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1.
Lancet Haematol ; 8(11): e818-e827, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34634256

RESUMO

BACKGROUND: Dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) is a front-line treatment for patients with aggressive B-cell lymphomas. Bcl-2 is associated with chemoresistance due to BCL2 gene rearrangement or protein overexpression and is antagonised by venetoclax. We aimed to assess the safety of venetoclax with dose-adjusted EPOCH-R as initial therapy in aggressive B-cell lymphoma. METHODS: We conducted a single-arm, phase 1 study across seven treatment centres in the USA. Eligible patients were aged 18-80 years with histologically confirmed, previously untreated diffuse large B-cell lymphoma, transformed indolent non-Hodgkin lymphoma, high-grade B-cell lymphoma with double-hit or not otherwise specified, or primary mediastinal B-cell lymphoma, with Ann Arbor stage II-IV and Eastern Cooperative Oncology Group performance status of 0-2. Participants received six cycles of oral venetoclax 400 mg, 600 mg, or 800 mg once daily for 10 days per cycle with dose-adjusted EPOCH-R (one cycle every 3 weeks; baseline doses were intravenous rituximab 375 mg/m2 on day 1, intravenous etoposide 50 mg/m2 on days 1-4, oral prednisone 60 mg/m2 twice daily on days 1-5, intravenous vincristine 0·4 mg/m2 on days 1-4, intravenous cyclophosphamide 750 mg/m2 on day 5, and intravenous doxorubicin 10 mg/m2 on days 1-4). A subsequent cohort received venetoclax 600 mg once daily for 5 days per cycle. The primary endpoints were the maximum tolerated dose, dose-limiting toxicities, and the recommended phase 2 dose of venetoclax. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov, NCT03036904, and enrolment is now closed. FINDINGS: Between Feb 3, 2017, and June 4, 2019, 34 patients were assessed for eligibility, and 30 were enrolled and received venetoclax with dose-adjusted EPOCH-R. The median patient age was 64·0 years (IQR 51·6-69·4). The maximum tolerated dose was 800 mg for 10 days and the established recommended phase 2 dose was 600 mg for 5 days due to tolerability for treatment duration. One (3%) of 30 patients had a dose-limiting toxicity in cycle one (grade 4 thrombocytopenia with 800 mg dose). The most common grade 3-4 adverse events were cytopenias (28 [93%] of 30 patients); febrile neutropenia occurred in 19 (63%) patients. Grade 3-4 non-haematological adverse events included hypophosphataemia (n=10), hypokalaemia (n=7), and hyperglycaemia (n=5). Serious adverse events included infection (n=7) and gastrointestinal toxicities including abdominal pain (n=3), colonic perforation (n=1), and small intestinal obstruction (n=1). There was one treatment-related death (sepsis). Overall response rate was 96·7% (95% CI 82·8-99·9); 28 (93·3% [77·9-99·2]) of 30 patients had complete response and one (3·3% [0·1-17·2]) had a partial response. INTERPRETATION: Venetoclax with dose-adjusted EPOCH-R showed an acceptable safety profile at the recommended phase 2 dose and had encouraging preliminary activity in this population at high risk of adverse outcomes, and is worthy of further study. The combination is being investigated in Alliance 051701 (NCT03984448). FUNDING: Genentech.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linfoma de Células B/tratamento farmacológico , Sulfonamidas/uso terapêutico , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Feminino , Humanos , Linfoma de Células B/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/efeitos adversos , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
2.
Ann Palliat Med ; 10(8): 8837-8847, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34488372

RESUMO

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS) is a severe disease that can lead to serious complication. Letrozole has been applied during controlled ovarian hyperstimulation (COH) to reduce the rate of OHSS in women undergoing long-term Gonadotropin-releasing Hormone Analog (GnRHa) treatment for assisted fertility. Prednisone can prevent vasodilatation and increased vascular permeability, which is common during OHSS. However, few studies have evaluated the combined effect of letrozole and prednisone in preventing severe OHSS and is the aim of our retrospective study of patients receiving GnRHa treatment. METHODS: A total of 296 women who accepted autologous in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatments were included in this retrospective study. There were three groups: 146 women had letrozole, including letrozole alone (LE group, n=60) and letrozole with prednisone (LE + Pre group, n=86), and 150 women had no treatment (C group). Severe OHSS was diagnosed according to clinical evidence of hydrothorax, severe dyspnea, oliguria/anuria, and intractable nausea/vomiting. RESULTS: The addition of prednisone to letrozole successfully reduced the occurrence rate of severe OHSS than those women administered letrozole alone (55.0% vs. 70.6%, P=0.022). However, the ongoing pregnancy rate was lower in the LE + Pre group than that in the LE-alone group (64.3% vs. 87.0%, P=0.025). Surprisingly, progesterone level on the trigger day (>0.895 ng/mL) is a strong predictor for pregnancy failure with a specificity of 68.3% and sensitivity of 65.7% in the LE-alone group. CONCLUSIONS: Treatment with a combination of letrozole and prednisone may lower the rate of severe OHSS in women with prolonged gonadotropin-releasing hormone agonist protocol during assisted fertility treatment. When the progesterone level on trigger day is over 0.895 ng/mL, letrozole treatment may negatively affect clinical pregnancy.


