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1.
Ann Hematol ; 99(1): 137-145, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768675

RESUMO

The combinations of melphalan, bortezomib, and prednisolone (VMP) and of lenalidomide and dexamethasone (Rd) are standard treatment strategies for transplant-ineligible newly diagnosed multiple myeloma (NDMM). To make the most of these two strategies, we investigated the efficacy and feasibility of first-line treatment with 4 cycles of VMP followed by continuous Rd therapy in a multi-institutional phase 2 study in Japanese patients with transplant-ineligible NDMM. Thirty-six patients of median age 74 years old with NDMM initially received 35-day cycles of VMP: oral melphalan (6 mg/m2) and prednisolone (60 mg/m2) on days 1 to 4 and bortezomib (1.3 mg/m2) on days 1, 8, 15, and 22. After 4 cycles of VMP, treatment was switched to 28-day cycles of Rd, which was continued until disease progression or emergence of an unacceptable adverse event (AE) in 33 patients, while one patient who achieved CR after VMP continued VMP at the physician's discretion. The overall response rates after VMP and after Rd were 66.7% and 86.1%, including CR rates of 5.6% and 36.1%, respectively. In a median follow-up period of 34.3 months, the progression-free survival and overall survival rates at 3 years were 43.2% and 81.3%, respectively. Grade 3-4 hematological AEs included neutropenia (39% with VMP and 24% with Rd) and thrombocytopenia (11% with VMP and 3% with Rd). There was no death due to an AE. In conclusion, sequential therapy with VMP followed by Rd is effective and mostly feasible for transplant-ineligible NDMM. The study is registered as UMIN000034815.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/mortalidade , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Mieloma Múltiplo/diagnóstico , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Taxa de Sobrevida
2.
Crit Rev Oncol Hematol ; 145: 102831, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31783290

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is an adverse effect of chemotherapy that is frequently experienced by patients receiving treatment for cancer. CIPN is caused by many of the most commonly used chemotherapeutic agents, including taxanes, vinca alkaloids, and bortezomib. Pain and sensory abnormalities may persist for months, or even years after the cessation of chemotherapy. The management of CIPN is a significant challenge, as it is not possible to predict which patients will develop symptoms, the timing for the appearance of symptoms can develop anytime during the chemotherapy course, there are no early indications that warrant a reduction in the dosage to halt CIPN progression, and there are no drugs approved to prevent or alleviate CIPN. This review focuses on the etiology of CIPN and will highlight the various approaches developed for prevention and treatment. The goal is to guide studies to identify, test, and standardize approaches for managing CIPN.


Assuntos
Antineoplásicos , Neoplasias , Doenças do Sistema Nervoso Periférico , Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Humanos , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Taxoides/uso terapêutico
3.
Lancet ; 395(10218): 132-141, 2020 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-31836199

RESUMO

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Bortezomib/administração & dosagem , Melfalan/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Prednisona/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Ásia , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Europa (Continente) , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , América do Norte , Prednisona/efeitos adversos , América do Sul , Análise de Sobrevida , Resultado do Tratamento
5.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1654-1663, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607328

RESUMO

OBJECTIVE: To compare the effects of intravenous and subcutaneous injection of bortezomib on incidence and relative risk of peripheral neuropathy in patients with multiple myeloma(MM). METHODS: The electronic database of PubMed, Embase, Cochrance library, CNKI and related meeting records were searched by computers. The data were derived all from a matched randomized controlled studies. The incidence, relative risk(RR) and 95% confidence interval of peripheral neuropathy caused by intravenous and subcustaneous injections were calculated by the statistical methods. RESULTS: Four RCT studies were selected for meta-analysis, with a total of 911 patients (479 cases and 432 cases in the subcutaneous injection and intravenous injection groups, respectively). The incidence of peripheral neuropathy in the intravenous injection group was 41.4% (95% CI=0.137-0.692, P=0.003), and the incidence of >2 grade of peripheral neuropathy was 15.6% (95% CI=0.005-0.308, P=0.043). The corresponding incidence rates of the subcutaneous injection group were 16% (95% CI=0.021-0.299, P=0.024) and 3.4% (95% CI=-0.011-0.080, P=0.141) respectively. Compared with the intravenous injection group, the RR of peripheral neuropathy and the relative risk of peripheral neuropathy above grade 2 were 0.525, 95% CI=0.297-0.928 (P=0.027) and 0.376, 95% CI=0.196-0.722 (P=0.003) respectively. CONCLUSION: Subcutaneous injection of bortezomib at therapeutic doses significantly reduces the incidence of peripheral neuropathy compared with intravenous injection.


