Clinical and economic aspects of the use of rituximab in non-Hodgkin's lymphoma

Non-Hodgkin's lymphoma (NHL) consists of a group of neoplasias involving mainly B cells and represents 90% of all lymphomas. The current available therapy is based on chemotherapy associated with the monoclonal antibody rituximab (Mab Thera(r)), which targets the CD20 protein, present in over 80% of NHL mature B cells. Recent clinical reports show a preference for combining the benefits of immunotherapy and adjuvant chemotherapy, thus generating safe and effective alternative treatments. The current review aimed at evaluating various aspects related to the use of rituximab for NHL, highlighting the possible inhibitory mechanisms of cell proliferation, the achieved clinical results, and the expected clinical and economic outcomes of treatments. The results from clinical tests indicate the need for a better understanding of the critical mechanisms of action of this antibody, which may maximize its therapeutic efficacy. This therapy not only represents a viable option to treat most types of NHLs, especially when associated with conventional chemotherapy, but also offers cost-utility and cost-effectiveness advantages.

O Linfoma não-Hodgkin (LNH) consiste em um grupo de neoplasias envolvendo, principalmente, as células B e representa 90% de todos os linfomas. A terapia atual disponível é baseada em quimioterapia associada ao anticorpo monoclonal rituximabe (Mab Thera(r)), que tem como alvo a proteína CD20, presente em mais de 80% das células B maduras do LNH. Recentes relatórios clínicos mostram preferência para combinar os benefícios da quimioterapia adjuvante e imunoterapia, gerando alternativas de tratamentos seguro e eficaz. O trabalho de revisão teve por objetivo avaliar vários aspectos relacionados à aplicação do rituximabe no LNH, destacando os possíveis mecanismos inibitórios da proliferação celular, os resultados clínicos obtidos e as implicações clínicas e econômicas esperadas para o tratamento. Os resultados de testes clínicos indicam a necessidade de uma melhor compreensão dos mecanismos críticos de ação deste anticorpo, que poderão maximizar a sua eficácia terapêutica. Essa terapia não representa apenas uma opção viável para o tratamento da maioria dos tipos de LNH, principalmente quando associado à quimioterapia convencional, mas, também, oferece vantagens em termos de custo-utilidade e custo-efetividade.

Linfomas asociados a infección por Virus de Inmunodeficiencia Humana: Experiencia de un centro hospitalario de la V región, Chile / Lymphomas associated with human immunodeficiency virus infection: Retrospective review of medical records

Background: The incidence oflymphoma increases enormously inpatients infecten with the human immunodeficiency virus (HIV). Aim: To describe the incidence, clinical and histológica! characteristics, treatments and survival of lymphomas associated with HTV infection. Material and Methods: Retrospective review of medical records ofpatients with HIV and lymphoma, treated in a public hospital, between January 2001 and June 2009. Results: Twenty-two mole patients were included but 14 had immunohistochemical confirmation ofthe lymphoma. The accumulated incidence for thisperiod was 2.8 percent. The median age at lymphoma diagnosis was 39.5 years. Twelvepatients (86 percent) had non-Hodgkin lymphoma (NHI) and two (14 percent) Hodgkin lymphoma. The main pathological type of non-Hodgkin lymphomas was diffuse large B cell in seven cases (50 percent). The mean CD4 cell count and viral load were 83 cell/mm³ (33.5-113.5) and 26.000 RNA copies/ml (1210-196500), respectively Twelve patients (86 percent) had B type symptoms of lymphoma at the moment of diagnosis. Eleven patients (29 percent) received chemotherapy with or without radiotherapy, onepatient (7 percent) received radiotherapy alone and two patients (14 percent) received palliative symptomatic treatment. Six cases (43 percent) received highly active antiretroviral therapy simultaneously with chemotherapy. Global mortality in this series was 57 percent (8patients) with a median survival time of 5.8 months (2.6-26.2). Conclusions: In this series ofpatients infected with HIV, a predominance of aggressive histológica! subtypes of lymphomas and low complete remission rates, were observed.

