How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation

ABSTRACT: The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

How to manage lymphoid malignancies during novel 2019 coronavirus (CoVid-19) outbreak: a Brazilian task force recommendation.

The novel Coronavirus (CoVid-19) outbreak is now consider a world pandemic, affecting more than 1,300,000 people worldwide. Cancer patients are in risk for severe disease, including a higher risk of intensive care unit (ICU) admission, need for invasive ventilation or death. Management of patients with lymphoid malignancies can be challenging during the outbreak, due to need of multiple hospital visits and admissions, immunosuppression and need for chemotherapy, radiotherapy and stem cell transplantation. In this article, we will focus on the practical management of patients with lymphoid malignancies during the COVID-19 pandemic, focusing on minimizing the risk for patients.

AUGMENT: A Phase III Study of Lenalidomide Plus Rituximab Versus Placebo Plus Rituximab in Relapsed or Refractory Indolent Lymphoma.

PURPOSE: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab. METHODS: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review. RESULTS: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively. CONCLUSION: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

Prespecified candidate biomarkers identify follicular lymphoma patients who achieved longer progression-free survival with bortezomib-rituximab versus rituximab.

PURPOSE: Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study. EXPERIMENTAL DESIGN: A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. RESULTS: In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. CONCLUSIONS: Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.

Psychometric properties of the multidimensional fatigue inventory in Brazilian Hodgkin's lymphoma survivors.

CONTEXT: Fatigue is the most common symptom among Hodgkin's lymphoma survivors. OBJECTIVES: To evaluate the psychometric properties of the Brazilian version of the Multidimensional Fatigue Inventory (MFI). METHODS: The MFI was translated into Brazilian Portuguese using established forward-backward translation procedures, and the psychometric properties were evaluated in a sample of 200 Hodgkin's lymphoma survivors. The psychometric properties evaluated included internal consistency and construct validity. The MFI was administered along with the informed consent form. RESULTS: The overall Cronbach's alpha coefficient for the 20 items was 0.84, ranging from 0.59 to 0.81 for each of the five scales. Correlations between items and scales ranged from 0.32 to 0.72. The factor analysis yielded a five-factor solution that explained 65% of the variance. The first factor merged the original "general fatigue" and "physical fatigue" scales, as has been previously reported. The second factor identified the original "mental fatigue" scale and the fifth factor identified the original "reduced activity" scale. Questions from the original "reduced motivation" scale were represented in both factors three and four. CONCLUSION: The Brazilian version of the MFI showed satisfactory psychometric properties and can be considered a valid research tool for assessing cancer-related fatigue.

Validation of the Brazilian Portuguese version of the Medical Outcomes Study-Social Support Survey in Hodgkin's lymphoma survivors.

PURPOSE: The aim of this study was to assess the psychometric properties of the Brazilian Portuguese version of the "Medical Outcomes Study-Social Support Survey (MOS-SSS)" in Hodgkin's lymphoma (HL) survivors. METHODS: The MOS-SSS is a 19-item questionnaire with five scales covering different aspects of social support (affection, positive social interaction, emotional, informational, and material). A sample of 200 HL survivors completed a self-administered questionnaire at the treatment center or at home. RESULTS: The median age of the patients at diagnosis was 29 years (16­77), and the median follow-up since diagnosis was 7 years (3.6-12.7). Item-corrected Pearson correlation coefficients between items and their dimensions varied from 0.57 to 0.76. Internal consistency, evaluated using Cronbach's alpha, was 0.95 for the overall scale, ranging from 0.78 to 0.87 for the five subscales proposed by the original instrument. An exploratory factor analysis yielded a three-factor solution, aggregating affection and positive social interaction, and emotional and informational dimensions of social support. Higher socioeconomic status and higher social network were associated with higher levels of all kinds of support. CONCLUSION: Results show good general psychometric properties of the Brazilian version of the MOS-SSS when applied to HL survivors. The three-factor structure identified in this study is in line with a previous validation among Brazilian healthy civil servants. The Brazilian Portuguese version will now be used to evaluate social support and its association with long-term disease outcomes and quality of life of Hodgkin's lymphoma survivors.