Assuntos
Síndrome de Hiperestimulação Ovariana , Feminino , Hormônio Liberador de Gonadotropina , Humanos , Letrozol/uso terapêutico , Síndrome de Hiperestimulação Ovariana/prevenção & controle , Indução da Ovulação , Prednisona/efeitos adversos , Gravidez , Estudos Retrospectivos
3.
Chron Respir Dis ; 18: 14799731211031935, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34569301

RESUMO

Currently prednisone is the first-line pharmacological treatment option for pulmonary sarcoidosis. Methotrexate is used as second-line therapy and seems to have fewer side-effects. No prospective comparative studies of first-line treatment with methotrexate exist. In this study, we evaluated patient reported presence and bothersomeness of side-effects of prednisone and methotrexate in a sarcoidosis population to guide the design of a larger prospective study. During a yearly patient information meeting 67 patients completed a questionnaire on medication use; 11 patients never used prednisone or methotrexate and were excluded from further analysis. Of the remaining 56 patients, 89% used prednisone and 70% methotrexate (present or former). Significantly more side-effects were reported for prednisone than for methotrexate, 78% versus 49% (p = 0.006). In conclusion, methotrexate seems to have fewer and less bothersome side-effects than prednisone. These findings need to be confirmed in a prospective study.


Assuntos
Metotrexato , Sarcoidose , Humanos , Imunossupressores , Metotrexato/efeitos adversos , Medidas de Resultados Relatados pelo Paciente , Prednisona/efeitos adversos , Estudos Prospectivos , Sarcoidose/induzido quimicamente , Sarcoidose/epidemiologia
4.
Nutrients ; 13(9)2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34579145

RESUMO

Short-term calorie reduction (SCR) requires individuals to reduce their calorie intake to less than 50% of normal requirements and has shown good tolerance and potential benefits in prior studies addressing gynecological cancer patients. More studies are needed to further confirm its safety, feasibility, and effects in patients with different cancers, including hematological malignancies. This pilot cohort study with a matched-pair comparison group was registered at ClinicalTrails.gov [201810112RIND]. Adult patients diagnosed with advanced-stage diffuse large-B cell lymphoma were recruited (SCR group) and matched with one comparison patient (comparison group), each in a manner blinded to their outcomes. The SCR group undertook at least two cycles of 48 h water fast along with their chemotherapy R-CHOP. Descriptive analysis and generalized estimating equations were used to analyze the data. Six participants completed multiple cycles of SCR and were compared to their six counterparts in the comparison group. The results showed that SCR is safe and feasible in terms of a high compliance rate and stable nutritional status. The SCR was associated with benefits in post-chemotherapy hematological parameters (i.e., erythrocyte [p < 0.001] and lymphocyte counts [p < 0.001]). More randomized controlled trials are needed to validate the effects of SCR on different types of cancer populations.


Assuntos
Restrição Calórica/métodos , Quimioterapia de Indução/métodos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Restrição Calórica/efeitos adversos , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Estudos de Viabilidade , Feminino , Humanos , Linfoma Difuso de Grandes Células B/dietoterapia , Masculino , Análise por Pareamento , Pessoa de Meia-Idade , Projetos Piloto , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêutico
5.
Korean J Intern Med ; 36(5): 1181-1189, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34265889