Revisión histopatológica de 20 casos de linfoma de Hodgkin infantil (0-14 años) provenientes de áreas de deficiente situación socioeconómica / Histopathological revision of 20 cases of Hodgkin's lymphoma of infants (0-14 years) coming from areas of poor socioeconomical conditions

Los resultados obtenidos en la revisión histopatológica de 20 casos con confirmación de su baja situación socioeconómica han mostrado que la totalidad de los mismos correspondieron a una forma histológica de mejor pronóstico y, por ende, a una aplicación terapéutica de menor agresividad para el paciente, permitiendo a su vez actuar sobre la hipotética causa primaria de la enfermedad con medidas dedicadas a mejorar la respuesta inmune del niño.

The results obtained from histopathological revision of 20 cases with corroboration of their bad socioeconomical condition proof about the total of the casuistry to pertain into a good prognostic histological type, and for this reason submitted to a low aggresive chemotherapy treatment for the patient, and consecutively to put in action the therapeutic to restore the immunological response.

Malignant lymphomas in Pakistan according to the WHO classification of lymphoid neoplasms.

OBJECTIVE: To determine the spectrum of malignant lymphomas in our set up, according to the WHO classification. METHODS: All the cases diagnosed as malignant lymphoma, during the year 2005, were retrieved from the institution based tumour registry record and classified according to WHO criteria depending on the immunohistochemical results of a panel of lymphoma markers. RESULTS: The male to female ratio was 2.5:1 for almost all types of malignant lymphomas. The age range was 3 to 80 years. The frequency of Hodgkin's lymphoma, Burkitt's lymphoma and lymphoblastic lymphoma were higher amongst the children, whereas follicular lymphomas, mantle cell lymphoma and CLL/SLL were more frequently reported in 5th, 6th and 7th decades. Of the total cases 62% were nodal and 38% extranodal (majority in the GI tract). Non Hodgkin's lymphoma was more (73%) frequent than Hodgkin's disease. Mixed cellularity and nodular sclerosis were the main histological variants of Hodgkin's disease. CONCLUSIONS: Immunohistochemistry is not very frequently used in our set up and also at very few other centres. Therefore, its application should be encouraged to raise the quality of data on lymphoid neoplasms and contribute to their control.

¿Cuál es su diagnóstico? / What is your diagnosis?

Niño de 8 años de edad que consulta por presenciade nodulaciones en región cervical izquierda de 6meses de evolución, que aumentaron de tamañoprogresivamente y se hicieron bilaterales. Sinantecedentes familiares ni personales de importancia.La ecografía informa nodulaciones en la cadenacervical posterior izquierda...

Incidence and Histologic Patterns of Bone Marrow Involvement of Malignant Lymphoma Based on the World Health Organization Classification: A Single Institution Study / 대한진단검사의학회지

BACKGROUND: Working Formulation and Revised European American Classification of Lymphoid Neoplasms (REAL) have mainly been used in the studies for bone marrow involvement of malignant lymphoma in Korea. We investigated the incidence and histologic patterns of malignant lymphoma according to the WHO classification. METHODS: This study included 507 cases of malignant lymphoma that were requested for bone marrow study for the staging during the period January 1999-December 2005 in Korea Cancer Center Hospital. Medical records, peripheral blood smears, bone marrow aspiration smears, biopsy sections, and histopathologic findings were analyzed retrospectively. RESULTS: Of the 507 cases of malignant lymphoma, 473 (93.3%) were non-Hodgkin lymphoma (NHL) and 34 (6.7%) were Hodgkin lymphoma (HL). The overall incidence of bone marrow involvement by NHL and HL was 12.5% (59/473) and 11.8% (4/34), respectively. Among NHL cases, the incidence of bone marrow involvement by B-cell and T-cell neoplasms was 11.4% (43/377) and 16.7% (16/96), respectively. Although the incidences of bone marrow involvement by several B-cell neoplasms were more than 30%, diffuse large B cell lymphoma showed a relatively low incidence of bone marrow involvement (4.6%). Of bone marrow involvement patterns, diffuse infiltration pattern was the most common (40.0%). Peripheral blood involvement by lymphoma was observed in 35.6% of cases with bone marrow involvement. CONCLUSIONS: We used WHO classification in the study for the bone marrow involvement of malignant lymphoma, and this single-institution study should give a useful, up-to-date histopathologic information.

Immunophenotyping of Hodgkin's disease--an aid to its classification.

