A 29-year-old woman with stage IVB Hodgkin's lymphoma was treated with doxorubicin, bleomycin, vinblastine, and dacarbazine. Two weeks after the first cycle was completed, she developed pruritic, linear erythematous lesions in a flagellate-like pattern on the trunk, neck and arms. After oral prednisone therapy and cessation of bleomycin, the lesions started to recede.

Introduction: Post-transplant lymphoproliferative disorders are a rare heterogenous group of diseases occurring in the setting of post-transplant immunossupression (IS). Clinically, extranodal involvement is common, and it occurs in the central nervous system (CNS) in approximately 7-15% of cases. Most data on PTLD-CNS are based on case series/reports and due to paucity of data no treatment algorithms have been established. In our series, we retrospectively analyzed 23 consecutively cases of PTLD-CNS in Hospital do Rim, Sao Paulo, Brazil. Methods: We retrospectively reviewed all cases of PTLD-CNS diagnosed between 2001 and 2014 at Hospital do Rim (HRim), a school hospital from the Federal University of São Paulo, Brazil. HRim is considered the leading renal transplant hospital in the world for the past 15 years. For this study, only PTLD patients with tumors whose histology could be confirmed by hemopathologist review, EBV-association established and whose clinical, epidemiological and laboratorial parameters could be retrieved were included in this study. Response was defined as complete (CR) or less than CR (partial response or refractory disease). Event was defined as treatment related mortality, progression (defined as time for initiation of second-line therapy) or relapse. Results: From 2001 to 2014, from a total of 98 PTLD patients, 23 patients (23%) were diagnosed with PTLD-CNS. Median age at time of diagnosis was 36, with a male:female ratio of 0.9:1. Fifteen (65%) patients received anti-thymocyte globulin (ATG) at the time of transplant and 17 (74%) had at least one episode of acute rejection. The most common immunossupressive regimen (IR) consisted of cyclosporine or tacrolimus associated with prednisone and azathioprine (15, 65%). Median time from transplant to PTLD diagnosis was 31 months (ranging from 8.4 to 153). EBV was positive in tumor lymphocytes by in situ hybridization in 21 cases (91%). Monomorphic cases were diagnosed in 21 (91%) patients. All patients had their IR reduced, usually with suspension of azathioprine and calcineurin inhibitors and change from prednisone to dexamethasone, 19 (82%) patients underwent WBRt (from 25 to 40 Gy) together with intra-thecal (IT) chemotherapy with methotrexate (MTX) 12mg and dexamethasone 2mg. Only 1 patient received high dose MTX and died due to treatment-related toxicities 1 month after diagnosis and 2 patients died before starting WBRt due to disease progression and poor performance status (PS). For those patients who received WBRt together with IT chemotherapy, fourteen patients (74%) had CR, 2 patients (10%) had refractory disease and 3 patients (16%) had relapsed disease within 2 years. Overall Survival (OS) for the group treated with WBRt and IT chemotherapy was 62% in 5 years (CI95% 69-82%). In our series, induction therapy with ATG and acute rejection were associated with increased risk of PTLD-CNS. Age and PS at diagnosis were the only 2 factors predictive of survival. No serious cognitive impairment was identified among the survivors. Conclusions: The current study demonstrated that PTLD-CNS is a serious late EBV-induced B-cell lymphoma, mostly monomorphic with an incidence of 23%, higher than previously described in the post renal transplant setting. Treatment with immunossupression reduction, intrathecal chemotherapy and whole-brain radiotherapy showed a high CR rate with favorable survival in many cases. Disclosures No relevant conflicts of interest to declare.

