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1.
Leuk Res ; 83: 106165, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31200147

RESUMO

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disease which is treated on the basis of small studies, making the literature still scarce of reports, especially of those conducted in Latin America. Here we intend to describe clinical characteristics, rates of response, survival and second neoplasms in HCL patients treated in a reference center in Brazil. All patients diagnosed with HCL between July/1987 and Jun/2018 were included in this analysis. Fifty-four patients were included in this analysis. Median age at diagnosis was 55 years (range, 26-88), with 37% being above 60 years-old. Most patients were treated with cladribine in our cohort (n = 36; 68%), administered through intravenous continuous infusion. Remaining patients were firstly managed with splenectomy (n = 7; 13%), IFN (n = 6; 11%) and rituximab (n = 2; 4%). In a univariate analysis, platelet count and B2M level at diagnosis were statistically associated with CR achievement (p = 0.004 and p = 0.024, respectively). A median follow-up time of 9 years was calculated. Estimated 10-year overall survival was 91.1% (95% confidence interval, 77-97). In this cohort, 10 patients had any second neoplasm, diagnosed before or after HCL. Regarding the sites of cancer, 69% were of skin - 8/16 carcinoma-type and 3/16 melanoma-type. Our response and survival data are similar to those reported by literature, which reaffirms the role of purine analogs in current HCL management. With a very long follow-up we also have observed a high incidence of second neoplasm.

4.
Artigo em Inglês | MEDLINE | ID: mdl-30509780

RESUMO

INTRODUCTION: Although a considerable improvement in survival of patients with acute promyelocytic leukemia (APL) has been seen over the past decades, real-life outcomes seem to be worse than those reported by prospective studies. We aim to describe clinical characteristics and outcomes of adult patients diagnosed with APL in an academic hospital from the University of Sao Paulo. PATIENTS AND METHODS: We retrospectively reviewed the medical charts of 61 patients with APL diagnosed between January 2007 and May 2017. Baseline clinical features and follow-up data were collected, focusing on early toxicity variables such as infection, bleeding, and thrombosis in the first 30 days from diagnosis. RESULTS: Among the 61 patients with APL, 54 received any chemotherapy. All patients also received all-trans retinoic acid (ATRA). Bleeding events were the main cause of death before receiving chemotherapy. Most patients belonged to the intermediate (43%) and high-risk (41%) groups, according to Sanz score. The '7 + 3 + ATRA' regimen was the most used regimen (n = 38). An early death rate of 20% was found, predominantly owing to sepsis. After a median follow-up of 5 years, only 1 relapse was diagnosed. The overall survival at 5 years was 59%. DISCUSSION: In comparison with prospective trials with ATRA-based regimens, we found an inferior overall survival, mostly on account of a high early-death rate. Our results are in line with other real-life retrospective reports published in the past decades. CONCLUSION: Results of real-life studies differ from those found by prospective trials. Accordingly, early actions and supportive care are still needed, aiming to decrease toxicity, especially in developing countries.

5.
Ann Hematol ; 97(12): 2269-2278, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30315344

RESUMO

Chronic lymphocytic leukemia (CLL), a disorder for which B cell heterogeneity and increased cellular proliferation play central pathogenic roles, displays several genetic abnormalities that are associated with poor prognosis and have therapeutic implications. In this review, we discuss the prognostic role and therapeutic implications of chromosome 17p deletions and TP53 mutations in CLL. Unlike other recurrent genetic abnormalities, the frequency of TP53 alterations is relatively low in newly diagnosed patients, but increases sharply with disease progression, which suggests that these alterations represent an evolutionary mechanism of resistance. In comparison with patients without such abnormalities, those with 17p deletions and TP53 mutations have lower response rates and more aggressive disease. One important consequence of the diverse molecular mechanisms that affect the TP53 pathway is the need to assess both the presence of 17p deletion and TP53 mutations before treatment initiation. Several authors have attempted to incorporate TP53 abnormalities in different prognostic models for CLL, and the recent International Prognostic Index for Chronic Lymphocytic Leukemia formally considers patients with TP53 abnormalities (deletion 17p or TP53 mutation or both) as high-risk. Several novel agents may improve results in patients with CLL, including in those with TP53 mutations. Ibrutinib, idelalisib, and venetoclax have been approved in various settings and countries for treatment of CLL. Further progress in targeted therapy and judicious use of chemotherapy, monoclonal antibodies, and reduced-intensity allogeneic transplantation will provide patients with CLL in general, and those with TP53 abnormalities in particular, with a better prognosis.