Assuntos
Bortezomib/efeitos adversos , Mieloma Múltiplo , Doenças do Sistema Nervoso Periférico , Antineoplásicos , Humanos , Incidência , Injeções Subcutâneas , Doenças do Sistema Nervoso Periférico/induzido quimicamente
6.
Ann Hematol ; 98(12): 2805-2814, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31620815

RESUMO

In the ALCYONE trial, daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) reduced the risk of disease progression or death by 50% versus bortezomib, melphalan, and prednisone (VMP) in patients with transplant-ineligible newly diagnosed multiple myeloma. Here, we report a subanalysis of East Asian patients from ALCYONE. After a median follow-up of 17.1 and 15.9 months for Japanese (n = 50) and Korean (n = 41) patients, respectively, median progression-free survival for D-VMP versus VMP was not reached (NR) versus 20.7 months in Japanese patients and NR versus 14.0 months in Korean patients. The overall response rate for D-VMP versus VMP was 96% versus 92% in Japanese patients and 91% versus 61% in Korean patients. Using next-generation sequencing, minimal residual disease negativity at 10-5 sensitivity for D-VMP versus VMP was 33% versus 8% among Japanese patients and 17% versus 0% among Korean patients. Rates of any grade and grade 3/4 pneumonia were consistent with the rates observed for the global safety population. Similar efficacy and safety findings were observed in the combined Japanese and Korean subgroup and ≥ 75 years of age subgroup. In conclusion, D-VMP was safe and efficacious in East Asian patients, consistent with the global ALCYONE population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Intervalo Livre de Doença , Extremo Oriente/epidemiologia , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Taxa de Sobrevida
7.
Lancet Haematol ; 6(12): e616-e629, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31624047

RESUMO

BACKGROUND: Multiple myeloma has been shown to have substantial clonal heterogeneity, suggesting that agents with different mechanisms of action might be required to induce deep responses and improve outcomes. Such agents could be given in combination or in sequence on the basis of previous response. We aimed to assess the clinical value of maximising responses by using therapeutic agents with different modes of action, the use of which is directed by the response to the initial combination therapy. We aimed to assess response-adapted intensification treatment with cyclophosphamide, bortezomib, and dexamethasone (CVD) versus no intensification treatment in patients with newly diagnosed multiple myeloma who had a suboptimal response to initial immunomodulatory triplet treatment which was standard of care in the UK at the time of trial design. METHODS: The Myeloma XI trial was an open-label, randomised, phase 3, adaptive design trial done at 110 National Health Service hospitals in the UK. There were three potential randomisations in the study: induction treatment, intensification treatment, and maintenance treatment. Here, we report the results of the randomisation to intensification treatment. Eligible patients were aged 18 years or older and had symptomatic or non-secretory, newly diagnosed multiple myeloma, had completed their assigned induction therapy as per protocol (cyclophosphamide, thalidomide, and dexamethasone or cyclophosphamide, lenalidomide, and dexamethasone) and achieved a partial or minimal response. For the intensification treatment, patients were randomly assigned (1:1) to cyclophosphamide (500 mg daily orally on days 1, 8, and 15), bortezomib (1·3 mg/m2 subcutaneously or intravenously on days 1, 4, 8, and 11), and dexamethasone (20 mg daily orally on days 1, 2, 4, 5, 8, 9, 11, and 12) up to a maximum of eight cycles of 21 days or no treatment. Patients were stratified by allocated induction treatment, response to induction treatment, and centre. The co-primary endpoints were progression-free survival and overall survival, assessed from intensification randomisation to data cutoff, analysed by intention to treat. Safety analysis was per protocol. This study is registered with the ISRCTN registry, number ISRCTN49407852, and clinicaltrialsregister.eu, number 2009-010956-93, and has completed recruitment. FINDINGS: Between Nov 15, 2010, and July 28, 2016, 583 patients were enrolled to the intensification randomisation, representing 48% of the 1217 patients who achieved partial or minimal response after initial induction therapy. 289 patients were assigned to CVD treatment and 294 patients to no treatment. After a median follow-up of 29·7 months (IQR 17·0-43·5), median progression-free survival was 30 months (95% CI 25-36) with CVD and 20 months (15-28) with no CVD (hazard ratio [HR] 0·60, 95% CI 0·48-0·75, p<0·0001), and 3-year overall survival was 77·3% (95% Cl 71·0-83·5) in the CVD group and 78·5% (72·3-84·6) in the no CVD group (HR 0·98, 95% CI 0·67-1·43, p=0·93). The most common grade 3 or 4 adverse events for patients taking CVD were haematological, including neutropenia (18 [7%] patients), thrombocytopenia (19 [7%] patients), and anaemia (8 [3%] patients). No deaths in the CVD group were deemed treatment related. INTERPRETATION: Intensification treatment with CVD significantly improved progression-free survival in patients with newly diagnosed multiple myeloma and a suboptimal response to immunomodulatory induction therapy compared with no intensification treatment, but did not improve overall survival. The manageable safety profile of this combination and the encouraging results support further investigation of response-adapted approaches in this setting. The substantial number of patients not entering this trial randomisation following induction therapy, however, might support the use of combination therapies upfront to maximise response and improve outcomes as is now the standard of care in the UK. FUNDING: Cancer Research UK, Celgene, Amgen, Merck, Myeloma UK.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Idoso , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Terapia Neoadjuvante , Análise de Sobrevida , Resultado do Tratamento , Reino Unido/epidemiologia
8.
Medicine (Baltimore) ; 98(39): e17147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574817