RESUMO

BACKGROUND/AIMS: Febrile neutropenia (FN) interferes with the proper chemotherapy dose density or intensity in non-Hodgkin's lymphoma (NHL) patients. Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) ± rituximab has an intermediate FN risk. Prophylactic granulocyte colony-stimulating factor (G-CSF) support is recommended for patients with other host-related risk factors. METHODS: We evaluated the risk factors for FN-related admission in NHL patients who have received primary G-CSF (lenograstim) prophylaxis. RESULTS: Data from 148 patients were analyzed. The incidence of neutropenic fever was 96 events (12.2%), and the median period was 3.85 days (range, 0 to 5.9); the median duration of neutropenia was 4.21 days (range, 3.3 to 5.07). Eighty-three FN-related admissions were reported. Advanced age (> 60 years), female sex, a low albumin level, and prednisone use were associated with FN-related admission in multivariable analysis (p = 0.010, p < 0.001, and p = 0.010, respectively). A comparison between diffuse large B-cell lymphoma patients treated with R-CHOP and pegylated G-CSF and those treated with R-CHOP and lenograstim did not reveal significant differences in the FN-related admission rate between the two groups, although the lenograstim-treated group had a higher incidence of severe neutropenia. CONCLUSION: Elderly patients, female patients, and patients with low albumin levels need to be actively followed-up for FN even when primary prophylaxis with G-CSF has been used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma não Hodgkin , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Vincristina/efeitos adversos
6.
BMC Cancer ; 21(1): 659, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078314

RESUMO

BACKGROUND: In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. METHODS: The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. RESULTS: Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS (p = 0.0240) and VAS (p = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. CONCLUSIONS: Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Qualidade de Vida , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Progressão da Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/psicologia , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Resultado do Tratamento
7.
Cancer Chemother Pharmacol ; 88(3): 451-464, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34080039

RESUMO

PURPOSE: Limited information is available regarding the drug-drug interaction (DDI) potential of molecular targeted agents and rituximab plus cyclophosphamide, doxorubicin (hydroxydaunorubicin), vincristine (Oncovin), and prednisone (R-CHOP) therapy. The addition of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib to R-CHOP therapy results in increased toxicity versus R-CHOP alone, including higher incidence of peripheral neuropathy. Vincristine is a substrate of P-glycoprotein (P-gp, ABCB1); drugs that inhibit P-gp could potentially cause increased toxicity when co-administered with vincristine through DDI. While the combination of the BTK inhibitor acalabrutinib and R-CHOP is being explored clinically, the DDI potential between these therapies is unknown. METHODS: A human mechanistic physiology-based pharmacokinetic (PBPK) model of vincristine following intravenous dosing was developed to predict potential DDI interactions with combination therapy. In vitro absorption, distribution, metabolism, and excretion and in vivo clinical PK parameters informed PBPK model development, which was verified by comparing simulated vincristine concentrations with observed clinical data. RESULTS: While simulations suggested no DDI between vincristine and ibrutinib or acalabrutinib in plasma, simulated vincristine exposure in muscle tissue was increased in the presence of ibrutinib but not acalabrutinib. Extrapolation of the vincristine mechanistic PBPK model to other P-gp substrates further suggested DDI risk when ibrutinib (area under the concentration-time curve [AUC] ratio: 1.8), but not acalabrutinib (AUC ratio: 0.92), was given orally with venetoclax or digoxin. CONCLUSION: Overall, these data suggest low DDI risk between acalabrutinib and P-gp substrates with negligible increase in the potential risk of vincristine-induced peripheral neuropathy when acalabrutinib is added to R-CHOP therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Modelos Biológicos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Vincristina/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Células CACO-2 , Simulação por Computador , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/farmacocinética , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/farmacocinética , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Distribuição Tecidual , Vincristina/efeitos adversos , Vincristina/farmacocinética , Adulto Jovem
9.
Leuk Res ; 106: 106591, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33957339