Assuntos
Antineoplásicos/uso terapêutico , Deleção Cromossômica , Leucemia Linfocítica Crônica de Células B , Síndrome de Smith-Magenis , Transplante de Células-Tronco , Proteína Supressora de Tumor p53/genética , Aloenxertos , Cromossomos Humanos Par 17/genética , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/terapia , Prognóstico , Síndrome de Smith-Magenis/diagnóstico , Síndrome de Smith-Magenis/genética , Síndrome de Smith-Magenis/terapia
6.
Leuk Res Rep ; 10: 41-43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30225192

RESUMO

Renal involvement in Hodgkin lymphoma (HL) is rare, although extralymphatic disease is usually found. Acute kidney injury is a recognized presentation of non-Hodgkin lymphoma, with bilateral kidney involvement, promptly requiring specific treatment. Regarding to HL, this manifestation is extremely rare and lacks pathologic description and management experiences. Herein, we describe a case of HL with atypical presentation as well as its management, current evaluation by PET-scan and histologic findings. This case report highlights clinical presentation and a successful experience on managing these cases. Moreover, it is important to drive biologic insights for understanding of kidney infiltration mechanism in HL.

7.
Hematol., Transfus. Cell Ther. (Impr.) ; 40(3): 245-249, July-Sept. 2018. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-953832

RESUMO

ABSTRACT Objective: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-D-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. Methods: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-D-glucose marrow uptake that resolved following chemotherapy. Results: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. Conclusion: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

8.
Hematol Transfus Cell Ther ; 40(3): 245-249, 2018 Jul-Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30128433

RESUMO

Objective: To investigate, in a large prospective multicenter study, whether 2-[18F]-fluoro-2-deoxy-d-glucose-positron emission tomography is sufficiently accurate to identify clinically important bone marrow involvement by Hodgkin's lymphoma to replace routine bone marrow biopsy in a developing tropical country. Methods: Patients newly diagnosed with Hodgkin's lymphoma were recruited from six cancer centers in Brazil. All were staged by the results of positron emission tomography/computed tomography that were centrally reviewed and by iliac crest bone marrow biopsy. Patients were classified as having marrow disease if they had lymphoma identified by marrow biopsy histology or had focal 2-[18F]-fluoro-2-deoxy-d-glucose marrow uptake that resolved following chemotherapy. Results: A total of 246 participants were recruited from six different centers and 62 (25.2%) were judged to have Hodgkin's lymphoma in the bone marrow. Positron emission tomography and biopsies were concordant in 206 patients (83%). Positron emission tomography correctly identified marrow disease in 59/62 patients (95.1%) and marrow biopsy in 25/62 patients (40.3%). In 22/62 (35.4%) patients, the two techniques were concordant in the diagnosis of marrow involvement. Of the forty discordant results, positron emission tomography found bone marrow involvement in 37 patients, upstaging 22 to stage IV and having an impact on therapeutic decision in nine cases given their reallocation from early to advanced stage. Three false negative positron emission tomography results were obtained with bone marrow biopsy giving positive findings. All three cases were classified as stage IV regardless of bone marrow findings implying no modification in the clinical management. The sensitivity, specificity and accuracy of positron emission tomography for detecting bone marrow disease were 95%, 100% and 98% and for bone marrow biopsy they were 40%, 100% and 84%, respectively. Conclusion: We conclude that positron emission tomography can replace marrow biopsy in Brazilian patients with Hodgkin's lymphoma without compromising clinical management.