Caracterização clínica e avaliação de sobrevida de uma coorte de pacientes com linfoma folicular diagnosticados eacompanhados no Instituto Nacional de Câncer / [Clinical characterization and survival assessment of a cohort of patients with follicular lymphoma diagnosed and followed up at the National Cancer Institute]

O linfoma folicular (LF) representa 25,0-30,0% dos linfomas em adultos, como neoplasia maligna de evolução indolente, sobrevida longa, resposta inicial ao tratamento seguida de recidivas. O evento crucial na história natural do LF é a transformação histológica para doença mais agressiva, associada a altas taxas de morbidade e mortalidade. O objetivo principal deste estudo foi descrever as características clínicas e avaliar o desfecho de pacientes portadores de LF diagnosticados, tratados e acompanhados no INCA entre 1996 a 2008. Foram analisados e validados três índices prognósticos internacionais conhecidos (IPI, ILI, FLIPI) na definição de grupos de riscos nesta série de pacientes, bem como testadas 2 simulações exploratórias (nomeadas ILI-B e FLIPI-B). Foram analisadas as informações clínicas retrospectivas, compiladas na base de dados dataLINFO de 136 pacientes com diagnóstico confirmado de LF (53,6% grau I, 32,4% grau II e 14,0% grau III). Na coorte estudada a maioria dos pacientes se apresentou com doença avançada ao diagnóstico (73,5%) porém assintomáticos (83,5% com PS<2). Durante o tempo de acompanhamento (6,5 anos) a transformação para linfoma de alto grau foi observada em 15 pacientes (11,0%)...

Follicular lymphoma (FL) represents 25,0-30,0% of lymphomas in adults, as an indolent malignancy, long survival, initial treatment response followed by relapse. The crucial event in the natural history of the LF is the histologic transformation to a more aggressive disease, associated with high morbidity and mortality. The main objective of this study was to describe and evaluate the clinical outcome of patients with LF diagnosed, treated and followed INCA in the period between 1996 to 2008. We reanalyzed and validated three known international prognostic (IPI, ILI, FLIPI) in the definition of risk groups in this series of patients, and tested two exploratory simulations (named ILI and FLIPI-B-B). We analyzed retrospective clinical information, compiled in the database dataLINFO of 136 patients with confirmed diagnosis of LF (53.6% grade I, 32.4% grade II and 14,0% grade III). In our cohort the majority of patients presented with advanced disease at diagnosis (73.5%) to asymptomatic (83.5% with PS <2). During the follow-up (6.5 years) the transformation to high grade lymphoma was observed in 15 patients (11,0%)...

Bortezomib plus rituximab versus rituximab alone in patients with relapsed, rituximab-naive or rituximab-sensitive, follicular lymphoma: a randomised phase 3 trial.

BACKGROUND: Bortezomib and rituximab have shown additive activity in preclinical models of lymphoma, and have been shown to be active and generally well tolerated in a randomised phase 2 study in patients with follicular and marginal zone lymphoma. We compared the efficacy and safety of rituximab alone or combined with bortezomib in patients with relapsed or refractory follicular lymphoma in a phase 3 setting. METHODS: In this multicentre phase 3 trial, rituximab-naive or rituximab-sensitive patients aged 18 years or older with relapsed grade 1 or 2 follicular lymphoma were randomly assigned (1:1) to receive five 35-day cycles consisting of intravenous infusions of rituximab 375 mg/m(2) on days 1, 8, 15, and 22 of cycle 1, and on day 1 of cycles 2-5, either alone or with bortezomib 1·6 mg/m(2), administered by intravenous injection on days 1, 8, 15, and 22 of all cycles. Randomisation was stratified by FLIPI score, previous use of rituximab, time since last therapy, and region. Treatment assignment was based on a computer-generated randomisation schedule prepared by the sponsor. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival analysed by intention to treat. This trial has been completed and is registered with ClinicalTrials.gov, number NCT00312845. FINDINGS: Between April 10, 2006, and Aug 12, 2008, 676 patients were randomised to receive rituximab (n=340) or bortezomib plus rituximab (n=336). After a median follow-up of 33·9 months (IQR 26·4-39·7), median progression-free survival was 11·0 months (95% CI 9·1-12·0) in the rituximab group and 12·8 months (11·5-15·0) in the bortezomib plus rituximab group (hazard ratio 0·82, 95% CI 0·68-0·99; p=0·039). The magnitude of clinical benefit was not as large as the anticipated prespecified improvement of 33% in progression-free survival. Patients in both groups received a median of five treatment cycles (range 1-5); 245 of 339 (72%) and 237 of 334 (71%) patients in the rituximab and bortezomib plus rituximab groups, respectively, completed five cycles. Of patients who did not complete five cycles, most discontinued early because of disease progression (77 [23%] patients in the rituximab group, and 56 [17%] patients in the bortezomib plus rituximab group). Rates of adverse events of grade 3 or higher (70 [21%] of 339 rituximab-treated patients vs 152 [46%] of 334 bortezomib plus rituximab treated patients), and serious adverse events (37 [11%] patients vs 59 [18%] patients) were lower in the rituximab group than in the combination group. The most common adverse events of grade 3 or higher were neutropenia (15 [4%] patients in the rituximab group and 37 [11%] patients in the bortezomib plus rituximab group), infection (15 [4%] patients and 36 [11%] patients, respectively), diarrhoea (no patients and 25 [7%] patients, respectively), herpes zoster (one [<1%] patient and 12 [4%] patients, respectively), nausea or vomiting (two [<1%] patients and 10 [3%] patients, respectively) and thrombocytopenia (two [<1%] patients and 10 [3%] patients, respectively). No individual serious adverse event was reported by more than three patients in the rituximab group; in the bortezomib plus rituximab group, only pneumonia (seven patients [2%]) and pyrexia (six patients [2%]) were reported in more than five patients. In the bortezomib plus rituximab group 57 (17%) of 334 patients had peripheral neuropathy (including sensory, motor, and sensorimotor neuropathy), including nine (3%) with grade 3 or higher, compared with three (1%) of 339 patients in the rituximab group (no events of grade ≥3). No patients in the rituximab group but three (1%) patients in the bortezomib plus rituximab group died of adverse events considered at least possibly related to treatment. INTERPRETATION: Although a regimen of bortezomib plus rituximab is feasible, the improvement in progression-free survival provided by this regimen versus rituximab alone was not as great as expected. The regimen might represent a useful addition to the armamentarium, particularly for some subgroups of patients. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Millennium Pharmaceuticals, Inc.