RESUMO

This pharmacoeconomic simulation (1) assessed the cost-efficiency of converting a panel of 20,000 patients at risk of chemotherapy-induced (febrile) neutropenia (CIN/FN) from reference pegfilgrastim to biosimilar pegfilgrastim-cbqv; (2) estimated how savings can be used to provide budget-neutral expanded access to R-CHOP therapy for non-Hodgkin lymphoma patients; and 3) determined the number-needed-to-convert (NNC) to purchase one additional dose of R-CHOP (US payer perspective). Model inputs included biosimilar conversion from pre-filled syringe [PFS] or on-body injector [OBI] reference pegfilgrastim; age-proportional blended costs for reference pegfilgrastim PFS and OBI, pegfilgrastim-cbqv and R-CHOP; medication administration costs; biosimilar conversion rates of 10-100 %; and 1-6 cycles of prophylaxis. Cost-savings were used to estimate the number of doses of R-CHOP that could be purchased and the NNC to purchase one additional dose. Converting a panel of 20,000 patients requiring CIN/FN prophylaxis to biosimilar pegfilgrastim-cbqv from a low of 1 cycle and 10 % conversion to a high of 6 cycles and 100 % conversion yielded savings from $1,567,195 to $96,668,126. The budget-neutral acquisition of R-CHOP doses afforded by these savings ranged from 227 to 13,999 doses, the latter enabling 2333 patients to receive 6 cycles of R-CHOP treatment with no additional cost to the payer. These results are achieved if all 20,000 panel patients requiring GCSF support are prophylacted with biosimilar pegfilgrastim-cbqv for 6 cycles, yielding an NNC of 1.43 patients per additional R-CHOP dose. This simulation underscores the clinic-economic benefit of prophylaxis with biosimilar growth factor and pegfilgrastim-cbqv specifically.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Custos de Medicamentos , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/epidemiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Medicamentos Biossimilares/administração & dosagem , Análise Custo-Benefício , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Filgrastim/administração & dosagem , Custos de Cuidados de Saúde , Humanos , Polietilenoglicóis/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
10.
Anticancer Res ; 41(5): 2647-2652, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33952495

RESUMO

BACKGROUND/AIM: Primary adrenal lymphoma (PAL) is rare and aggressive. The aim of this retrospective study was to compare the results of surgery and chemotherapy compared to chemotherapy alone for the treatment of this condition. PATIENTS AND METHODS: Sixteen patients, 10 men and 6 women of a median age of 63 years (IQR=56-70.5 years), admitted for the treatment of PAL, were retrospectively reviewed. Six patients (37.5%) underwent surgical resection of the mass followed by CHOP (cyclophosphamide, doxorubicin, vincristine, bleomycin and prednisone) - based chemotherapy (Group A). Ten patients (62.5%) underwent chemotherapy alone, consisting of CHOP alone in one case and Rituximab-CHOP (R-CHOP) in 9 cases (Group B). As primary study endpoints of the study, overall survival (OS) and progression-free survival (PFS) were considered. RESULTS: At two years follow-up, OS was 50% in Group A and 60% in group B (p=0.69). The PFS was 50% in group A and 30% in group B (p=0.42). CONCLUSION: PAL exhibits overall a dismal prognosis. Chemotherapy remains the most appropriate treatment, although unable to ensure long-term survival. Surgery combined with chemotherapy is ineffective in improving survival and may, at best, have a limited role in relieving the pain related to the local mass effect.


Assuntos
Neoplasias das Glândulas Suprarrenais/tratamento farmacológico , Neoplasias das Glândulas Suprarrenais/cirurgia , Linfoma/tratamento farmacológico , Linfoma/cirurgia , Neoplasias das Glândulas Suprarrenais/patologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos de Coortes , Terapia Combinada , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos
11.
Lancet Glob Health ; 9(7): e1008-e1016, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34022150