RESUMO

The study aims to examine the treatment effect and adverse reactions of patients with newly diagnosed MM receiving different bortezomib-based regimens.This was a retrospective study of patients with newly diagnosed MM and who were treated with bortezomib-based combined chemotherapy at the Department of Hematology of the 2 affiliated hospitals of Wenzhou Medical University between July 2009 and May 2016. Cox proportion hazard multivariate analyses were carried out to assess the differences in treatment effect and adverse events between standard (1.3 mg/m on days 1, 4, 8, 11) and weekly (1.6 mg/m on days 1, 8, 15) cohorts, as well as the differences between intravenous injection and subcutaneous injection therapy. Progression-free survival (PFS) and overall survival (OS) were assessed using Kaplan-Meier method and the log-rank test.Among the 117 patients, 78 patients were treated with bortezomib standard therapy and 39 patients were treated with bortezomib weekly therapy (all with intravenous injection). In all patients, the treatment strategy was not independently associated with PFS or OS. The patients in the weekly therapy group had less thrombocytopenia events than those in the standard therapy group. The subcutaneous route had similar treatment effect as the intravenous route, but the incidence of peripheral neuropathy was lower.The once-weekly bortezomib regimen was similar in effectiveness to standard therapy in treating patients with newly diagnosed MM, but the incidence of thrombocytopenia was lower with the weekly regimen compared with the standard regimen.


Assuntos
Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Idoso , Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , China , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Injeções Intravenosas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Estudos Retrospectivos , Resultado do Tratamento
9.
Blood ; 134(16): 1337-1345, 2019 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-31484647

RESUMO

Achieving and maintaining a high-quality response is the treatment goal for patients with newly diagnosed multiple myeloma (NDMM). The phase 3 PETHEMA/GEM2012 study, in 458 patients aged ≤65 years with NDMM, is evaluating bortezomib (subcutaneous) + lenalidomide + dexamethasone (VRD) for 6 cycles followed by autologous stem cell transplant (ASCT) conditioned with IV busulfan + melphalan vs melphalan and posttransplant consolidation with 2 cycles of VRD. We present grouped response analysis of induction, transplant, and consolidation. Responses deepened over time; in patients who initiated cycle 6 of induction (n = 426), the rates of a very good partial response or better were 55.6% by cycle 3, 63.8% by cycle 4, 68.3% by cycle 5, and 70.4% after induction. The complete response rate of 33.4% after induction in the intent-to-treat (ITT) population, which was similar in the 92 patients with high-risk cytogenetics (34.8%), also deepened with further treatment (44.1% after ASCT and 50.2% after consolidation). Rates of undetectable minimal residual disease (median 3 × 10-6 sensitivity) in the ITT population also increased from induction (28.8%) to transplant (42.1%) and consolidation (45.2%). The most common grade ≥3 treatment-emergent adverse events during induction were neutropenia (12.9%) and infection (9.2%). Grade ≥2 peripheral neuropathy (grouped term) during induction was 17.0%, with a low frequency of grade 3 (3.7%) and grade 4 (0.2%) events. VRD is an effective and well-tolerated regimen for induction in NDMM with deepening response throughout induction and over the course of treatment. This trial was registered at www.clinicaltrials.gov as #NCT01916252 and EudraCT as #2012-005683-10.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia de Indução/métodos , Mieloma Múltiplo/tratamento farmacológico , Terapia Neoadjuvante/métodos , Adulto , Idoso , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Quimioterapia Adjuvante/métodos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Pessoa de Meia-Idade , Condicionamento Pré-Transplante/métodos , Transplante Autólogo
10.
Cancer Sci ; 110(10): 3267-3274, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31444836