Based on morphological, phenotypic, genotypic and clinical findings, Hodgkin's disease has recently been classified into two subtypes: Nodular lymphocyte predominant and classical Hodgkin's disease. Forty-two cases of Hodgkin's disease were subjected to detailed morphological assessment and immunophenotyping. The commonest subtype was Nodular Sclerosis seen in 27 cases. The panel of antibodies used was CD 15, CD 30, CD 3, CD 20, CD 45 and Epithelial Membrane Antigen. Immunophenotyping was done by Streptavidin Biotin Peroxidase complex technique. CD 30 was expressed in 86% and CD 15 in 76% cases. Immunophenotype helped reclassify two cases, according to the WHO classification scheme. Although morphology remains the gold standard in the diagnosis of Hodgkin's disease, immunophenotype is a useful adjunct in differentiating prognostically distinct subtypes.

Significado prognóstico dos graus histológicos do linfoma de Hodgkin do tipo esclerose nodular / Prognostic significance of histopathological grading of nodular sclerosing HodgkinÆs lymphoma

INTRODUÇAO: A esclerose nodular (EN), do tipo histológico freqüente do linfoma de Hodgkin (LH), apresenta grande variabilidade em sua composição celular. Na década de 80, pesquisadores do British National Lymphoma Investigation (BNLI) propuseram uma subclassificação histológica do LH EN. Eles identificaram dois graus histológicos - o LH EN grau I (LH EN I) e o LH EN grau II (LH EN II) - e demonstraram que os portadores de LH EN II apresentavam menor sobrevida em comparação aos portadores de LH EN I. Outros estudos, entretanto, não reproduziram esses achados. OBJETIVO: Avaliar o significado prognóstico da graduação histológica proposta pelo BNLI. MATERIAIS E MÉTODOS: Estudo retrospectivo que incluiu 69 casos de LH EN. Mais de 90 por cento dos casos foram tratados com terapia combinada ou quimioterapia exclusiva, não havendo diferença no tipo de tratamento oferecido a depender do grau histológico. RESULTADOS: Trinta e cinco casos (51 por cento) foram classificados com EN I e 34 (49 por cento) como EN II. Não observamos diferenças na distribuição de outros fatores prognósticos entre os portadores dos dois graus. Remissão completa após o tratamento inicial foi obtida em 85,7 por cento dos casos de EN I e em 82,4 por cento dos casos de EN II (p = 0,75). A probabilidade estimada de sobrevida global em cinco anos foi de 67 por cento para EN I e de 83,5 por cento para EN II (p = 0,13) e a taxa de sobrevida livre de doença em cinco anos foi de 85,2 por cento versus 87 por cento, respectivamente (p = 0,72). CONCLUSAO: Nesta população de pacientes uniformemente tratados a graduação histológica BNLI não esteve associada com o prognóstico do LH EN.

Histological classification of 1,025 cases of Hodgkin's lymphoma from the state of São Paulo, Brazil

CONTEXTO E OBJETIVO: Tem-se afirmado correntemente que, em países industrializados, a esclerose nodular é o tipo mais freqüente de linfoma de Hodgkin, ao contrário de países em desenvolvimento, onde a celularidade mista e a depleção linfocitária são mais freqüentes. O objetivo do estudo é rever os dados histológicos de linfoma de Hodgkin das cidades de São Paulo e Campinas. TIPO DE ESTUDO E LOCAL: Transversal, por análise histopatológica, em quatro hospitais universitários e um centro oncológico de referência. MÉTODOS: 1.025 casos com o diagnóstico de linfoma de Hodgkin entre 1990 e 2000 foram coletados de cinco instituições. Em 631 (61,5%) casos fora feito estudo imunoistoquímico para os marcadores CD20, CD3, CD15 e CD30. As freqüências relativas dos tipos histológicos (informadas pelos autores que são hematopatologistas de suas respectivas instituições) foram determinadas nos diversos grupos etários e por gênero. RESULTADOS: Os tipos de linfoma de Hodgkin foram assim distribuídos: predominância linfocitária 4,8%, esclerose nodular 69,2%, celularidade mista 21,1% e depleção linfocitária 4,6%. CONCLUSÕES: Dados controversos sobre a freqüência dos tipos de linfoma de Hodgkin em nosso meio parecem ser devidos ao pequeno número de casos dos trabalhos anteriores. Nossos dados são comparáveis aos dos países industrializados.