RESUMO

BACKGROUND: There are no clinical trials involving patients with diffuse large B-cell lymphoma (DLBCL) in sub-Saharan Africa since antiretroviral therapy (ART) for HIV became widely available in this region. We aimed to establish the safety and efficacy of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with DLBCL in Malawi. METHODS: This prospective, single-arm, non-randomised phase 1/2 clinical trial was done at Kamuzu Central Hospital Cancer Clinic (Lilongwe, Malawi). Eligible patients were adults (aged 18-60 years) with newly diagnosed DLBCL, an Eastern Cooperative Oncology Group performance status of 0-2, a CD4 count of 100 cells per µL or higher (if HIV-positive), measurable disease by physical examination, an absolute neutrophil count of 1000 × 109 cells per L or higher, a platelet count of 100 × 109 platelets per L or higher, a serum creatinine concentration of 132·60 µmol/L or less, a total bilirubin concentration of 34·21 µmol/L or less, a negative urine pregnancy test in women of childbearing potential, and no previous cytotoxic therapy. Pregnant or breastfeeding women, and individuals with CNS involvement from DLBCL, chronic hepatitis B infection (unless they were receiving tenofovir plus lamivudine), or any other comorbidities that would compromise the protocol objectives were excluded. Eligible patients received intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum 2 mg/m2), and oral prednisone 100 mg or an equivalent drug every 21 days for up to six cycles. HIV-positive patients received concurrent ART. The primary outcome was the proportion of patients with National Cancer Institute Common Terminology Criteria for Adverse Events grade 3 or 4 non-haematological toxic effects or treatment-related deaths after six cycles of treatment. Secondary efficacy outcomes included the proportion of patients with a complete response after six cycles of treatment, and progression-free survival and overall survival at 12 months and 24 months. This trial is registered with ClinicalTrials.gov, NCT02660710. FINDINGS: Between Aug 1, 2016, and July 31, 2019, 76 patients were screened, of whom 37 were eligible for the study and received R-CHOP. The median age of patients was 44 years (IQR 39-49) and 16 (43%) were women. Of all 37 patients, 20 (54%) had stage III or IV DLBCL, and the age-adjusted international prognostic index was 2 or higher in 25 (68%) patients. 27 (73%) patients were HIV-positive, with a median CD4 count of 208 cells per µL (IQR 144-422), and 21 (78%) patients were receiving ART at enrolment. Patients completed a median of six cycles (IQR 4-6). Grade 3 or 4 non-haematological toxic effects were reported in 12 (32% [95% CI 19-49]) patients, the most common of which was infection (nine [24%] patients). Of 16 (43%) deaths, ten were due to progression of DLBCL, four were due to treatment-related complications, and two were due to other causes, yielding a treatment-related mortality of 11% (95% CI 4-26%). Grade 3 or 4 neutropenia was observed in 26 (70%) patients, and grade 3 or 4 anaemia was observed in 11 (29%) patients. A total of 22 (59%) patients had a complete response. Overall survival was 68% (95% CI 50-80) at 12 months and 55% (37-70) at 24 months, and progression-free survival was 59% (42-73) at 12 months and 53% (35-68) at 24 months. INTERPRETATION: R-CHOP could be feasible, safe, and efficacious in patients with DLBCL in Malawi. This is the first completed clinical trial on DLBCL focused on sub-Saharan African populations. Given the paucity of data on treatment of DLBCL from this region, these results could inform emerging cancer treatment programmes in sub-Saharan Africa. FUNDING: The University of North Carolina Lineberger Comprehensive Cancer Center.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Malaui , Masculino , Pessoa de Meia-Idade , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Estudos Prospectivos , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
12.
J Cardiovasc Electrophysiol ; 32(8): 2165-2170, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33942420

RESUMO

OBJECTIVE: To assess the safety and efficacy of a novel immunosuppressive regimen-combination Methotrexate/Prednisone (cMtx/P)-in the management of severe refractory rPPP. METHODS: In this multicenter, nonrandomized, retrospective, observational study, 408 consecutive patients diagnosed with persistent rPPP between 2017 and 19 were included. Patients with refractory symptoms despite 3 months of conventional therapy were initiated on a 4-week regimen of oral steroids. Persistence of symptoms at this point, that is, rPPP (n = 25; catheter based = 18, open surgical = 7) prompted therapy with Methotrexate (7.5-15 mg weekly) with folate supplementation along with low dose prednisone (5 mg PO) for a further 3 months. Patients were followed for a total of 11.3 ± 1.8 months. RESULTS: Treatment refractory rPPP occurred in 6.1% of the study population prompting immunosuppressive therapy with cMtx/P. All patients demonstrated complete symptom resolution following 3 months of treatment with an 85% decline in clinically significant pericardial effusions. One patient developed recurrent pericarditis during the 11-month follow-up. Therapy was well tolerated with no significant drug related adverse effects. CONCLUSION: cMtx/P therapy is a safe and effective adjunct in the management of rPPP refractory to standard therapy.


Assuntos
Imunossupressores , Pericardite , Humanos , Imunossupressores/efeitos adversos , Metotrexato/efeitos adversos , Pericardite/induzido quimicamente , Pericardite/diagnóstico , Pericardite/tratamento farmacológico , Prednisona/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
13.
Ann Oncol ; 32(7): 896-905, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33836265

