotípicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Doença Crônica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Masculino , Pessoa de Meia-Idade , Omalizumab/efeitos adversos , Gravidade do Paciente , Indução de Remissão , Urticária/imunologia , Adulto Jovem
5.
Nat Med ; 25(9): 1402-1407, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501610

RESUMO

Natalizumab (NZM), a humanized monoclonal IgG4 antibody to α4 integrins, is used to treat patients with relapsing-remitting multiple sclerosis (MS)1,2, but in about 6% of the cases persistent neutralizing anti-drug antibodies (ADAs) are induced leading to therapy discontinuation3,4. To understand the basis of the ADA response and the mechanism of ADA-mediated neutralization, we performed an in-depth analysis of the B and T cell responses in two patients. By characterizing a large panel of NZM-specific monoclonal antibodies, we found that, in both patients, the response was polyclonal and targeted different epitopes of the NZM idiotype. The neutralizing activity was acquired through somatic mutations and correlated with a slow dissociation rate, a finding that was supported by structural data. Interestingly, in both patients, the analysis of the CD4+ T cell response, combined with mass spectrometry-based peptidomics, revealed a single immunodominant T cell epitope spanning the FR2-CDR2 region of the NZM light chain. Moreover, a CDR2-modified version of NZM was not recognized by T cells, while retaining binding to α4 integrins. Collectively, our integrated analysis identifies the basis of T-B collaboration that leads to ADA-mediated therapeutic resistance and delineates an approach to design novel deimmunized antibodies for autoimmune disease and cancer treatment.


Assuntos
Anticorpos Neutralizantes/administração & dosagem , Epitopos de Linfócito T/imunologia , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Neutralizantes/química , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Linfócitos B/efeitos dos fármacos , Humanos , Imunoglobulina G/química , Imunoglobulina G/imunologia , Integrina alfa4/antagonistas & inibidores , Integrina alfa4/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Conformação Proteica/efeitos dos fármacos , Linfócitos T/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
6.
Internist (Berl) ; 60(10): 1059-1073, 2019 Oct.
Artigo em Alemão | MEDLINE | ID: mdl-31471629

RESUMO

Large-vessel vasculitis includes giant cell arteritis (GCA) and Takayasu arteritis (TA). GCA can affect persons from the age of 50 years and is more frequent among women. The disease course generally begins with an acute phase, with patients feeling very unwell and experiencing temporal headaches. Rapid diagnosis and treatment are necessary to reduce the risk of blindness. A suspected diagnosis must be confirmed by imaging, histology is optional. Initial treatment comprises oral prednisone. Recent studies have demonstrated inhibition of interleukin­6 with tocilizumab (TCZ) to be highly effective. Alternatively, methotrexate can be administered in a steroid-sparing approach. In contrast, TA onset is generally during childhood or adolescence, and begins with moderate systemic inflammation. The aorta and its main branches are affected. Treatment comprises steroids, disease-modifying antirheumatic drugs, and the tumor necrosis factor inhibitor infliximab or TCZ.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Arterite de Células Gigantes/tratamento farmacológico , Imunossupressores/administração & dosagem , Arterite de Takayasu/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Feminino , Células Gigantes , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Humanos , Metotrexato/administração & dosagem , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Resultado do Tratamento
8.
Medicine (Baltimore) ; 98(32): e16682, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31393368

RESUMO

Some patients have poor response to adult-onset Still disease (AOSD) traditional treatment, which easily recurs during the reduction of prednisone. We observed the efficacy and safety of tocilizumab combined with methotrexate (MTX) in the treatment of refractory AOSD, and to explore the possibility of reducing the dosage of tocilizumab after disease control.A total of 28 refractory AOSD cases who had an inadequate response to corticosteroids combined with at least 1 traditional immunosuppressive agent, and even large-dose prednisone could not relieve their conditions after recurrence, were selected in this study. They were treated with tocilizumab (intravenous 8 mg/kg) combined with MTX (oral 12.5 mg once a week). In detail, tocilizumab was firstly given every 4 weeks and after 6-month remission, it was then given every 8 weeks. Some items including body temperature, skin rash, joint swelling and pain, hepatosplenomegaly, blood routine, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum ferritin, and dosage of prednisone were observed before treatment as well as 2, 4, 8, 12, 24, 36, and 48 weeks after treatment. The adverse reactions occurring during the treatment were recorded.The body temperature was normal, the skin rash as well as joint swelling and pain disappeared, and laboratory indexes including CRP, ESR, white blood cell, neutrophilic granulocyte, platelet, hemoglobin, and ferritin were significantly improved after 8-week treatment (all P < .05). The clinical symptoms and laboratory indexes above mentioned were continuously improved 12, 24, 36, and 48 weeks after treatment. The mean dosage of prednisone was reduced from 71.4 ±â€Š20.7 mg/day to 55.0 ±â€Š11.1 mg/day after 2-week treatment, and to 3.3 ±â€Š2.1 mg/day after 48-week treatment (all P < .05). Prednisone was discontinued in 5 cases after 36-week treatment and in 7 cases after 48-week treatment. No serious adverse reactions occurred during the treatment.Tocilizumab can rapidly and markedly improve the clinical symptoms and laboratory indexes and contribute to reduction and discontinuation of prednisone in refractory AOSD. The patients' conditions are stable after reduction or discontinuation of prednisone and the tocilizumab possesses good safety.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Metotrexato/administração & dosagem , Doença de Still de Início Tardio/tratamento farmacológico , Administração Intravenosa , Administração Oral , Adulto , Anticorpos Monoclonais Humanizados/farmacologia , Antirreumáticos/farmacologia , Quimioterapia Combinada , Feminino , Glucocorticoides/administração & dosagem , Glucocorticoides/efeitos adversos , Humanos , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do Tratamento
10.
Lancet Haematol ; 6(9): e470-e479, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31324600