[ frequency of Epstein-Barr Virus [EBV] expression in various histological subtypes of Hodgkin's lymphoma]

The incidence of Hodgkin's Lymphoma [HL] shows marked heterogenecity according to age, gender, race, geographical state, socioeconomic position and histological subtypes. Recently, multiple studies in different countries have been applied by newer technologies such as Immunohistochemistry [IHC] and polymerase chain reaction [PCR], being more familiar with the pathogenesis of this neoplasm. The Epstein-Barr virus [EBV] is detected with high incidence in HL cases, approximately 40-50% in developed countries and much more [up to 95% of cases] in developing countries. There is evidences that mixed cellularity [MC] Hodgkin's Lymphoma is more likely to be EBV-associated which is against association of nodular sclerosis [NS] subtype. With regard to the geographical location of Iran and absence of similar documented research in our knowledge, it is needed to perform studies like this. This study was done by IHC method with antibody against latent membrane protein-1 [LMP-1] antigen of EBV for assessment of relationship between EBV infection and parameters such as age, gender and histological subtype. We collected 30 paraffin section samples of classic HL and positive cytoplasmic reactivity of Reed-Steinberg [RS] cells was evaluated. From 30 cases surveyed in this study only 2 cases were not immunoreactive for EBV marker of which both were NS subtype in two adult males. We confirm frequency of 93% EBV associated HL in our cases, and also confirm the above histological subtype distribution, and that childhood cases are more likely to be EBV-associated than adult cases. There is possible female predominance of EBV associated HL. This survey as a pilot study needs further studies with more cases for distinct confirmation. It seems that EBV is a strong etiologic factor especially in developing countries like Iran and in childhood cases

Envolvimento secundário pulmonar por linfomas e leucemias / Secondary lung involvement by lymphomas and leukemias

Estudamos o envolvimento secundário pulmonar por leucemias em estudo retrospectivo de 12 anos de autópsias. Descrevemos o padrão de infiltração pulmonar em 77 linfomas e 50 leucemias. Os linfomas apresentaram maior freqüência do padrão peribrônquico/ perivascular de infiltração. O padrão intersticial foi mais freqüente nas leucemias. Mais de um padrão de infiltração estavam presentes por paciente. Linfomas de Hodgkin apresentaram maior freqüência do padrão nodular em relação aos linfomas B e T. Linfomas T apresentaram maior freqüência de infiltração intersticial do que os linfomas B / We have studied the secondary lung involvement by lymphomas and leukemias in a retrospective 12-year autopsy study. We have described histological infiltration patterns in lymphomas and leukemias. Lymphomas showed peribronchial/perivascular infiltration pattern. Leukemias had more frequently interstitial pattern. More than one infiltration pattern was present per patient. Hodgkin lymphomas had increased frequency of nodular infiltration pattern than B or T cell lymphomas. T cell lymphomas had more frequent interstitial pattern than B cell lymphomas. Pleural and intrapulmonary lymphnode involvement was more frequent in lymphomas than in leukemias...

Enfermedad de Hodgkin en el hospital Dr. Gustavo Fricke: revisión de pacientes en el período 1988-1998 / Hodgkin disease at Dr. G. Fricke Hospital: patient review, 1988-1998

La enfermedad de Hodgkin (E.H.) se define como una neoplasia del tejido linfoide, manifestada por adenopatias. Presenta una incidencia de 3-3,2 casos/100000habs/año, con mayor frecuencia en hombres, raza blanca, nivel socioeconómico alto y reducido grupo familiar; sigue una curva de edad bimodal con dos pics marcados: adolescentes y mayores de 55 años. Se clasifica histologicamente en 4 tipos, que por frecuencia son: esclerosis nodular, celularidad mixta, predominio linfocitario y deplecion linfocitaria, que junto al estadio, determinan en forma importante el pronostico de la enfermedad. El objetivo de este trabajo esconocer las caracteristicas de los pacientes con E.H. diagnosticados en el Hospital G. Fricke de Viña en el período entre enero 1988 y diciembre 1998

Linfoma de Hodgkin, nova classificaqão da OMS (2000) / Hodgkin's lymphoma, the new classification of WHO (2000)

Recentemente, ocorreram avanços no conhecimento da biologia do linfoma de Hodgkin. A Organização Mundial de Saúde agora reconhece dois tipos de linfomas de Hodgkin, a nodular tipo predominância linfocitária, nos quais as células neoplásicas são CDZO positivas e os tipos clássicos, nos quais as células são comumente CD15 e CD30 positivas.

