Pembrolizumab in relapsed or refractory primary mediastinal large B-cell lymphoma: final analysis of KEYNOTE-170.

Previous analyses of the phase 2 KEYNOTE-170 (NCT02576990) study demonstrated effective antitumor activity and acceptable safety of pembrolizumab 200 mg given every 3 weeks for up to 35 cycles (∼2 years) in patients with relapsed/refractory (R/R) primary mediastinal B-cell lymphoma (PMBCL) whose disease progressed after or who were ineligible for autologous stem cell transplantation. The end points included objective response rate (ORR), progression-free survival (PFS), and duration of response (DOR) according to the investigator per 2007 Response Criteria; overall survival (OS); and safety. In this final analysis, median duration of follow-up was 48.7 months (range, 41.2-56.2). The ORR was 41.5% (complete response, 20.8%; partial response, 20.8%). The median DOR was not reached; no patients who achieved a complete response progressed at the data cutoff. The median PFS was 4.3 months; the 4-year PFS rate was 33.0%. The median OS was 22.3 months; the 4-year OS rate was 45.3%. At the data cutoff, 30 patients (56.6%) had any-grade treatment-related adverse events (AEs); the most common were neutropenia, asthenia, and hypothyroidism. Grade 3/4 treatment-related AEs occurred in 22.6% of the patients; no grade 5 AEs occurred. After 4 years of follow-up, pembrolizumab continued to provide durable responses, with promising trends for long-term survival and acceptable safety in R/R PMBCL.

Quality-of-life analysis of pembrolizumab vs brentuximab vedotin for relapsed/refractory classical Hodgkin lymphoma.

KEYNOTE-204 (NCT02684292) demonstrated a progression-free survival advantage for pembrolizumab over brentuximab vedotin (BV) in patients who had relapsed or refractory classical Hodgkin lymphoma (R/R cHL) following, or who were ineligible for, autologous stem cell transplantation (ASCT). Health-related quality of life (HRQoL), measured by patient-reported outcomes (PROs) from KEYNOTE-204, are reported from patients who received ≥1 dose of study treatment and completed ≥1 PRO assessment. The EORTC QoL Questionnaire Core 30 (QLQ-C30) and EuroQoL EQ-5D were administered at baseline, every 6 weeks until week 24, and every 12 weeks thereafter. Prespecified end points included least squares mean (LSM) changes from baseline to week 24 and time to true deterioration (TTD; ≥10-point decline from baseline). Comparisons were evaluated using 2-sided P values uncontrolled for multiplicity. High compliance at baseline (>90%) and through week 24 (>80%) was demonstrated across treatment groups (PRO analysis set: pembrolizumab, n = 146; BV, n = 150). The EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) score improved from baseline to week 24 on pembrolizumab and worsened on BV and demonstrated significant LSM differences at 24 weeks (GHS/QoL: 8.60 [95% confidence interval, 3.89-13.31]; P = .0004). Significant improvements were observed in each QLQ-C30 domain except emotional and cognitive functioning. Compared with BV, pembrolizumab prolonged TTD for GHS/QoL (hazard ratio, 0.40 [95% CI, 0.22-0.74]; P = .003) and each QLQ-C30 domain except cognitive functioning. In conclusion, pembrolizumab demonstrated overall improvements in PROs of HRQoL measures over BV in the KEYNOTE-204 study. These data and previously reported efficacy results support pembrolizumab as the preferred treatment option for patients with R/R cHL who are ineligible for or experience relapse after ASCT.

BCL-2 Inhibition as Treatment for Chronic Lymphocytic Leukemia.