RESUMO

BACKGROUND: In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie, <1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients. METHODS: We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up. FINDINGS: Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred. INTERPRETATION: Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed. FUNDING: Roche, Janssen.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Esquema de Medicação , Feminino , Gastroenteropatias/etiologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Neoplasia Residual , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Taxa de Sobrevida , Trombocitopenia/etiologia , Resultado do Tratamento , Proteína Supressora de Tumor p53/genética
11.
Drugs ; 79(12): 1355-1361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31313098

RESUMO

Camrelizumab (AiRuiKa™), a programmed cell death 1 (PD-1) inhibitor being developed by Jiangsu Hengrui Medicine Co. Ltd, recently received conditional approval in China for the treatment of relapsed or refractory classical Hodgkin lymphoma. The drug is also being investigated as a treatment for various other malignancies, including B cell lymphoma, oesophageal squamous cell carcinoma, gastric/gastroesophageal junction cancer, hepatocellular carcinoma, nasopharyngeal cancer and non-squamous, non-small cell lung cancer. This article summarizes the milestones in the development of camrelizumab leading to this first approval for classical Hodgkin lymphoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , China , Aprovação de Drogas , Neoplasias Esofágicas/tratamento farmacológico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Gástricas/tratamento farmacológico
12.
JAMA ; 322(1): 37-48, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31265100

RESUMO

Importance: Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments. Objective: To assess 2 subcutaneous tanezumab dosing regimens for OA. Design, Setting, and Participants: A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit). Patients enrolled were 18 years or older with hip or knee OA, inadequate response to OA analgesics, and no radiographic evidence of prespecified joint safety conditions. Interventions: Patients received by subcutaneous administration either tanezumab, 2.5 mg, at day 1 and week 8 (n = 231); tanezumab, 2.5 mg at day 1 and 5 mg at week 8 (ie, tanezumab, 2.5/5 mg; n = 233); or placebo at day 1 and week 8 (n = 232). Main Outcomes and Measures: Co-primary end points were change from baseline to week 16 in Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) Pain (0-10, no to extreme pain), WOMAC Physical Function (0-10, no to extreme difficulty), and patient global assessment of osteoarthritis (PGA-OA) (1-5, very good to very poor) scores. Results: Among 698 patients randomized, 696 received 1 or more treatment doses (mean [SD] age, 60.8 [9.6] years; 65.1% women), and 582 (83.6%) completed the trial. From baseline to 16 weeks, mean WOMAC Pain scores decreased from 7.1 to 3.6 in the tanezumab, 2.5 mg, group; 7.3 to 3.6 in the tanezumab, 2.5/5 mg, group; and 7.3 to 4.4 in the placebo group (least squares mean differences [95% CI] vs placebo were -0.60 [-1.07 to -0.13; P = .01] for tanezumab, 2.5 mg, and -0.73 [-1.20 to -0.26; P = .002] for tanezumab, 2.5/5 mg). Mean WOMAC Physical Function scores decreased from 7.2 to 3.7 in the 2.5-mg group, 7.4 to 3.6 in the 2.5/5-mg group, and 7.4 to 4.5 with placebo (differences vs placebo, -0.66 [-1.14 to -0.19; P = .007] for tanezumab, 2.5 mg, and -0.89 [-1.37 to -0.42; P < .001] for tanezumab, 2.5/5 mg). Mean PGA-OA scores decreased from 3.4 to 2.4 in the 2.5-mg group, 3.5 to 2.4 in the 2.5/5-mg group, and 3.5 to 2.7 with placebo (differences vs placebo, -0.22 [-0.39 to -0.05; P = .01] for tanezumab, 2.5 mg, and -0.25 [-0.41 to -0.08; P = .004] for tanezumab, 2.5/5 mg). Rapidly progressive OA occurred only in tanezumab-treated patients (2.5 mg: n = 5, 2.2%; 2.5/5 mg: n = 1, 0.4%). The incidence of total joint replacements was 8 (3.5%), 16 (6.9%), and 4 (1.7%) in the tanezumab, 2.5 mg; tanezumab, 2.5/5 mg; and placebo groups, respectively. Conclusions and Relevance: Among patients with moderate to severe OA of the knee or hip and inadequate response to standard analgesics, tanezumab, compared with placebo, resulted in statistically significant improvements in scores assessing pain and physical function, and in PGA-OA, although the improvements were modest and tanezumab-treated patients had more joint safety events and total joint replacements. Further research is needed to determine the clinical importance of these efficacy and adverse event findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02697773.