Recently, there have heen advances inunderstanding the biology of Hodgkin'slymphoma. The WHO now recognizes two types of Hodgkin's lymphoma, which are the nodular lymphocyte predominante type, where the neoplastics cells are CD20 positive, and the classical types, in which the diagnostic cells are usually positive to CD15 and CD30.

Linfoma de Hodgkin: estudo interdepartamental em São Paulo com areclassificação histológica de 1044 casos / Hodgkin´s lymphoma: interdepartmental study in Sao Paulo with the histologic reclassification of 1044 cases

Neste breve relato, cinco instituições brasileiras apresentam um estudoI Cristiano H. Lima Jr. de 1044 casos de pacientes com Linfoma de Hodgkin, sendo observado 2 como dado releuante apresença de uma curva unimodal de incidência Yara Menezes por idade nesta casuística.

In this brief report five Brazilian institutions present a study of 1044 Hodgbin's lymphoma patients. The aim was to study the presence of a unimodal curve of incidence in relation to age.

Pediatric solid cancer; a larkana experience

This prospective study was conducted to evaluate pattern and frequency of solid pediatric cancers of children in upper Sindh. Total number of cases was 214. Male to female ratio was 1.97:1 and mean age of patients was 8.7 years. Maximum number of patients were in 10-15 year age group [43.94%]. The five most frequent tumours were lymphoma [46.29%], soft tissue sarcoma [19.62%], retinoblastoma [11.68%], bone tumour [9.34%] and Wilm's tumour [7.0%]. CNS tumours were not represented in the study due to lack of neurosurgical facilities. Retinoblastoma and Wilm's tumour were more common in 0-4 year age group, whereas rest of the tumours were more frequent in 5-9 and 10-15 year age groups. Hodgkin's disease [62 cases] was more common than non-Hodgkin's lymphoma [37 cases], with higher male preponderance in the former [4.16:1] than in the latter [2.7:1]. Mixed cellularity was the largest subtype of HD [66.14%], whereas diffuse small cell [45.96%] dominated the NHL variants. We observed that HD was more common than NHL, and male to female ratio was higher in the former than in the latter in our study as compared to those reported from abroad. Further studies will confirm our findings

Doença de Hodgkin / Hodgkin's disease

Destacando a importância da doença de Hodgkin na infância, responsável por cerca de 10 porcento de todos os tumores malignos em Pediatria, o autor resume seu histórico, descreve o comportamento da célula neoplásica na doença, estuda o quadro clínico, diagnóstico, avaliaçäo inicial e estadiamento, a relaçäo do linfoma de Hodgkin com o vírus Epstein-Baar, sua classificaçäo, segundo a OMS, e as formas de tratamento, que incluem radio e quimioterapia, finalizando com um resumo das complicaçöes eventualmente encontradas

Tratamento da doença de Hodgkin / Treatment of Hodgkin's disease: un update

O autor discute os aspectos mais atuais da doença de Hodgkin, enfatizando especialmente a eficácia e a toxicidade de longo prazo de seus tratamentos quimioterápico, radioterático e combinado, definindo especificamente a melhor estratégia terapêutica para cada estadiamento

Estudo da função gonadal de pacientes com Doença de Hodgkin tratados com o esquema C-MOPP/ABV ou "Híbrido modificado"