9.
J. bras. econ. saúde (Impr.) ; 10(2): 118-125, Agosto/2018.
Artigo em Inglês | LILACS, ECOS | ID: biblio-914923

RESUMO

Background: In 2016, Hodgkin's Lymphoma (HL) was responsible for 2,470 new cases in Brazil and, despite recent scientific advances, there are unmet medical needs that affects patients' outcome. Therefore, we aimed to explore the unmet medical needs in the management of HL patients in Brazil, based on experts' perspective. Methods: A questionnaire was developed to address the unmet medical needs including barriers for the diagnosis and treatment of HL in Brazil. The questionnaire results were presented in a panel discussion to validate participants' responses and to collect additional data. Main results: Eight experts participated in the panel. On both healthcare systems, public and private, a slight majority of patients was women and most of them were under 60 yearsold. In addition, the majority of patients were referred from another specialty on both systems. The time from onco-hematologist appointment to diagnosis was different between public and private sector (median of 30 and 12.5 days, respectively). Most patients in the public sector were on stage III (33%) and IV (33%); in the private sector, most patients were on stages II (36%) and III (24%). The most common barriers were the delayed diagnosis and the unavailability of diagnostic procedures and treatment options. Conclusion: According to participants, issues related to infrastructure and healthcare resource allocation affects the management of HL. Improvements in the infrastructure and educational measures for physicians and patients may contribute to minimize the barriers.


Introdução: Em 2016, o Linfoma de Hodgkin (LH) foi responsável por 2.470 novos casos no Brasil e, apesar dos recentes avanços científicos, há necessidades médicas não atendidas que afetam os pacientes. Portanto, o estudo teve como objetivo explorar as necessidades médicas não atendidas no manejo de pacientes com LH no Brasil, com base na perspectiva de especialistas. Métodos: Um questionário foi desenvolvido para abordar as necessidades médicas não atendidas, incluindo as barreiras para o diagnóstico e tratamento do LH no Brasil. Os resultados do questionário foram apresentados em um painel de discussão para validar as respostas dos participantes e coletar dados adicionais. Principais resultados: Oito especialistas participaram do painel. De acordo com os especialistas, em ambos os sistemas de saúde público e privado, uma pequena maioria dos pacientes era mulher e a maioria tinha menos de 60 anos. Além disso, a maioria dos pacientes foi encaminhada por outra especialidade em ambos os sistemas. O tempo entre a consulta com o onco-hematologista até o diagnóstico foi diferente entre o setor público e privado (mediana de 30 e 12,5 dias, respectivamente). A maioria dos pacientes do setor público apresenta estádios III (33%) e IV (33%); no setor privado, a maioria dos pacientes apresenta estádios II (36%) e III (24%). As barreiras mais comuns foram o atraso no diagnóstico e a indisponibilidade de procedimentos diagnósticos, e opções de tratamento. Conclusão: De acordo com os participantes, as questões relacionadas à infraestrutura e à alocação de recursos de saúde afetam o gerenciamento do LH. Melhorias na infraestrutura e medidas educacionais para médicos e pacientes podem contribuir para minimizar as barreiras.


Assuntos
Humanos , Doença de Hodgkin , Assistência ao Paciente , Necessidades e Demandas de Serviços de Saúde
10.
J. bras. econ. saúde (Impr.) ; 10(2): 172-178, Agosto/2018.
Artigo em Inglês | LILACS, ECOS | ID: biblio-915110

RESUMO

Background: Hodgkin's Lymphoma (HL) is a curable type of cancer, with a wide variety of therapies, especially for refractory/relapsing cases. Therefore, the study aims to explore the treatment patterns used in the management of HL patients in Brazil. Methods: A survey was developed to explore the treatment patterns in Brazil, addressing topics such as clinical characteristics, lines of therapy, transplant information and cure rates. Then, results were presented in a panel discussion to validate participants' responses and gain additional insights. Main results: The eight experts reported that most patients are women and under 60 years old. In both private and public healthcare systems, ABVD was the most commonly used first-line therapy for patients of all stages. The median cure rates for patients in stages I and II were 80% and 87.5%, and for stages III and IV 60% and 67.5%, respectively, in public and private sectors. For the subsequent lines of therapy, different regimens such as DHAP, GVD, GEV, ICE and allogeneic transplant are used, among others. Brentuximab vedotin was present mainly in the private sector. In the public sector, 70% of the patients are eligible for autologous stem cell transplant; of them, 75% actually receive the transplant. In the private sector, 80% of the patients are eligible, and 100% of them receive the transplant. Conclusion: Similarities were found between the public and private sectors in first-line therapy and cure rates. However, barriers for subsequent lines of therapy are more evident in the public system.