RESUMO

BACKGROUND: Treatment of poor prognosis metastatic castration-resistant prostate cancer (mCRPC) includes taxane chemotherapy and androgen receptor pathway inhibitors (ARPI). We sought to determine optimal treatment in this setting. PATIENTS AND METHODS: This multicentre, randomised, open-label, phase II trial recruited patients with ARPI-naive mCRPC and poor prognosis features (presence of liver metastases, progression to mCRPC after <12 months of androgen deprivation therapy, or ≥4 of 6 clinical criteria). Patients were randomly assigned 1 : 1 to receive cabazitaxel plus prednisone (group A) or physician's choice of enzalutamide or abiraterone plus prednisone (group B) at standard doses. Patients could cross over at progression. The primary endpoint was clinical benefit rate for first-line treatment (defined as prostate-specific antigen response ≥50%, radiographic response, or stable disease ≥12 weeks). RESULTS: Ninety-five patients were accrued (median follow-up 21.9 months). First-line clinical benefit rate was greater in group A versus group B (80% versus 62%, P = 0.039). Overall survival was not different between groups A and B (median 37.0 versus 15.5 months, hazard ratio (HR) = 0.58, P = 0.073) nor was time to progression (median 5.3 versus 2.8 months, HR = 0.87, P = 0.52). The most common first-line treatment-related grade ≥3 adverse events were neutropenia (cabazitaxel 32% versus ARPI 0%), diarrhoea (9% versus 0%), infection (9% versus 0%), and fatigue (7% versus 5%). Baseline circulating tumour DNA (ctDNA) fraction above the cohort median and on-treatment ctDNA increase were associated with shorter time to progression (HR = 2.38, P < 0.001; HR = 4.03, P < 0.001). Patients with >30% ctDNA fraction at baseline had markedly shorter overall survival than those with undetectable ctDNA (HR = 38.22, P < 0.001). CONCLUSIONS: Cabazitaxel was associated with a higher clinical benefit rate in patients with ARPI-naive poor prognosis mCRPC. ctDNA abundance was prognostic independent of clinical features, and holds promise as a stratification biomarker.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Antagonistas de Androgênios/uso terapêutico , Androstenos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína , Prednisona/efeitos adversos , Prognóstico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Taxoides/uso terapêutico , Resultado do Tratamento
14.
Ann Hematol ; 100(7): 1769-1778, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33885924

RESUMO

Despite the significant proportion of older patients with newly diagnosed multiple myeloma (MM), most clinical trials driving therapeutic decisions in routine practice include younger and presumably healthier patients than those in the real world. Furthermore, longitudinal studies suggest that elderly, transplant-ineligible patients with MM are not benefitting enough from new anti-MM agents. We retrospectively analyzed the profile of and treatment patterns and outcomes in 675 transplant-ineligible patients with MM who started frontline therapy in routine practice. The mean (SD) age was 75.6 (6.7) years; 152 (47.4%) had Eastern Cooperative Oncology Group performance status (ECOG PS) 2-4, and 73 (25.1%) had high cytogenetic risk. The most frequent frontline therapy was non-VMP bortezomib-based regimens (n=207; 30.7%), which were more frequent among patients with ECOG PS 0/1 and higher risk (e.g., international staging system (ISS) stage III, severely impaired glomerular filtrate rate (GFR), high lactate dehydrogenase (LDH), and high-risk cytogenetics); 185 patients (27.4%) started an attenuated (lite) VMP regimen, and 159 (23.6%) a VMP (VISTA) regimen. Median progression-free survival and overall survival (OS) were 15.3 months (95%CI 14.0-16.9) and 33.5 months (95%CI 29.1-37.2), respectively; 405 patients (78.2%) achieved partial response or better. Age, ECOG PS, ISS stage, serum LDH, GFR, cytogenetic risk, and treatment regimen significantly influenced OS. In this study, a remarkable proportion of transplant-ineligible patients with MM were older, frontline regimens were highly heterogeneous, and patients at higher risk often received less efficacious combinations. These findings suggest that clinicians have limited objective criteria for therapeutic decisions for this patient group.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Estimativa de Kaplan-Meier , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Masculino , Melfalan/administração & dosagem , Melfalan/efeitos adversos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Intervalo Livre de Progressão , Estudos Retrospectivos , Resultado do Tratamento
15.
Artigo em Inglês | MEDLINE | ID: mdl-33865545

RESUMO

Prednisone (PD) is one of the most commonly used corticosteroids in immunosuppressive therapy for patients with autoimmune diseases and transplants. Chronic use of corticosteroids is associated with several side effects and an increase in neoplasia. Since genotoxic effects are associated with an increased risk of cancer development, this study evaluated the genotoxic and cytotoxic activities of PD using the SMART/wing assay in Drosophila melanogaster and the micronucleus test and comet assay in mouse bone marrow cells. Further, the toxic effects of PD on mouse organ tissues were assessed using histopathological analyses. In the SMART/wing assay, PD showed a significant genotoxic activity at all concentrations tested (0.375, 0.75, 1.5, and 2.0 mg/mL) compared to the negative control (p < 0.05). The micronucleus test and comet assay also showed an elevated genotoxicity of PD at all treatment conditions (24, 48, and 120 h with doses ranging from 0.5 to 1.5 mg/kg) compared to the negative control (p < 0.05). The histopathological analyses did not show toxicity of PD in mouse cells and tissues. Therefore, our results demonstrate that PD is a potent genotoxic immunosuppressant in mice and D. melanogaster cells. Somatic recombination was the primary contributor (46%-82%) to the induced genotoxicity observed in the SMART test.