RESUMO

Although the proteasome inhibitor bortezomib (BTZ) shows excellent efficacy in multiple myeloma (MM), a fraction of patients has a suboptimal or no response to this agent. In addition, BTZ-induced peripheral neuropathy (BiPN), a frequent side-effect of this therapy, limits its use in some patients. This study aimed to explore serum lipid biomarker candidates to predict the response to BTZ and the severity of BiPN. Fifty-nine serum samples were collected from patients with MM prior to receiving BTZ plus low-dose dexamethasone therapy. Serum levels of phospholipids, sphingolipids, neutral lipids, and polyunsaturated fatty acids and their oxidation products were measured by a comprehensive lipidomic study. Overall, 385 lipid metabolites were identified in patients' sera; lower levels of several glycerophospholipids, sphingolipids, and cholesteryl esters were associated with a poor treatment response. Metabolites related to platelet-activating factor biosynthesis and cholesterol metabolism appeared particularly relevant. Furthermore, several lysophosphatidylcholines, phosphatidylcholines, ceramides, neutral lipids, and oxidative fatty acids were significantly increased or decreased in patients with BiPN grades ranging from G0 to G3. Among these compounds, mediators reportedly inducing myelin breakdown and stimulating inflammatory responses were prominent. Although further study is necessary to validate these biomarker candidates, our results contribute to the development of predictive biomarkers for response to BTZ treatment, or ensuing severe BiPN, in patients with MM.


Assuntos
Bortezomib/administração & dosagem , Lipídeos/sangue , Metabolômica/métodos , Mieloma Múltiplo/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Bortezomib/efeitos adversos , Ésteres do Colesterol/sangue , Feminino , Glicerofosfolipídeos/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue , Mieloma Múltiplo/química , Índice de Gravidade de Doença , Esfingolipídeos/sangue , Resultado do Tratamento
11.
Support Care Cancer ; 27(10): 3729-3737, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31363906

RESUMO

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual's specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.


Assuntos
Antineoplásicos/efeitos adversos , Síndromes Neurotóxicas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Bortezomib/efeitos adversos , Predisposição Genética para Doença/genética , Humanos , Taxoides/efeitos adversos , Alcaloides de Vinca/efeitos adversos
12.
J Cancer Res Clin Oncol ; 145(9): 2343-2355, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280348

RESUMO

PURPOSE: Combinations of bortezomib (Velcade), cyclophosphamide and dexamethasone have shown significant efficacy and safety for patients of newly diagnosed multiple myeloma (NDMM). In this study, we compared the efficacy and safety of modified VCD regimens with novel changes in bortezomib dose and schedule for NDMM. METHODS: Eighty-five NDMM patients from multiple centers were randomly assigned to a high-dose (1.6 mg/m2) (group A) or a low-dose (1.3 mg/m2) (group B) bortezomib, administrated on days 1, 6, 11, and 16 subcutaneously in a 4-week cycle for nine cycles, combined with 40 mg dexamethasone on bortezomib days and cyclophosphamide 300 mg/m2 on days 1-3 intravenously. RESULTS: After four cycles, complete response (CR) or better in group A (43.6%) was higher than that in group B (12.8%) (P = 0.002). During induction, for patients with R-ISS stage III, the CR or better rate in group A was superior to that in group B (P = 0.01). Of patients < 65, the CR or better rate of group A was superior to that of group B (P = 0.004). Rapid onset of CR occurred in group A (P < 0.01). Meanwhile, rate of 3-4 diarrhea was higher in group A (P = 0.03), which caused higher rate of dose reduction for patients ≥ 65 (P = 0.041). No significant difference between the two groups in PFS and OS. CONCLUSIONS: The studied high-dose VCD as induction regimen had an improved CR rate, especially in patients < 65 or with R-ISS stage III, and is feasible for young and high-risk patients. Trial registration ClinicalTrials.gov: NCT02086942.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Teniposídeo/administração & dosagem , Resultado do Tratamento
13.
Eur J Haematol ; 103(3): 255-267, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31231828