Introdução: O linfoma de Hodgkin (LH) é um tipo de câncer curável, com ampla variedade de terapias, especialmente para casos refratários/recidivantes. Portanto, o estudo visa explorar os padrões de tratamento utilizados no manejo de pacientes com LH no Brasil. Métodos: Uma pesquisa foi desenvolvida para explorar os padrões de tratamento no Brasil, abordando tópicos como: características clínicas, linhas de terapia, informações sobre transplantes e taxas de cura. Em seguida, os resultados foram apresentados em um painel de discussão para validar as respostas dos participantes e coletar os insights adicionais. Principais resultados: Os oito especialistas relataram que maioria dos pacientes é composta por mulheres com idade menor de 60 anos. Em ambos os sistemas de saúde, privado e público, ABVD foi a terapia de primeira linha mais comumente usada para pacientes de todos os estágios. As medianas das taxas de cura para pacientes nos estágios I e II foram de 80% e 87,5%, e para os estádios III e IV, de 60% e 67,5%, nos setores público e privado, respectivamente. Para as linhas subsequentes de terapia, diferentes regimes como DHAP, GVD, GEV, ICE e transplante alogênico são utilizados, entre outros. Brentuximabe vedotina estava presente principalmente no setor privado. No setor público, 70% dos pacientes são elegíveis para transplante autólogo de células-tronco; deles, 75% recebem o transplante. No setor privado, 80% dos pacientes são elegíveis e 100% recebem o transplante. Conclusão: Foram encontradas semelhanças entre o setor público e privado na terapia de primeira linha, bem como nas taxas de cura. No entanto, as barreiras para as linhas subsequentes de terapia são mais evidentes no sistema público.


Assuntos
Humanos , Doença de Hodgkin , Pesquisas sobre Serviços de Saúde , Tratamento Farmacológico
11.
J. bras. econ. saúde (Impr.) ; 10(2): 190-197, Agosto/2018.
Artigo em Inglês | LILACS, ECOS | ID: biblio-915117

RESUMO

Hodgkin's lymphoma (HL) is a B-cell malignancy with a classical bimodal distribution with incidence peaking in the third and sixth decades of life. The purpose of this review is to describe the current unmet medical need for relapsing/refractory HL and the main data of emerging treatments, including brentuximab vedotin, the immune checkpoint inhibitors nivolumab and pembrolizumab, as well as other compounds in development. Available guidelines for relapsing/refractory HL are discussed.


O linfoma de Hodgkin (LH) é uma neoplasia de células B com distribuição bimodal clássica com pico de incidência na terceira e sexta décadas de vida. O objetivo desta revisão é descrever as atuais necessidades médicas não atendidas dos pacientes com LH recidivante/refratário e os dados principais dos tratamentos emergentes, incluindo brentuximabe vedotina, os inibidores do ponto de verificação imunológico, nivolumabe e pembrolizumabe, bem como outros compostos em desenvolvimento. Além disso, discutem-se as diretrizes disponíveis para LH recidivante/refratário.


Assuntos
Humanos , Doença de Hodgkin , Tratamento Farmacológico
12.
Clin Lymphoma Myeloma Leuk ; 18(6): e255-e259, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29605423

RESUMO

BACKGROUND: Acute lymphoblastic leukemia (ALL) in adults is an invariably aggressive and rare disease. Its treatment is based on the use of multidrug regimens, which have been improved since the 1970s. Few published data are available on the results of adult ALL treatment in Latin America. MATERIALS AND METHODS: We retrospectively analyzed the data from 59 patients with ALL treated from 2009 to 2015 at Hospital of Clinics of University of São Paulo, using an adapted German Multicenter ALL (GMALL) protocol (07/2003). RESULTS: The median patient age was 35 years (range, 16-71 years), with 76% of new cases of B-cell lineage. Central nervous system involvement was present in 29%. Most patients were in the high-risk group, using the original GMALL criteria (68%). The early death rate was 17%, preventing early evaluation of the response in these patients. Despite a reasonable complete remission rate (76%), most patients eventually died of sepsis, especially during the induction phase and salvage regimens. The median overall survival was 17 months. CONCLUSION: Intensified chemotherapy protocols for adult ALL have succeeded in achieving better survival rates in adults, especially younger adults. The low overall survival found with GMALL in Brazil's public hospital denotes the importance of optimizing the adaptations of international protocols for treatment of ALL in nondeveloped countries and, in parallel, improving supportive care in public services.