OPINION STATEMENT: At the end of the 1990s, with the advent of imatinib for chronic myeloid leukemia and rituximab for B cell lymphoproliferative diseases with CD20 expression, there was a great conceptual evolution in the treatment of onco-hematological diseases. Researchers from around the world and the pharmaceutical industry began to focus their efforts on the so-called target therapy used alone or associated with classic chemotherapeutic drugs. In chronic lymphocytic leukemia, the development of second-generation anti-CD20 antibodies, biosimilars, PI3K (phosphatidylinositol 3-kinases) inhibitors, BTK (Bruton's tyrosine kinase) inhibitors, and anti-bcl 2 drugs represented mainly by venetoclax brought new, broader, and more effective opportunities in the treatment of this disease. This breakthrough occurred mainly regarding patients with alteration in 17p or mutation of the p53 gene for whom selecting the new drugs that act on B cell signaling (BTK and PI3K inhibitors) in the first line is mandatory. In fit patients with immunoglobulin heavy chain mutation, it is still acceptable to use the chemotherapy regimen with fludarabine, cyclophosphamide, and rituximab (FCR) and, in those who do not fit or are not IgVH-mutated, bendamustine-rituximab regimen. However, the first-line use of ibrutinib or venetoclax associated with immunotherapy within the concepts of infinite (ibrutinib) or finite (venetoclax) treatment has been increasingly used. In the second line, venetoclax, ibrutinib, and idelalisib have become the preferred treatments. I believe that a process of instruction and decision shared with patients considering the risks-benefits-cost and access to treatments should guide the choices within these concepts. Another fundamental aspect to discuss is the objective of the treatment for chronic lymphocytic leukemia (CLL) for a specific patient: the increase progression-free survival and overall survival and/or the achievement of minimal residual disease. CLL is the most common leukemia in adults with a median age at diagnosis of 72 years. The clinical course is heterogeneous, and outcomes are influenced by individual clinical presentation and disease biology. Molecular and genomic factors, including fluorescence in situ hybridization (FISH) testing, karyotype, and immunoglobulin heavy chain variable region gene (IGHV) mutational status, are important to treatment decisions and to predict the clinical course. However, despite disease biology, the presence of active disease is the most important criteria to initiate treatment. In the past decade, target therapies that inhibit B cell receptor signaling pathways and, more recently, BCL2 antagonists have emerged as a new treatment paradigm: chemo-free with fixed duration therapy. Bruton's tyrosine kinase inhibitors (BTK) are a class of oral medications approved for frontline and relapsed disease, effective for achieving lasting response and disease control with a good safety profile. BTK inhibitors are an attractive option for high-risk patients who are not candidates for an intensive regimen. However, it is a continuous therapy, and drug resistance or severe adverse events could lead to treatment suspension. BCL2 antagonists are an attractive alternative to BTK inhibitors. Anti-apoptotic BCL2 is associated with tumor genesis and chemotherapy resistance. The BCl2, an anti-apoptotic protein located in the mitochondrial membrane, is a major contributor to the pathogenesis of lymphoid malignancies and is overexpressed in CLL cells promoting clonal cell survival. Venetoclax is a potent and selective member of the BH3 mimetic drugs and a physiologic antagonist of BCL2. Venetoclax has demonstrated quick and durable responses in naïve and relapsed or refractory CLL (r/r CLL) patients, including high-risk patients. Furthermore, it has shown deeper responses, achieving a higher incidence of negative minimal residual disease (MRD) with a fixed duration therapy. In the past decade, there was a remarkable progress in CLL treatment. However, neither of the new target therapies is considered curative or free of toxicity. This article will focus on the treatment approach of CLL patients with BCl2 antagonists. Treatment strategy (combined versus monotherapy; continuous versus limited duration therapy), toxicity profile, and future directions will be exposed in this review.

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.

Assessment of the Efficacy of Therapies Following Venetoclax Discontinuation in CLL Reveals BTK Inhibition as an Effective Strategy.

PURPOSE: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. EXPERIMENTAL DESIGN: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. RESULTS: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. CONCLUSIONS: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies.See related commentary by Rogers, p. 3501.

Pembrolizumab in Relapsed or Refractory Primary Mediastinal Large B-Cell Lymphoma.