Introduction: Molecular alterations involved in development of classical Hodgkin lymphoma (cHL) are only partially known. Genetic alterations in NFkB pathway and the imbalance of T regulatory (Treg) and TH17 lymphocytes has been recognized as critical pathogenetic mechanism involved in immune scape and blockade of apoptosis in Reed-Sternberg cells. Emerging evidences suggests that NFkB activation can promote lymphocyte proliferation and survival, and therapeutic inhibition of the NFkB pathway have been proposed. Recently, our group showed an increase of circulating Treg cells in patients with cHL at diagnosis, however, after therapy, elevated levels of circulating TH17 cells was observed. Increased frequencies of Treg lymphocytes in the tumor microenvironment and peripheral blood have been proposed as one of the mechanisms for this anergic state. TH17 exhibit effector functions in immune system and tumor-infiltrating TH17 cells are associated with better prognosis in human. Objectives: In this study we aimed to evaluate the immune gene expression profile in whole blood of cHL patients at diagnosis and after treatment, and evaluate pathways and gene interaction networks. Methods: This is an open multicenter study and, so far, we included 51 patients consecutively from February 2011 to November 2015. Twenty consecutively diagnosed cHL patients, with whole blood RNA extracted at diagnosis and after treatment, were recruited for this study and prospectively evaluated. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. The general expression of 96 messengers RNAs present in the peripheral blood and involved in immune response was performed by a customized quantitative real-time PCR array (TaqMan¨ Low Density Array). The data was normalized with B2M mRNAs levels and relative gene expression was calculated by the 2^DDCt method, considering Wilcoxon test and Benjamini-Hochberg adjustment to correct p-values. The differentially expressed genes were used to conduct functional/pathway enrichment analysis and construct gene interaction networks. Functional annotation networks were generated using Ingenuity Pathway Analysis (IPA; Ingenuity Systems) software. Results: From the 20 patients included for this study, 12 (60%) were male, 5 (31%) had Epstein Barr virus related cHL, 18 (90%) patients presented with B symptoms, 19 (95%) patients had advanced diseases at diagnosis (stage IIBX, III and IV) and 10% of patients relapsed. We considered paired samples from 15 patients before and after treatment. At diagnosis we observed that cHL patients presented higher expression of CD274 (2 fold, p=0.018), CD28 (1.5 fold, p=0.041), CTLA-4(1.5 fold, p=0.004), FAS (1.4 fold, p=0.041), ICOS (2.1 fold, p=0.015) and IL-10 (2.7 fold, p=0.002), and decreased expression of CCL2 (-2.7 fold, p=0.026), CCL5 (-1.6 fold, p=0.012), CD40 (-1.9 fold, p=0.003), CSF2 (-1.9 fold, p=0.012). We found no association between clinical and epidemiological characteristics with immune gene expression profile. We have found that after treatment, patients displayed a specific gene expression profile related to the top 5 canonical pathways summarized in following figure: We also built a biological network to investigate the connection between the differentially expressed genes and to predict the status (activation/inhibition) of the other connected genes (nodes). The in silico analysis revealed that NFkB, a node which its signaling activation is predicted to be activated before treatment and inhibited after (following figures). The network also showed different central node molecules (molecules connected with multiple other nodes from the network), that are indirectly related to Hodgkin lymphoma and should be further investigated as potential drugable targets. Conclusions: In this study, we showed that, at diagnosis, cHL patients presented an inflammatory gene expression profile in blood that changes after treatment to an effector/immunological one. NFkB is predicted to be activated before treatment and inhibited after ABVD chemotherapy and radiotherapy. This kind of system biology approach helped us to understand that cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new prognostic factors and treatment strategies as well as identify drugable targets. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.

No abstract

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. RESUMOO 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.

Introduction: Interleukin (IL)-10 is an anti-inflammatory cytokine with potent inhibitory effects in immune response. Higher expression of IL-10 has also been detected in classical Hodgkin lymphoma (cHL), and it has been suggested that the cytokine is involved in the pathogenesis of these tumors. CTLA-4 has long been recognized as regulatory function, potentially decreasing antitumor immune response. Augmentation of the immune response via blockade of CTLA-4 has shown an improvement in survival for patients with metastatic melanoma, Overexpression of PD-L1 on Reed-Sternberg cells is related with downregulation of effector T cell function and represents a potent mechanism of tumor evasion. PD-L1 inhibitors have shown excellent results in refractory cHL patients. Objectives: The aim of the study was to evaluate the immune gene expression profile in peripheral blood of cHL patients at diagnosis and post-treatment and correlate these findings with clinical and epidemiological aspects. Patient and Methods: This is an open multicenter study and, so far, we included 51 patients consecutively from February 2011 to November 2015. Twenty consecutively diagnosed cHL patients, with whole blood RNA extracted at diagnosis and after treatment, were recruited for this study and prospectively evaluated. The general expression of 96 messengers RNAs present in the peripheral blood and involved in immune response was performed by a customized quantitative real-time PCR array (TaqMan¨Low Density Array). The data was normalized with B2M mRNAs levels and relative gene expression was calculated by the 2^DDCt method, considering Wilcoxon test and Benjamini-Hochberg adjustment to correct p-values. In this study, only cHL patients whose histology could be confirmed were studied. All patients were HIV negative and received ABVD chemotherapy protocol and radiotherapy if necessary. Results: From the 20 patients included in this study, 12 (60%) were male, 5 (31%) had Epstein Barr virus related cHL, 18 (90%) patients presented with B symptoms, 19 (95%) patients had advanced disease at diagnosis (stage IIBX, III and IV). Results of immune gene expression profile in paired samples from 15 patients before (pre) treatment and after (post) treatment are summarized in the following table: We observed higher expression of CD274 (PD-L1), CTLA-4 and IL-10 mRNAs in patients at diagnosis compared to expression after treatment. We found no association between relapse and immune gene expression or epidemiological and clinical characteristics. Conclusions: In this study we showed that IL-10, CD274 (PD-L1) and CTLA4 are downregulated after therapy, which suggests a mechanism for tumor immune evasion that was reverted by ABVD chemotherapy and radiotherapy. Understanding cHL associated immunosuppression and the immune reconstitution after treatment maybe the key to develop new prognostic factors and treatment strategies. Table Table. Disclosures No relevant conflicts of interest to declare.

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. RESUMO 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

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. RESUMO 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 partici