Cell cycle characteristics and Epstein-Barr virus are differentially associated with aggressive and non-aggressive subsets of Hodgkin lymphoma in pediatric patients.

We investigated the correlation of tumor characteristics with clinico-biological markers of aggressive disease, evaluated by Ann Arbor stage, risk group, B-symptoms, number of involved anatomic areas, mediastinal mass, nodular sclerosis (NS) grade, and risk, in pediatric Hodgkin lymphoma (HL). Leukopenia and extranodal disease influenced event-free survival (p = 0.032 and p = 0.041). In multivariate analysis, extranodal disease was associated with high number of tumor-infiltrating eosinophils (p = 0.035) and Ki67 < 50% (p = 0.024); B-symptoms with Ki67 > or =75% (p = 0.027) and high LDH levels (p = 0.001); and mediastinal mass with leukopenia (p = 0.048), NS grade II (p = 0.025), and high-risk (p = 0.046). Furthermore, low stages correlated with Ki67 > or =50% (p = 0.005) and Epstein-Barr virus (EBV) (p = 0.065). Low-risk NS was associated with EBV (p = 0.014). Hierarchical cluster analysis identified two clusters, one composed of high-risk patients and cell cycle and apoptosis features, and the other including low-risk patients, EBV, and low-risk NS. Our results show the association of biological markers with disease aggressiveness in pediatric HL.

Advanced Hodgkin's lymphoma: results in 216 patients treated with ABVD in Brazil / Linfoma de Hodgkin em estádio avançado: resultados do tratamento em 216 pacientes tratados com ABVD no Brasil

The outcome of Hodgkin's lymphoma (HL) has markedly improved over the last few decades, placing HL among the human cancers with highest cure rates. However, data about treatment outcomes in developing countries are scarce. From 1996 to 2005, 370 consecutive patients with HL treated in three public institutions in Rio de Janeiro were identified. A total of 216 patients who presented with advanced stage (IIB-IV) HL were selected for the present analysis. Patients with advanced disease were treated with ABVD, complemented or not by radiation therapy. The median follow-up time of survivors was 6.3 years (1-11.8). Fifteen patients died during first-line treatment. The complete remission rate was 80 percent. The 5-year progression-free survival (PFS) and the 5-year overall survival (OS) probabilities were 69 percent and 83 percent, respectively. The 5-year PFS in low-risk and high-risk patients were 81 percent and 62 percent (p=0.003), respectively. The 5-year OS in low-risk and high-risk International Prognostic Score patients were 89 percent and 78 percent (p=0.02), respectively. The present study provides a representative estimate of current treatment results for advanced HL in public institutions in an urban area in Brazil. It is clear that full treatment can be given to most patients, although those with very low socio-economic status might require special attention and support. Since Brazil is a large country, with substantial interregional heterogeneity, a nationwide registry of HL patients is currently being implemented.