Assuntos
Analgésicos/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Artralgia/tratamento farmacológico , Fator de Crescimento Neural/antagonistas & inibidores , Osteoartrite do Quadril/tratamento farmacológico , Osteoartrite do Joelho/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Analgésicos/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Artroplastia de Substituição/estatística & dados numéricos , Progressão da Doença , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Osteoartrite do Quadril/fisiopatologia , Osteoartrite do Joelho/fisiopatologia , Medição da Dor
13.
Expert Opin Drug Saf ; 18(9): 769-776, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31303060

RESUMO

Introduction: Cutaneous T-cell lymphomas (CTCL) are rare non-Hodgkin lymphomas of skin-homing T-cells that initially or mainly manifest cutaneously. Treatment of CTCL is challenging given the disease states' varying presentation and prognosis. Systemic treatment options often lack comparative evidence and have relatively low response rates and short duration of response. The recent Food and Drug Administration (FDA) approval of mogamulizumab in adult patients with relapsed or refractory (R/R) CTCL after at least one prior line of therapy provided a new treatment option to patients with advanced disease. Areas covered: The authors discuss basic information about CTCL and mogamulizumab's mechanism of action. Then, the authors discuss the agent's efficacy. Finally, the authors evaluate the safety of mogamulizumab in comparison to other agents available in CTCL. Expert opinion: Mogamulizumab has been shown to be an effective and well tolerated therapy for patients with relapsed and refractory MF/SS with excellent activity in the circulating component of the disease.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Animais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Humanos , Linfoma Cutâneo de Células T/patologia , Prognóstico , Neoplasias Cutâneas/patologia
14.
Medicine (Baltimore) ; 98(27): e16164, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277120

RESUMO

Thrombosis are severe complications of paroxysmal nocturnal hemoglobinuria (PNH), effectively reduced by eculizumab. Extracellular vesicles (EVs) may play a central role. The objective of this study was to assess the procoagulant activity of plasma isolated from PNH patients (treated or not by eculizumab) and to quantify their circulating EVs.We iteratively collected the platelet-free-plasma of 17 PNH patients and 16 matched healthy volunteers, quantified their circulating EVs by flow cytometry and evaluated their procoagulant activity by thrombin generation and STA-Procoag-procoagulant phospholipid (PPL) assays.A significant decrease of EVs from platelets (P = .024) and an increase of the STA-Procoag-PPL clotting time (P = .049) was observed after initiation of eculizumab and up to 11 weeks after. This reduction of prothrombotic biomarkers was not observed with the thrombin generation test due to a lack of sensitivity of this assay. Active hemolysis was observed in 90% of patients and elevated D-dimers in 41% of them. However, no significant difference was observed between patients and control subjects regarding the procoagulant activity, the EVs quantity, or the cellular origin. Lactate dehydrogenase (LDH) levels were lower in eculizumab-treated patients compared to nontreated patients (441 vs 2448 IU/L). D-dimers and LDH decreased after administration of eculizumab (mean decrease of 1307 ng/mL and 4159 IU/L, respectively).These observations suggest a decrease of the phospholipid-dependent procoagulant potential of EVs after eculizumab therapy in PNH patients. TRIAL REGISTRATION:: NUB: B039201214365.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , Vesículas Extracelulares/efeitos dos fármacos , Hemoglobinúria Paroxística/tratamento farmacológico , Administração Intravenosa , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Estudos de Casos e Controles , Citometria de Fluxo , Hemoglobinúria Paroxística/sangue , Hemoglobinúria Paroxística/complicações , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Trombose/etiologia
15.
Medicine (Baltimore) ; 98(27): e16285, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31277158