Assuntos
Dano ao DNA/efeitos dos fármacos , Prednisona/efeitos adversos , Animais , Animais Geneticamente Modificados , Animais não Endogâmicos , Ensaio Cometa , Drosophila melanogaster , Feminino , Masculino , Camundongos , Testes para Micronúcleos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade
16.
Int J Hematol ; 114(2): 246-251, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33864237

RESUMO

Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS) and angioimmunoblastic T-cell lymphoma (AITL) are common subtypes of T-cell lymphoma. Although CHOP is a standard regimen for T-cell lymphoma, it has unsatisfactory outcomes. Pirarubicin is an anthracycline antibiotic with lower cardiotoxicity than doxorubicin. THP-COP (pirarubicin, cyclophosphamide, vincristine, and prednisone) is sometimes used for elderly patients with non-Hodgkin's lymphoma in Japan. We performed a retrospective analysis using data from the population-based Osaka Cancer Registry as well as administrative data from 2010 to 2015. Of 82 enrolled patients, 51 received CHOP and 31 received THP-COP. The median age was 65 years in the CHOP group and 75 years in the THP-COP group. The probability of 3-year overall survival (OS) was 49.0% in the CHOP group and 44.9% in the THP-COP group. In the propensity score-adjusted analysis, there was no significant difference between the THP-COP and CHOP groups in the OS of the total sample [hazard ratio (HR) 0.46, 95% CI 0.14-1.55, P = 0.2]. Although our study was limited by its retrospective nature, it showed that clinical outcomes with the THP-COP regimen were comparable to those with the CHOP regimen in PTCL-NOS and AITL. Our findings should be re-assessed in larger studies in the future.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/análogos & derivados , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Gerenciamento Clínico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Pesquisas sobre Serviços de Saúde , Hospitalização , Humanos , Japão/epidemiologia , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/epidemiologia , Masculino , Pessoa de Meia-Idade , Prednisolona/efeitos adversos , Prednisolona/uso terapêutico , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
17.
Pediatr Hematol Oncol ; 38(4): 305-318, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33646922

RESUMO

This study was conducted with the aim to assess the clinico-pathological profile, treatment outcomes and the challenges faced in Low Middle Income Countries (LMIC) during management of pediatric Burkitt lymphoma cases on intensive chemotherapy protocol. This was a single center retrospective analysis of pediatric Burkitt lymphoma cases (age <18 years) managed uniformly with Lymphomes Malins B (LMB) 96 chemotherapy protocol between January 2015 and September 2019. 40 cases were analyzed with a median age 11.5 years (range 4-18 years) and male: female ratio =4.7:1. Patients belonging to different LMB risk groups were: A-3 (7.5%), B-31 (77.5%), and C-06 (15%). 25 (62.5%) patients had abdominal disease at presentation. The survival analysis of different treatment risk groups showed statistically significant difference in mean Overall Survival (OS) between group A-100%, group B- 87%±6.1% and group C-44.4%±16.2%; (p value = .016). On multivariate analysis of prognostic factors affecting survival, CNS involvement (p value = .03) and median time from diagnosis to treatment initiation more than 30 days (p value = .04) were significantly associated with poor outcome. Incidence of culture positive febrile neutropenia episodes was 28.2% of which 69.2% infections were caused due to carbapenem resistant gram-negative organisms. In our study, although the outcomes in risk group A and B patients were comparable to LMB 96 treatment results, the outcome in risk group C was considerably poor primarily due to advanced disease at presentation and delayed diagnosis. The critical challenges that we faced in our cohort were delayed diagnosis, treatment cost affordability, poor nutritional status, and high infection related mortality.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/efeitos adversos , Asparaginase/uso terapêutico , Linfoma de Burkitt/diagnóstico , Criança , Pré-Escolar , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Citarabina/efeitos adversos , Citarabina/uso terapêutico , Gerenciamento Clínico , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Masculino , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Resultado do Tratamento , Vincristina/efeitos adversos , Vincristina/uso terapêutico
18.
Acta Derm Venereol ; 101(4): adv00431, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33686448