Os resultados do tratamento do linfoma de Hodgkin (LH) melhoraram substancialmente ao longo das últimas décadas e tornaram o LH uma das neoplasias humanas com maior chance de cura. Entretanto, os dados sobre tratamento em países em desenvolvimento são escassos. Entre 1996 e 2005, 370 pacientes consecutivos com LH tratados em três instituições públicas no Rio de Janeiro foram identificados. Destes, 216 em estádio avançado (IIB-IV) foram selecionados para esta análise. Os pacientes foram tratados com o protocolo ABVD (doxorrubicina, bleomicina, vinblastina e dacarbazina). A mediana do tempo de seguimento dos sobreviventes foi de 6,3 anos (1-11,8). Quinze pacientes morreram durante o tratamento de primeira linha. A probabilidade de sobrevida livre de progressão (SLP) em cinco anos e a probabilidade de sobrevida global (SG) em cinco anos foram de 69 por cento e 83 por cento, respectivamente. A SLP nos grupos de baixo risco e de alto risco, de acordo com o "International Prognostic Score", foi de 81 por cento e 62 por cento (p=0,003), respectivamente. A SG em cinco anos nos grupos de baixo risco e de alto risco foi de 89 por cento e 78 por cento (p=0,02), respectivamente. O presente estudo apresenta uma estimativa representativa dos resultados atuais do tratamento do LH avançado em instituições públicas no Brasil. Fica claro que o tratamento completo pode ser oferecido à grande maioria dos pacientes, embora aqueles com baixo status socioeconômico possam exigir atenção especial. Em vista das dimensões continentais do Brasil, com substancial heterogeneidade interregional, um registro nacional de pacientes com LH está sendo implementado.

Human germinal center-associated lymphoma protein expression is associated with improved failure-free survival in Brazilian patients with classical Hodgkin lymphoma.

The human germinal center-associated lymphoma (HGAL) gene has prognostic value in diffuse large B-cell lymphoma, and expression of its cognate protein is germinal center-specific. A previous study had suggested that HGAL protein expression might also be related to the outcome in patients with Hodgkin lymphoma (HL). The aim of this study was to confirm the prognostic impact of HGAL protein expression in an independent, well-characterized cohort of 232 patients with classic HL treated uniformly with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Tissue microarray analysis showed HGAL staining in 188 specimens (81%). Failure-free survival (FFS) was superior in patients with early-stage disease, low-risk IPS, and HGAL-positive patients. The estimated 5-year FFS for HGAL-positive and HGAL-negative patients was 82% and 67%, respectively (p = 0.03). In the multivariate analysis, advanced stage and absence of HGAL staining were independent predictors of a worse FFS. This study confirms and validates recent findings of a correlation between HGAL expression and outcome in classical HL.

Evaluation of intra- and interobserver agreement and its clinical significance for scoring bcl-2 immunohistochemical expression in diffuse large B-cell lymphoma.

Immunohistochemistry (IHC) has become an essential part of diagnosis and clinical research in lymphomas. There is considerable heterogeneity, however, in IHC findings regarding expression rate and positivity cut-offs, which creates a degree of uncertainty that has prevented its incorporation for prognostic purposes. The purpose of the present study was to assess intra- and interobserver agreement in scoring bcl-2 expression on IHC. The study materials were 81 diffuse large B-cell lymphomas. Slides were processed in the same laboratory, and were analyzed independently and in a blinded manner by four pathologists twice, at least 1 month apart. The positivity rates ranged from 31% to 41% in the first evaluation, and from 30% to 43% in the second evaluation. The two analyses by the same pathologist gave concordant results in 88-93% of cases (kappa = 0.71-0.83). Complete agreement among all observers varied from 72% to 79%. The experience of the observer did not influence intra-observer concordance. Cooperative analysis of discordant slides led to consensus in all cases. The variation observed in scoring bcl-2 expression is acceptable for use in lymphoma diagnosis and classification. The use of IHC stratification, however, for clinical decisions regarding treatment will require standardization and centralized consensus review, and must await the results of ongoing prospective trials.

Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study.

BACKGROUND: The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. METHODS: Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. FINDINGS: Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037). INTERPRETATION: Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.

PKC-beta II expression has prognostic impact in nodal diffuse large B-cell lymphoma.