13.
Rev. bras. hematol. hemoter ; 39(3): 216-222, July-Sept. 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-898924

RESUMO

Abstract Background Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. Methods A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. Results Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. Conclusion Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.


Assuntos
Humanos , Masculino , Feminino , Dor Intratável , Doença de Hodgkin/terapia , Everolimo
14.
Rev Bras Hematol Hemoter ; 39(3): 216-222, 2017 Jul - Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28830600

RESUMO

BACKGROUND: Despite all the scientific progress that has been made on understanding the disease, prognosis for patients with relapsed and refractory Hodgkin's lymphoma remains poor and the treatment is palliative in the majority of the cases. Thus, the aim of this study was to present the results on the compassionate use of everolimus in a group of patients who were monitored at nine different centers in Brazil. METHODS: A 10-mg oral dose of everolimus was given to each patient daily. Response time was evaluated from the beginning of medication use until loss of response, toxicity or medical decision to cease treatment. RESULTS: Thirty-three patients were evaluated. The median age at the beginning of medication administration was 29 years. Patients had received a median of five prior therapies. Overall response rate was 45.4%, with 13 patients achieving partial response, two achieved clinical response, 14 remained with stable disease, two had disease progression, and two were not evaluated. Patients received a median of 14 cycles. Progression-free survival was nine months, and overall survival was estimated to be 36 months. Three patients used the medication for more than four years. The most frequently reported adverse events were thrombocytopenia and hypercholesterolemia. Three patients had pulmonary toxicity. Grade III and IV adverse events occurred in 39% of the patients. CONCLUSION: Everolimus was found to provide a response in a group of patients with refractory or relapsed Hodgkin's lymphoma who had adequate tolerability to the drug.

17.
Rev. bras. hematol. hemoter ; 38(4): 346-357, Oct.-Dec. 2016. tab
Artigo em Inglês | LILACS | ID: biblio-829948

RESUMO

ABSTRACT Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.


Assuntos
Citogenética , Imunofenotipagem , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/terapia , Estadiamento de Neoplasias , Prognóstico
18.
Rev Bras Hematol Hemoter ; 38(4): 346-357, 2016 Oct - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27863764

RESUMO

Chronic lymphocytic leukemia is characterized by clonal proliferation and progressive accumulation of B-cell lymphocytes that typically express CD19+, CD5+ and CD23+. The lymphocytes usually infiltrate the bone marrow, peripheral blood, lymph nodes, and spleen. The diagnosis is established by immunophenotyping circulating B-lymphocytes, and prognosis is defined by two staging systems (Rai and Binet) established by physical examination and blood counts, as well as by several biological and genetic markers. In this update, we present the recommendations from the Brazilian Group of Chronic Lymphocytic Leukemia for the diagnosis and treatment of chronic lymphocytic leukemia. The following recommendations are based on an extensive literature review with the aim of contributing to more uniform patient care in Brazil and possibly in other countries with a similar social-economic profile.