RESUMO

OBJECTIVE: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression-free survival (PFS) post autologous stem cell transplantation (ASCT). METHODS: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18-60 or 61-75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35-day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. RESULTS: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18-60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61-75 years (n = 155), respectively. Bortezomib consolidation post-ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high-dose therapy. CONCLUSION: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation.


Assuntos
Antineoplásicos/uso terapêutico , Bortezomib/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Terapia Combinada , Quimioterapia de Consolidação , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Estadiamento de Neoplasias , Prognóstico , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
14.
BMC Ophthalmol ; 19(1): 110, 2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31088416

RESUMO

BACKGROUND: The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management strategies, and to propose a treatment algorithm for eyelid complications in this patient population. METHODS: This retrospective case series included sixteen patients found to have chalazia and/or blepharitis while receiving proteasome inhibitors for plasma cell disorders at Mount Sinai Hospital in New York, NY from January 2010 through January 2017. Main outcomes were complete resolution of eyelid complications and time to resolution. Student's t-test was used to compare average values and Fisher's exact test was used to compare proportions. RESULTS: Fourteen patients had chalazia and 10 had blepharitis. Chalazia averaged 5.4 mm, and 11 patients with chalazia experienced two or more lesions. Median follow-up time was 17 months. Average time from bortezomib exposure to onset of first eyelid complication was 3.4 months. Chalazia episodes were more likely to completely resolve than blepharitis episodes (p = 0.03). Ocular therapy alone was trialed for an average of 1.8 months before proceeding to bortezomib omission. Average time to eyelid complication resolution using ocular therapy alone was 1.8 months versus 3.1 months after bortezomib omission. In this series, the combination of ocular therapy and bortezomib omission led to complete resolution of eyelid complications more often than ocular therapy alone. CONCLUSION: Proteasome inhibitor associated eyelid complications were identified in sixteen patients with plasma cell disorders. Eyelid complications may be treated with a 2-month trial of conservative ocular therapies alone, followed by continuation of ocular therapy in combination with bortezomib omission if eyelid signs persist.


Assuntos
Blefarite/induzido quimicamente , Bortezomib/efeitos adversos , Calázio/induzido quimicamente , Inibidores de Proteassoma/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Plasmócitos/tratamento farmacológico , Estudos Retrospectivos
15.
Biochim Biophys Acta Gen Subj ; 1863(6): 1108-1115, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30974160

RESUMO

Proteasomes play a key role in maintaining cellular homeostasis by the proteolytic removal of proteins, including ubiquitinated proteins and/or oxidatively-damaged proteins. The proteasome inhibitor bortezomib (BTZ) has been reported to exert testicular toxicity in mice. In the current study, we treated SOD1-knockout (KO) mice with BTZ and investigated the issue of whether oxidative stress is involved in the development of testicular toxicity. The BTZ treatment significantly increased superoxide production and cell death in the testes of SOD1-KO mice compared to wild-type (WT) mice. We also found that high levels of both ubiquitinated proteins and p62 accumulated and underwent aggregation in the seminiferous tubules of BTZ-injected SOD1-KO mice. Furthermore, the proteolytic activities of proteasomes were significantly decreased in the testes of BTZ-injected SOD1-KO mice compared to their WT counterparts. These results suggest that a combination of oxidative stress caused by an SOD1 deficiency and proteasome inhibition by BTZ accelerates the impairment of proteasomes, which results in severe testicular damage in SOD1-KO mice.