Recent studies of gene expression and immunohistochemistry have shown that protein kinase C-beta II (PKC-beta II) might have prognostic significance in patients with diffuse large B-cell lymphoma (DLBCL). We sought to determine the prognostic significance of the expression of PKC-beta II in patients with nodal DLBCL. Formalin-fixed, paraffin-embedded tissues were stained with a monoclonal antibody to PKC-beta II protein. A total of 125 patients were studied; 83 patients (66%) were in the low-risk International Prognostic Index (IPI) group. Forty-eight patients (38%) were positive for PKC-beta II. Complete remission was obtained in 70%, and was not influenced by the PKC-beta II status (67 vs 71%). The 5-year event-free survival (EFS) was worse in high-risk patients (14 vs 58%, P<0.001) and in those with PKC-beta II positivity (36 vs 49%, P=0.054). In low-risk IPI patients, PKC-beta II expression was related to a worse 5-year overall survival (OS) (60 vs 76%, P=0.033) and a worse 5-year EFS (48 vs 66%, P=0.014). In a Cox regression analysis for EFS, both PKC-beta II expression (hazard ratio=1.68, P=0.037) and the IPI (HR=3.07, P<0.001) were independent poor prognostic factors. PKC-beta II (HR=1.72, P=0.046) and the IPI (HR=5.16, P<0.001) were also independent poor prognostic factors for the OS. PKC-beta II expression, along with the IPI, were associated with a worse EFS and OS in patients with nodal DLBCL specially in low-risk IPI patients.

Socioeconomic inequality and short-term outcome in Hodgkin's lymphoma.

Socioeconomic status (SES) is a determinant of outcome in various types of cancer. The aim of this study is to analyze the impact of the SES in Hodgkin's lymphoma (HL). From 2001 to 2005, 194 consecutive patients were prospectively followed in 5 institutions. Patients answered a questionnaire with a set of items used to determine the SES, and were then divided in 2 groups according to their SES score. There were 151 patients (78%) with a higher SES and 43 patients (22%) with a lower SES. The complete remission (CR) rate was 82%. Patients with a higher SES had a higher CR rate than those with a lower SES (85 vs. 72%, crude odds ratio = 2.27, p = 0.046). A lower SES and the performance status >1 were independently associated with a trend towards a lower CR, even when controlled for the other covariables of interest. Ten patients (5%) died during treatment. Death during treatment was associated with a lower SES (16 vs. 2%, p = 0.001), a performance status >1 (p < 0.0001), a lower lymphocyte count (p = 0.012) and weakly with a lower albumin level (p = 0.065). With a median follow-up of 1.7 years, a higher SES was associated with a better 2-year overall survival (93 vs. 79%, p = 0.01). In underprivileged countries, patients with a lower SES require a more careful monitoring during treatment, possibly with specific support measures. Regimens more intense than doxorubicin, bleomycin, vinblastine and dacarbazine could pose a prohibitive risk of complications in this group of patients. (c) 2006 Wiley-Liss, Inc.

Detection of free circulating Epstein-Barr virus DNA in plasma of patients with Hodgkin's disease.

CONTEXT AND OBJECTIVE: Free circulating Epstein-Barr virus (EBV) DNA is often present in the plasma of Hodgkins disease patients. The aim here was to evaluate the prevalence of this finding, its correlation with the immunohistochemical expression of LMP-1 (latent membrane protein 1) and the influence of other clinical factors. DESIGN AND SETTING: Prospective study in two public tertiary institutions: Hematology Service, Universidade Federal do Rio de Janeiro, and Oncology Service, Instituto Nacional do Câncer, Rio de Janeiro. METHODS: A cohort of 30 patients with newly diagnosed Hodgkins disease was studied. The control group consisted of 13 healthy adult volunteers. EBV DNA was determined by conventional polymerase chain reaction (PCR). RESULTS: The median age was 28 years, and 16 patients were women. Advanced disease was present in 19 patients, and six were HIV-positive. EBV DNA was present in the plasma of 13 patients and one control (43% versus 8%, p = 0.03). EBV DNA prevalence was higher in HIV-positive patients (100% versus 29%, p = 0.0007) and those with advanced disease (63% versus 9%, p = 0.006). Among HIV-negative patients alone, EBV DNA prevalence remained higher in those with advanced disease. EBV DNA was found in 10/11 patients with LMP-1 expression in the lymph nodes, and in 3/19 without LMP-1 expression (kappa coefficient = 0.72). CONCLUSION: EBV DNA was present in 91% of patients with EBV-associated Hodgkins disease, and in all patients with HIV-associated Hodgkins disease. EBV DNA prevalence was higher in patients with advanced disease, irrespective of HIV status.