19.
Lancet Haematol ; 3(3): e128-38, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26947201

RESUMO

BACKGROUND: Part one of the two-part SAWYER study predicted that subcutaneous rituximab 1600 mg would achieve trough serum concentrations that were non-inferior to those achieved with intravenous rituximab 500 mg/m(2) in patients with chronic lymphocytic leukaemia. In part two of the study, we aimed to confirm the pharmacokinetic non-inferiority of subcutaneous rituximab, and investigate its safety and efficacy. METHODS: We did this phase 1b, open-label, randomised controlled non-inferiority study at 68 centres in 19 countries in Europe, North America, South America, and Australasia. Patients aged 18 years or older with untreated chronic lymphocytic leukaemia were randomly assigned, via an interactive voice-response system with a permuted block randomisation scheme (block size of ten), to receive subcutaneous rituximab 1600 mg or intravenous rituximab 500 mg/m(2) plus fludarabine and cyclophosphamide every 4 weeks for up to six cycles. In cycle one, all patients received intravenous rituximab 375 mg/m(2). Randomisation was stratified by Binet stage and fludarabine and cyclophosphamide administration route (oral vs intravenous). Study investigators and patients were not masked to group allocation, but allocation was concealed from the statistician, clinical scientist, and clinical pharmacologist. The primary endpoint was trough serum concentration at cycle five, with a non-inferiority margin of 0·8 for the adjusted geometric mean ratio of the subcutaneous to the intravenous dose. We did the primary analysis in patients in the intention-to-treat population with complete pharmacokinetic data (pharmacokinetic population). This trial is registered with ClinicalTrials.gov, number NCT01292603, and is ongoing, although the treatment stage is now complete. FINDINGS: Between Aug 20, 2012, and June 17, 2013, we randomly assigned 176 patients to receive subcutaneous rituximab (n=88) or intravenous rituximab (n=88); 134 (76%) patients comprised the pharmacokinetic population. As of May 7, 2014, median follow-up was 13·9 months (IQR 11·9-16·0) for patients in the subcutaneous group and 14·1 months (11·6-16·5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97·5 µg/mL vs 61·5 µg/mL), with an adjusted geometric mean ratio of 1·53 (90% CI 1·27-1·85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 [96%] of 85 patients and 81 [91%] of 89 patients; serious adverse events: 25 [29%] and 29 [33%] patients; grade ≥3: 59 [69%] and 63 [71%] patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 [56%] patients in the subcutaneous group and 46 [52%] patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 [11%] and n=4 [4%], respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 [12%] and n=0, respectively) and nausea (n=2 [2%] and n=11 [12%], respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 [42%]) than after intravenous rituximab (n=2 [2%]); most of these reactions were grade 1 or 2. INTERPRETATION: When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in combination regimens with approved and emerging oral regimens. FUNDING: F Hoffmann-La Roche.


Assuntos
Antineoplásicos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Rituximab , Administração Cutânea , Administração Intravenosa , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/farmacocinética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Rituximab/farmacocinética , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/farmacocinética
20.
Br J Clin Pharmacol ; 80(5): 1001-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25900065

RESUMO

AIMS: The aim of the phase Ib, two part SAWYER study (BO25341; NCT01292603) was to investigate the pharmacokinetics and safety of subcutaneous (s.c.) rituximab compared with intravenous (i.v.) rituximab, both in combination with fludarabine and cyclophosphamide (FC), as first line treatment for patients with chronic lymphocytic leukaemia (CLL). METHODS: During part 1 (dose-finding), CLL patients received rituximab i.v. followed by a single dose of rituximab s.c. at one of three fixed doses (1400, 1600 or 1870 mg) in cycle 6. The primary objective was to identify a fixed s.c. dose that would achieve comparable rituximab serum trough concentrations (Ctrough ) to those achieved with the standard 4 weekly 500 mg m(-2) rituximab i.v. dose. RESULTS: Fifty-five patients received a fixed dose of rituximab s.c., 16 received 1400 mg, 17 received 1600 mg and 22 received 1870 mg. The 1600 mg dose was predicted to achieve non-inferior Ctrough to standard rituximab i.v. TREATMENT: The rituximab s.c. safety profile was comparable with rituximab i.v., except that local administration-related reactions, mainly mild/moderate injection site reactions, occurred more frequently with rituximab s.c., which was not unexpected. Subcutaneous administration was preferred to i.v. administration by >90% of patients and nurses (n = 112). CONCLUSIONS: SAWYER part 1 data predict that rituximab s.c. 1600 mg will achieve non-inferior Ctrough concentrations to rituximab i.v. 500 mg m(-2) , administered 4 weekly. This fixed s.c. dose is currently undergoing formal non-inferiority assessment in SAWYER part 2. In future, CLL treatment regimens comprising rituximab s.c. and oral FC could substantially reduce i.v. chair time.


Assuntos
Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Rituximab/efeitos adversos , Rituximab/farmacocinética , Vidarabina/análogos & derivados , Administração Intravenosa , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicação , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Preferência do Paciente , Rituximab/administração & dosagem , Vidarabina/administração & dosagem , Vidarabina/uso terapêutico
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