Este trabalho propô-se a estudar a função gonadal de 21 pacientes adultos do sexo masculino, com idades entre 17 e 23 anos (18 1,99), sobreviventes de Doença de Hodgkin (grupo A), tratados com quimiotrapia na infância e adolescência, com seis ou mais ciclos do esquema C-MOPP/ABV ou "híbrido modificado" (ciclofosfamida, vincristina, prednisona, adriamicina, blenoxane, vimblastina). A média da idade no diagnóstico foi de 11,3 ± 4,01 anos, 14 eram impúberes e 7 já haviam iniciado a puberdade. O intervalo de tempo entre o início do tratamento e o estudo foi de 3 a 11 anos (7,42±2,82) e, todos se encontravam no estágio puberal V de Tanner quando foram avaliados, tendo a puberdade evoluido normalmente. Estabelecemos como grupo controle (grupo B) 20 indivíduos do sexo masculino com idades entre 18 e 25 anos (20,95±1,53). Avaliamos o volume testicular, os níveis basais de testosterona total (TT), índice de testosterona livre (ITL), SHBG, prolactina (PRL), FSH, LH, inibina B (IB), relações TT/LH, IB/FSH e resposta do FSH e do LH após estímulo com GnRH e espermograma. A média do volume testicular foi menor (p=0,001) nos pacientes (15,42±5,46ml) do que nos controles (21,0±3,47ml). Não encontramos diferença significativa na média dos níveis de TT, ITL, SHBG, PRL, IB, LH e relação TT/LH entre os grupos A e B. A mediana da relação IB/FSH foi menor (P=0,0002) nos pacientes 31,01 (3,8-267,9) do que nos controles 142,10 (47,6767,3). Os níveis de FSH e inibina B foram significativamente e inversamente relacionados (r=-0,50,p=0,02) nos pacientes do grupo A. Amediana dos níveis basais do FSH 5,4UI/ml (1,2-22,4 UI/ml) e a média do valor máximo do FSH (18,34±14,7 ui/mL) e do LH (30,99±20,88 UI/mL) após estímulo com GnRH do grupo A, foi maior do que a mediana dos níveis basais do FSH 1,5 UI/mL (0,3-35 UI/mL), média do valor máximo do FSH (5,58±1,98 UI/mL) e do LH (13,75±5,16 UI/mL) do grupo B, com significância de: p=0,0001;p=0,0002, respectivamente. Observamos azoospermia em 11, oligospermia em 4 e espermograma normal em 3 pacientes. Apenas 1 paciente recuperou a espermatogênese após 11 anos do tratamento. Concluimos que o esquema C-MOPP/ABV quando administrado em crianças e adolescentes causa dano ao epitélio germinativo e discreta disfunção das células de Leydig e de Sertoli, entretanto é necessário um tempo longo de acompanhamento para se observar possível recuperação da função gonadal.

The aim of this study was to asses the gonadal function in 21 adult (group A) male patients, with Hodgkins’disease, who had received combination chemotherapy consisting of C-MOPP/ABV hybrid program (cyclophosphamide, vincristine, procarbazine, doxorubicin, bleomycin, vinblastine). Twenty healthy young men were the control group (group B). The age of the patients at the time of the study was 18,7±1,99 years, and at the time of chemotherapy was 1l, 33±4,01 years. At that time 14 patients were prepubertal and 7 were pubertal and at the time of the study all were Tanner V. The mean interval from the treatment until the study was 7,42±2,82 years. Puberty had progressed normally in all patients. We evaluated testicular size, total testosterone (TT), SHBG, free androgen index (F AI), prolactin (PRL), FSH, LH, Inhibin B (IB) levels, testosterone/LH (TILH), Inhibin B/FSH (IB/FSH) ratio, FSH and LH after GnRH test and sperm counts. The mean testicular volume was 15,42±5,46 ml and 21,0±3,47 ml for patients and controls (p= 0,001) respectively. We found no significant differences in TT, F AI, SHBG, PRL, IB, LH and TT/LH ratio between patients and controls. The median IB/FSH ratio in the patients was lower (p=0,0002) than in the controls (31,01 vs 142,10). FSH levels and inhibin B were significantly and inversely correlated (r= -0,50; p=0,02). We detected an appreciable difference in peak FSH levels (p=0,002) and in peak LH levels (p= 0,0002). The results of semen analyses were: 11 patients had azoospermIa, 4 oligospermia and 3 patients had a normal semem analysis. Only one patient had recovered fertility, with normalization of sperm count 11 years following treatment. These results suggest that C-MOPP/ABV hybrid program causes damage to the germinal ephithelium even when given during prepubertal and adolescent age. Cytotoxic chemotherapy-induced testicular damage is associated with subtle Sertoli and Leydig cells dysfunction, and long-term follow up is necessary to ascertain if gonadal function will recover.