Detection of free circulating Epstein-Barr virus DNA in plasma of patients with HodgkinÆs disease / Detecção do DNA livre circulante do vírus Epstein-Barr no plasma de pacientes com doença de Hodgkin

CONTEXT AND OBJECTIVE: Free circulating Epstein-Barr virus (EBV) DNA is often present in the plasma of HodgkinÆs disease patients. The aim here was to evaluate the prevalence of this finding, its correlation with the immunohistochemical expression of LMP-1 (latent membrane protein 1) and the influence of other clinical factors. DESIGN AND SETTING: Prospective study in two public tertiary institutions: Hematology Service, Universidade Federal do Rio de Janeiro, and Oncology Service, Instituto Nacional do Câncer, Rio de Janeiro. METHODS: A cohort of 30 patients with newly diagnosed HodgkinÆs disease was studied. The control group consisted of 13 healthy adult volunteers. EBV DNA was determined by conventional polymerase chain reaction (PCR). RESULTS: The median age was 28 years, and 16 patients were women. Advanced disease was present in 19 patients, and six were HIV-positive. EBV DNA was present in the plasma of 13 patients and one control (43 percent versus 8 percent, p = 0.03). EBV DNA prevalence was higher in HIV-positive patients (100 percent versus 29 percent, p = 0.0007) and those with advanced disease (63 percent versus 9 percent, p = 0.006). Among HIV-negative patients alone, EBV DNA prevalence remained higher in those with advanced disease. EBV DNA was found in 10/11 patients with LMP-1 expression in the lymph nodes, and in 3/19 without LMP-1 expression (kappa coefficient = 0.72). CONCLUSION: EBV DNA was present in 91 percent of patients with EBV-associated HodgkinÆs disease, and in all patients with HIV-associated HodgkinÆs disease. EBV DNA prevalence was higher in patients with advanced disease, irrespective of HIV status.

CONTEXTO E OBJETIVO: O DNA do vírus Epstein-Barr (EBV) está freqüentemente presente no sangue periférico de pacientes com doença de Hodgkin. O objetivo deste estudo foi avaliar a prevalência deste achado, e correlacioná-lo com a expressão imunoistoquímica da LMP-1 (latent membrane protein 1) e a presença de outros fatores clínicos. TIPO DE ESTUDO E LOCAL: Estudo prospectivo realizado no Serviço de Hematologia da Universidade Federal do Rio de Janeiro e no Serviço de Oncologia do Instituto Nacional do Câncer, Rio de Janeiro, Brasil. MÉTODOS: Trinta pacientes com doença de Hodgkin recém-diagnosticada foram estudados, assim como um grupo controle composto por 13 indivíduos saudáveis. O DNA do EBV no plasma foi determinado pela reação em cadeia da polimerase (PCR) convencional. RESULTADOS: A idade mediana foi 28 anos e 16 pacientes eram do sexo feminino. A doença disseminada esteve presente em 19 pacientes e seis eram HIV+. O DNA do EBV foi detectado no plasma de 13 pacientes e um controle (43 por cento versus 8 por cento, p = 0,03). A prevalência do DNA do EBV foi maior nos pacientes HIV+ (100 por cento versus 29 por cento, p = 0,0007) e naqueles com doença disseminada (63 por cento versus 9 por cento, p = 0,006). Quando somente os pacientes HIV-negativos foram analisados, a prevalência do DNA do EBV permaneceu maior nos pacientes com doença disseminada. A prevalência do DNA do EBV variou de acordo com o subtipo histológico: foi de 32 por cento nos pacientes com esclerose nodular e de 100 por cento nos pacientes com celularidade mista e depleção linfocítica (p = 0,02). O DNA do EBV foi encontrado em 10/11 pacientes com a expressão da LMP-1 em linfonodos, e em 3/19 pacientes sem a expressão da LMP-1 (coeficiente de kappa = 0,72). CONCLUSÕES: O DNA circulante do EBV foi detectado no plasma de 91 por cento dos pacientes com doença de Hodgkin associada ao EBV, e em todos os pacientes com doença de Hodgkin associada ao HIV. A prevalência do DNA circulante do EBV foi detectado no plasma de 91% dos pacientes com doença de Hodgkin associada ao EBV, e em todos os pacientes com doença de Hodgkin associada ao HIV. A prevalência do DNA circulante do EBV foi maior nos pacientes com doença avançada, independentemente do status para o HIV.

CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group.

BACKGROUND: The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients. METHODS: 824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116. FINDINGS: After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events. INTERPRETATION: Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.