PURPOSE: Patients with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) have a poor prognosis, and their treatment represents an urgent and unmet need. Because PMBCL is associated with genetic aberrations at 9p24 and overexpression of programmed cell death-1 (PD-1) ligands (PD-L1), it is hypothesized to be susceptible to PD-1 blockade. METHODS: In the phase IB KEYNOTE-013 (ClinicalTrials.gov identifier: NCT01953692) and phase II KEYNOTE-170 (ClinicalTrials.gov identifier: NCT02576990) studies, adults with rrPMBCL received pembrolizumab for up to 2 years or until disease progression or unacceptable toxicity. The primary end points were safety and objective response rate in KEYNOTE-013 and objective response rate in KEYNOTE-170. Secondary end points included duration of response, progression-free survival, overall survival, and safety. Exploratory end points included association between biomarkers and pembrolizumab activity. RESULTS: The objective response rate was 48% (7 complete responses; 33%) among 21 patients in KEYNOTE-013 and 45% (7 complete responses; 13%) among 53 patients in KEYNOTE-170. After a median follow-up time of 29.1 months in KEYNOTE-013 and 12.5 months in KEYNOTE-170, the median duration of response was not reached in either study. No patient with complete response experienced progression, including 2 patients with complete response for at least 1 year off therapy. Treatment-related adverse events occurred in 24% of patients in KEYNOTE-013 and 23% of patients in KEYNOTE-170. There were no treatment-related deaths. Among 42 evaluable patients, the magnitude of the 9p24 gene abnormality was associated with PD-L1 expression, which was itself significantly associated with progression-free survival. CONCLUSION: Pembrolizumab is associated with high response rate, durable activity, and a manageable safety profile in patients with rrPMBCL.

Hodgkin's lymphoma unmet medical needs in Brazil: experts' perspective / Necessidades médicas não atendidas no tratamento de linfoma de Hodgkin no Brasil: perspectiva de médicos

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.

Treatment patterns of Hodgkin's lymphoma in Brazil: experts' perspective / Padrões de tratamento do linfoma de Hodgkin no Brasil: a perspectiva dos especialistas

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.

New treatment approaches for relapsing/refractory Hodgkin's lymphoma: An overview of the Brazilian scenario / Novas abordagens de tratamento para o linfoma de Hodgkin recidivante/refratário: uma revisão

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.

BCL-2 as therapeutic target for hematological malignancies.

Disruption of the physiologic balance between cell proliferation and cell death is an important step of cancer development. Increased resistance to apoptosis is a key oncogenic mechanism in several hematological malignancies and, in many cases, especially in lymphoid neoplasias, has been attributed to the upregulation of BCL-2. The BCL-2 protein is the founding member of the BCL-2 family of apoptosis regulators and was the first apoptosis modulator to be associated with cancer. The recognition of the important role played by BCL-2 for cancer development and resistance to treatment made it a relevant target for therapy for many diseases, including solid tumors and hematological neoplasias. Among the different strategies that have been developed to inhibit BCL-2, BH3-mimetics have emerged as a novel class of compounds with favorable results in different clinical settings, including chronic lymphocytic leukemia (CLL). In April 2016, the first inhibitor of BCL-2, venetoclax, was approved by the US Food and Drug Administration for the treatment of patients with CLL who have 17p deletion and had received at least one prior therapy. This review focuses on the relevance of BCL-2 for apoptosis modulation at the mitochondrial level, its potential as therapeutic target for hematological malignancies, and the results obtained with selective inhibitors belonging to the BH3-mimetics, especially venetoclax used in monotherapy or in combination with other agents.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience

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.

Everolimus as a single agent in refractory or relapsed Hodgkin's lymphoma: the Brazilian Named Patient Program Experience.

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.

A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids: The first case report in Latin America.