RESUMO

RATIONALE: It is known that 5% to 34% of Sjögren's syndrome (SS) cases are complicated by neuropathy in the form of myelitis. Although SS myelopathy (SSM) is often treated with glucocorticoid (GC) and immunosuppressants such as cyclophosphamide (CY), a therapeutic strategy for SSM has not been established. PATIENT CONCERNS: A 65-year-old female was admitted with weakness and thermal hypoalgesia in the lower limbs. Four months before this admission, she showed weakness in her lower limbs and thermal hypoalgesia of bilateral upper and lower limbs. Magnetic resonance imaging (MRI) revealed that the cause of her neurological symptoms was cervical myelitis. She was diagnosed with SS because she tested positive for the ophthalmic test (Schirmer's test and fluorescent test) and for the anti-SS-A antibodies. Therefore, myelitis was thought to be a complication of SS. She was treated with GC and CY. Both neurological symptoms and MRI findings temporarily improved, and the GC dose was gradually decreased. One month before this admission, her neurological symptoms and MRI findings were exacerbated. Upon relapse of SSM, serum amyloid A protein (SAA) level was markedly elevated. DIAGNOSES: Based on MRI findings, the diagnosis was SSM relapse. INTERVENTIONS: Treatment by subcutaneous tocilizumab (TCZ) 162 mg every two weeks was introduced. OUTCOMES: After introducing TCZ, her neurological symptoms and MRI findings gradually improved. SAA levels remained low. At eight months after the introduction of TCZ, the GC dose has been decreased and so far, the myelitis has not relapsed. LESSONS: This case report is the first report suggesting the effectiveness of TCZ for refractory SSM. Subcutaneous TCZ might be an effective therapeutic option for treating refractory SSM when SAA levels are elevated.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Mielite/tratamento farmacológico , Síndrome de Sjogren/complicações , Idoso , Vértebras Cervicais , Relação Dose-Resposta a Droga , Feminino , Humanos , Injeções Subcutâneas , Imagem por Ressonância Magnética , Mielite/diagnóstico , Mielite/etiologia
16.
Lancet Haematol ; 6(9): e459-e469, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327687

RESUMO

BACKGROUND: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Miocardite/etiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Recidiva , Síndrome de Stevens-Johnson/etiologia , Taxa de Sobrevida , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do Tratamento
17.
Lancet Haematol ; 6(9): e448-e458, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31327689

RESUMO

BACKGROUND: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual. FINDINGS: Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure). INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing. FUNDING: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Dexametasona/administração & dosagem , Lenalidomida/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dexametasona/efeitos adversos , Feminino , Humanos , Lenalidomida/efeitos adversos , Masculino , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Pneumonia/etiologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Resultado do Tratamento
18.
Medicine (Baltimore) ; 98(29): e16417, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31335691

RESUMO

We aimed to assess serial F-FDG PET/CT imaging according to morphological (RECIST1.1, iRECIST) and functional (PERCIST, PECRIT) criteria to predict clinical response to therapy in patients with advanced melanoma receiving immune checkpoint blocking agents.Retrospective data collection and analysis was done for 37 patients with unresectable metastatic cutaneous melanoma eligible for immunotherapy (cycles: 4 for ipilimumab and pembrolizumab/ 6 for nivolumab).F-FDG PET/CT imaging was performed prior to (F-FDG PET/CT 0) and 14 weeks after ICI onset (F-FDG PET/CT 1). Some cases during the follow-up required imaging (F-FDG PET/CT 2). Assessment of patient response to treatment was done according to RECIST1.1, iRECIST, PERCIST and PECRIT criteria.Among 37 assessed patients, 27 had 1 line of ICI, 8 had 2 lines of ICI and 2 patients had 3 lines of ICI: total of 49 PET/CTs. Mean time between initiation of ICI and F-FDG PET/CT (1 or 2) were respectively 13.82 ±â€Š4.32 and 24.73 ±â€Š9.53 weeks. Time between F-FDG PET/CT 1 and F-FDG PET/CT 2 was at mean +/- SD: 11.19w ±â€Š5.59. Median PFS was 29.62 months (range 22.52-36.71) (P = .001: RECIST 1.1), (P < .0001: iRECIST), (P = .000: PERCIST), (P = .072: PECRIT). Median OS was 36.62 months (30.46-42.78) (P = .005: RECIST 1.1), (P < .0001: iRECIST), (P = .001: PERCIST), (P = .082 PECRIT).F-FDG PET/CT could detect eventual ICI-response in patients with metastatic melanoma undergoing ICI using iRECIST and PERCIST criteria.


Assuntos
Anticorpos Monoclonais Humanizados , Ipilimumab , Melanoma , Nivolumabe , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Neoplasias Cutâneas , Tomografia Computadorizada por Raios X/métodos , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Protocolos Antineoplásicos , Feminino , Fluordesoxiglucose F18/farmacologia , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Melanoma/patologia , Estadiamento de Neoplasias , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Valor Preditivo dos Testes , Prognóstico , Compostos Radiofarmacêuticos/farmacologia , Reprodutibilidade dos Testes , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia
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