Assuntos
Bortezomib/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteassoma/efeitos adversos , Superóxido Dismutase-1/deficiência , Testículo , Ubiquitinação/efeitos dos fármacos , Animais , Bortezomib/farmacologia , Masculino , Camundongos , Camundongos Knockout , Inibidores de Proteassoma/farmacologia , Testículo/lesões , Testículo/metabolismo , Testículo/fisiologia
16.
Acta Haematol ; 141(2): 111-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30726834

RESUMO

We assessed the efficacy and safety of weekly cyclophosphamide-bortezomib-dexamethasone (CBD) induction prior to autologous stem cell transplantation (ASCT) in newly diagnosed Japanese patients with multiple myeloma (MM). This regimen consisted of four 28-day cycles of once-weekly oral cyclophosphamide (300 mg/m2), subcutaneous bortezomib (1.3 mg/m2), and oral dexamethasone (40 mg). Responding patients underwent stem cell collection followed by ASCT. The primary endpoint was the postinduction rate of achieving a near complete response (nCR) or better. Among the 38 enrolled patients, a complete response (CR), an nCR, a very good partial response (VGPR), and a partial response (PR) were achieved in 10.5, 2.6, 23.7, and 36.8% of cases, respectively. A grade 4 hematological adverse event (AE) was observed in 1 patient. Grade 3-4 infection, including febrile neutropenia, was observed in 4 patients (10.5%). Although 2 patients dropped out due to AE, 94.7% of the patients completed the induction phase. However, because of a poor response to induction chemotherapy (

Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Ciclofosfamida/efeitos adversos , Dexametasona/efeitos adversos , Esquema de Medicação , Feminino , Doenças Hematológicas/etiologia , Transplante de Células-Tronco Hematopoéticas , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Análise de Sobrevida , Transplante Autólogo , Resultado do Tratamento , Adulto Jovem
17.
Mol Pain ; 15: 1744806919837429, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30810076

RESUMO

Chemotherapy-induced painful peripheral neuropathy (CIPN) is the most common toxicity associated with widely used chemotherapeutics. CIPN is the major cause of dose reduction or discontinuation of otherwise life-saving treatment. Unfortunately, CIPN can persist in cancer survivors, which adversely affects their quality of life. Moreover, available treatments are vastly inadequate, warranting a better understanding of the biochemical and metabolic mechanisms that occur in response to chemotherapeutics which would be critical for the development of novel therapies for CIPN. Using extracellular flux analysis, this study demonstrated that the proteasome inhibitor, bortezomib, enhanced glycolysis while suppressing oxidative phosphorylation in the sensory neurons of mice. This metabolic phenotype is known as aerobic glycolysis. Bortezomib upregulated lactate dehydrogenase A and pyruvate dehydrogenase kinase 1, which consequently enhanced the production of lactate and repressed pyruvate oxidation, respectively. Moreover, lactate dehydrogenase A- and pyruvate dehydrogenase kinase 1-driven aerobic glycolysis was associated with increased extracellular acidification, augmented calcium responses, and pain in bortezomib-induced CIPN. Remarkably, pharmacological blockade and in vivo knockdown of lactate dehydrogenase A or pyruvate dehydrogenase kinase 1 reversed the metabolic phenotype, attenuated calcium responses, and alleviated pain induced by bortezomib. Collectively, these results elucidate the mechanisms by which bortezomib induces aerobic glycolysis. Moreover, these findings establish aerobic glycolysis as a metabolic phenotype that underpins bortezomib-induced CIPN.


Assuntos
Antineoplásicos/efeitos adversos , Bortezomib/efeitos adversos , Glicólise/efeitos dos fármacos , Dor/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Western Blotting , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Dor/etiologia , Doenças do Sistema Nervoso Periférico/etiologia , Qualidade de Vida
18.
Phytomedicine ; 55: 282-292, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30668440