RATIONALE: This is the report of the first case of TAFRO syndrome (Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction, Organomegaly) in Latin America. PATIENT CONCERNS: The patient was a 61-year-old white woman of Ashkenazi Jewish descent, who presented with a history of 8 days of nausea, vomiting, and fever; severe pitting edema in both legs, ascites, splenomegaly, and palpable axillary lymph nodes. DIAGNOSES: Abdominal computed tomography (CT) showed bilateral pleural effusion and retroperitoneal lymph node enlargement. INTERVENTIONS: Anasarca and worsening of renal function led to admission to the intensive care unit (ICU) with multiple organ failure, requiring mechanical ventilation, vasopressor medications, and continuous renal replacement therapy (CRRT). Diagnosis of TAFRO syndrome was made on day 18 after admission, based on clinical findings and results of bone marrow and lymph node biopsies. She was treated with methylprednisolone, tocilizumab, and rituximab. One week after the first tocilizumab dose, she had dramatic improvements in respiratory and hemodynamic status, and was weaned from ventilator support and vasopressor medications. OUTCOMES: After 2 weeks of therapy, CRRT was switched to intermittent hemodialysis. On day 46, the patient was discharged from the ICU to the general ward, and 3 months after admission, she went home. LESSONS: Provided the interleukin-6 measurement is available, this approach is suggested in cases of TAFRO syndrome, in order to customize the treatment.

Imbalance of Pro- and Anti-Inflammatory Cytokines in Patients With cHL Persists Despite Treatment Compared With Control Subjects.

BACKGROUND: Classical Hodgkin lymphoma (cHL) is a malignant lymphoma that most commonly affects young adults. The lymphomagenesis of cHL depends largely on immune alterations that contribute to proliferation and maintenance of the Hodgkin-Reed-Sternberg (HRS) neoplastic cells. A combination of different immune processes is responsible for the escape of HRS cells, the imbalance between pro- and anti-inflammatory cytokines being one of them. In this study, we aimed to measure serum levels of pro- and anti-inflammatory cytokines in cHL patients before and after treatment compared with a healthy controls group, and to investigate associations with clinical and pathologic characteristics. PATIENTS AND METHODS: We prospectively studied all cases of cHL diagnosed between March 2009 to March 2013 at the Universidade Federal de São Paulo and Hospital Santa Marcelina, in Sao Paulo, Brazil. Twenty-nine cases with sufficient clinical data were included in this study. Additionally, 18 healthy control subjects were included and recruited from our University Blood Bank. Serum cytokine levels of interleukin (IL)-2, IL-4, IL-5, IL-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, soluble IL-2 receptor (sCD25), vascular endothelial growth factor (VEGF), and interferon (IFN)-γ were determined in serum of patients and controls using a multiplexed immunoassay system. RESULTS: Higher International Prognostic Score was positively correlated with increased levels of IL-6 (P = .003); sCD25 levels were higher in patients with low serum albumin (P = .04), and IFN-γ seemed to correlate with B symptoms, although did not reach statistical significance (P = .057). Pretreatment levels of IL-10, IL-6, TNF-α, and sCD25 were increased in cHL patients compared with in healthy control subjects (P < .001), with median values of 7 pg/mL (range, 0.3-230.9), 5.3 pg/mL (range, 0.4-72.7), 14.6 (range, 4.0-60.4), and 575.9 pg/mL (range, 7.5-1813.3), respectively. Treatment significantly reduced levels of IL-10 (7.0 to 0.3; P < .001), IL-6 (5.3 to 0.4; P = .014), and sCD25 (575.9 to 93.5; P < .001), however, levels of IL-4 increased (0.6 to 2.2; P = .002). Compared with normal control subjects, increased levels of IL-6 (0.4 to 0.4; P = .027), sCD25 (93.5 to 7.5; P = .002), and TNF-α (12 to 8.7; P = .003) persisted after treatment. CONCLUSION: In this study we showed higher levels of IL-6, IL-10, TNF-α, and sCD25 in cHL patients at diagnosis than in healthy control subjects. After treatment, levels of IL-6, IL-10, and sCD25 decreased gradually but did not normalize. Understanding the cytokine pattern is extremely important in the development of future therapies that target interactions between neoplastic cells and the inflammatory microenvironment.

Primary central nervous system lymphoma: what a neurologist/neurosurgeon should know?

Primary central nervous system lymphoma is a rare disease, with bad prognosis. Neurologists and neurosurgeons should be familiar with the diagnostic,and biologic features, as well as the initial management of patients. A correct approach to these patients is mandatory for a better outcome.