RESUMO

Pyoderma gangrenosum is an uncommon ulcerative neutrophilic dermatosis. Clinical presentation, location and associated diseases are diverse. Treatment of pyoderma gangrenosum includes treating the underlying comorbidity supplemented with topical and/or systemic agents. However, treatment is often challenging. The aim of this study was to explore the diversity of pyoderma gangrenosum and its treatments. A total of 64 patients with pyoderma, at the Department of Dermatology, Aarhus University hospital, Denmark, were included in the study. The patients' records were reviewed over a 6-year period for clinical presentation, associated diseases, treatments and response to treatment, time to mortality after diagnosis and prednisone dose over time. A variety of accompanying comorbidities were found, including a possible association with diabetes. Tumour necrosis α inhibitors were used as third- or fourth-line therapy, but showed the shortest time to remission, and use of prednisone was associated with a higher mortality rate. These findings are discussed in relation to future approaches to treatment of pyoderma gangrenosum.


Assuntos
Pioderma Gangrenoso , Comorbidade , Humanos , Prednisona/efeitos adversos , Pioderma Gangrenoso/diagnóstico , Pioderma Gangrenoso/tratamento farmacológico , Pioderma Gangrenoso/epidemiologia , Estudos Retrospectivos
19.
Acta Oncol ; 60(6): 744-749, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33734921

RESUMO

BACKGROUND: Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is standard of care first line treatment for diffuse large B-cell lymphoma (DLBCL), though outcomes remain suboptimal. METHODS: We performed a systemic review and meta-analysis of randomized controlled trials comparing the efficacy and safety of R-CHOP vs. R-CHOP + X (addition of another drug to R-CHOP) as first line treatment for DLBCL. We searched Cochrane Library, PubMed and conference proceedings up to September 2020. RESULTS: Our search yielded ten trials including 4206 patients. The added drug was bortezomib or lenalidomide in three trials each, and gemcitabine, bevacizumab and ibrutinib, each drug in one trial. R-CHOP + X was associated with statistically significant improved disease control (HR 0.88, 95% CI 0.78-0.99). The point estimate was in favor of improved overall survival with R-CHOP + X (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.75-1.00), although this was not statistically significant. Subgroup analysis revealed improved disease control with the addition of lenalidomide and in patients younger than 60 years. R-CHOP + X was associated with an increase in serious adverse events and grade III/IV hematologic toxicity. CONCLUSION: The addition of another drug to frontline R-CHOP treatment for DLBCL did not result in a significant improvement in OS, although we did observe improved disease control compared to R-CHOP, perhaps most evident with the addition of lenalidomide. Yet, RCHOP + X was associated with an increased risk for serious and hematological adverse events. Further studies could reveal subgroups that would benefit most from augmentation of standard R-CHOP.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Anticorpos Monoclonais Murinos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prednisona/efeitos adversos , Rituximab/uso terapêutico , Vincristina/efeitos adversos
20.
Int J Hematol ; 113(6): 823-831, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33738702

RESUMO

The long-term effects of pegfilgrastim administered in the first cycle of chemotherapy in day-to-day practice remain unclear. We retrospectively identified 114 patients aged ≥ 70 years with diffuse large B-cell lymphoma who received a rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) regimen in our institution. Twenty-six patients received pegfilgrastim (pegfilgrastim group); of the 88 patients scheduled to receive conventional granulocyte-colony stimulating factor (G-CSF) when their neutrophil count decreased (neut-adjusted-G group), conventional G-CSF was ultimately administered to 57. During the first cycle of R-CHOP, the incidence of febrile neutropenia was lower in the pegfilgrastim group than in the neut-adjusted-G group (0% vs. 18%, p = 0.020). Throughout all cycles, a higher proportion of patients exhibited sustained relative dose intensity (≥ 80%) in the pegfilgrastim group than in the neut-adjusted-G group (25% vs. 4.0%, p = 0.008). A lower proportion of patients received a reduced dose in the second cycle in the pegfilgrastim group than in the neut-adjusted-G group (0% vs. 10%, p = 0.116). Although the differences were not significant, the pegfilgrastim group showed higher progression-free survival and overall survival than the neut-adjusted-G group. Adequate prevention of febrile neutropenia using pegfilgrastim during the first cycle of R-CHOP may contribute to avoidance of dose intensity reduction in all cycles.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Filgrastim/administração & dosagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Polietilenoglicóis/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Masculino , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Estudos Retrospectivos , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversos
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