RESUMO

BACKGROUND: Arctiin is a main component from the fruits of Arctium lappa L., that can be prescribed for cold or flu in East Asian countries; it has also been found to exert chemopreventive actions against various tumor cells. HYPOTHESIS: In view of this evidence, we examined arctiin for its ability to trigger apoptosis and inhibit the activation of signal transducer and activator of transcription 3 (STAT3) in human multiple myeloma (MM) cells. METHODS: We evaluated the effect of arctiin on STAT3 signaling cascades and its regulated functional responses in MM cells. RESULTS: Arctiin effectively blocked the constitutive activation of STAT3 phosphorylation in the residue of tyrosine 705. Arctiin also abrogated the constitutive activation of Src phosphorylation and Janus-activated kinases (JAKs) 1/2. Furthermore, it was found that arctiin treatment clearly enhanced the mRNA and protein levels of protein tyrosine phosphatase ε (PTPε), and the silencing of PTPε caused a reversal of the arctiin-induced PTPε expression and the blockadge of STAT3 phosphorylation. Interestingly, arctiin could not repress IL-6-induced STAT3 activation in serum-starved U266 cells and when arctiin was incubated with a complete culture medium in RPMI 8226 and MM.1S cells. Arctiin suppressed cell proliferation, accumulated cells in the G2/M cell-cycle phase, and induced apoptosis within U266 cells, although the knockdown of PTPε prevented PARP cleavage and caspase-3 activation induced by the arctiin. In addition, arctiin exerted cytotoxicity in MM cells, but did not do so in peripheral blood mononuclear cells. Arctiin down-modulated diverse oncogenic gene products regulated by STAT3, although the induction of apoptosis by arctiin was abrogated upon transfection with pMXs-STAT3C in mouse embryonic fibroblast (MEF) cells. Arctiin also potentiated bortezomib-induced antitumor effects in U266 cells. CONCLUSION: On the whole, our results indicate that arctiin is a potentially new inhibitor of constitutive STAT3 activation through the induction of PTPε in MM, cells and therefore has great value in treating various tumors sheltering constitutively activated STAT3.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Furanos/farmacologia , Furanos/uso terapêutico , Glucosídeos/farmacologia , Glucosídeos/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Fosforilação/efeitos dos fármacos , Tirosina/efeitos dos fármacos , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/uso terapêutico , Arctium/química , Bortezomib/efeitos adversos , Linhagem Celular Tumoral/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/efeitos dos fármacos , Fator de Transcrição STAT3/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos
19.
Support Care Cancer ; 27(8): 3053-3059, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30607681

RESUMO

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a devastating pain condition of cancer therapy that may force chemotherapy dose reduction or discontinuation. Since treatment options for CIPN are quite limited, we investigated the effect of 10% amitriptyline cream on neuropathic pain. PATIENTS AND METHODS: This pilot study enrolled patients with hematological or solid tumors presenting hands and feet CIPN (for less than 1 month without previous treatment for CIPN [Group 1]; for more than 1 month with previous treatment [Group 2]). Patients applied 10% amitriptyline cream twice a day. Pain intensity was evaluated at 1, 2, and 4 weeks then monthly up to 1 year. The primary endpoint was change from baseline to 4-week treatment in median pain score assessed by visual analogue scale (VAS). RESULTS: Overall, 44 patients were enrolled. Median (range) age was 67 (46-80) years, 34% were female. The majority (88.6%) had hematological malignancies, and the most commonly used chemotherapeutic agents were bortezomib and oxaliplatin. The median (range) VAS pain score decreased from 7 (4-9) at baseline to 2 (0-4) after 4-week topical treatment. No difference was seen between Group 1 and Group 2. Reduced initial chemotherapy doses in 11 patients as well as chemotherapy discontinued in 5 patients at baseline were resumed after treatment with 10% amitriptyline cream. CONCLUSION: Considering the limited efficacy of conventional systemic treatments in CIPN and their safety profile, 10% topical amitriptyline appears to be a good candidate for first-line CIPN therapy, allowing continuation of chemotherapy at effective doses. The results are worth to be confirmed in a placebo-controlled clinical trial.


Assuntos
Amitriptilina/administração & dosagem , Antineoplásicos/efeitos adversos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/tratamento farmacológico , Administração Cutânea , Administração Tópica , Idoso , Idoso de 80 Anos ou mais , Analgésicos não Entorpecentes/administração & dosagem , Antineoplásicos/administração & dosagem , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/tratamento farmacológico , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Projetos Piloto
20.
J Clin Oncol ; 37(7): 589-597, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30653422

RESUMO

PURPOSE: Single-cycle melphalan 200 mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression. PATIENTS AND METHODS: Patients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS. RESULTS: The study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms. CONCLUSION: Second AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Dexametasona/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Lenalidomida/administração & dosagem , Mieloma Múltiplo/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/efeitos adversos , Quimioterapia de Consolidação , Dexametasona/efeitos adversos , Progressão da Doença , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Agonistas Mieloablativos/administração & dosagem , Intervalo Livre de Progressão , Estudos Prospectivos , Indução de Remissão , Reoperação , Fatores de Tempo , Transplante Autólogo , Estados Unidos , Adulto Jovem
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