Lymphoma In HIV-infected Patients Research Articles

A Rare but Sinister Case of Hodgkin Lymphoma Transforming into Large B-cell Lymphoma in HIV Infected Patient

A dual diagnosis of cancer and HIV places a greater psychosocial burden on the patient. From a medical perspective, it complicates treatment for both diseases. Potential drug interactions, compounded side effects, and chemotherapy’s tendency to negatively impact CD4 count or HIV viral load, can all complicate treatment. It is imperative to advocate a keen and subtle vigilance while managing such patients to enhance the overall care for the patients. Here, we report such a case in a 36-year-old man who presented with HL as first manifestation of HIV infection that later transformed into DLBCL despite successful virologic suppression with ART

Burkitt’s Lymphoma in HIV-Infected Patients (Literature Review with Own Clinical Cases)

This article presents the X-ray morphological and clinical picture of three cases of Burkitt’s lymphoma in HIV-infected patients. Burkitt’s lymphoma is a very aggressive B–cell non-Hodgkin’s lymphoma and the fastest growing tumor. In view of this, it is a medical problem, since untimely diagnosis of this tumor leads to a high frequency of relapses, which means an unfavorable prognosis.

Determining the risk of developing EBV­-associated lymphoma in HIV-­infected patients

Objective — to increase the efficiency of predicting the development of EBV-associated lymphomas in patients with HIV infection.
 Materials and methods. In order to improve the prediction of the development of Epstein—Barr associated lymphomas in HIV-infected patients, a comparative analysis of various indicators (clinical-epidemiological, laboratory, serological, etc.) was carried out in 57 HIV patients who had clinical and laboratory confirmation of the presence of co-infection with the Epstein—Barr.Of the 57 patients, manifestations of primary CNS lymphoma were registered in 7 patients (12.3 %), another 1 patient was diagnosed with B-cell large cell lymphoma of the frontal sinus, centroblastic variant (1.8 %), in 1 patient — Burkitt’s lymphoma with lesions of the cervical lymph nodes (1.8 %). To clarify the main trends in the development of lymphomas in patients with HIV and EBV coinfection, a detailed analysis was carried out in two groups: the main group consisted of 9 patients with lymphomas, the remaining 48 patients without detected neoplasms formed the comparison group.
 Results and discussion. To improve the efficiency of the forecast, multifactorial logistic regressions were constructed, taking into account not only the independent, but also the joint influence of the considered risk factors. To do this, the sum of the scores for each observation was calculated using the corresponding predictive coefficient rank qualification created using the Wald analysis. Based on a multivariate prognostic model, an algorithm was created to determine the risk of developing EBV-associated lymphomas in patients co-infected with EBV and HIV.
 Conclusions.The created algorithm for determining the risk of developing EBV-associated lymphomas in patients with HIV makes it possible to identify patients with different risks of developing lymphomas under conditions of infection with EBV and HIV, which further creates the possibility for predicting an unfavorable course of HIV infection.The proposed algorithm has a high predictive efficiency, which makes it possible to determine the risk at the individual level and lays the foundation for optimizing the diagnosis of Epstein—Barr virus infection in HIV-infected patients.

A Comprehensive Clinicopathologic and Molecular Study of 19 Primary Effusion Lymphomas in HIV-infected Patients.

Primary effusion lymphoma (PEL) is associated with human herpesvirus 8 and frequently with Epstein-Barr virus (EBV). We report here a single-center series of 19 human immunodeficiency virus-associated PELs, including 14 EBV+ and 5 EBV- PELs. The objectives were to describe the clinicopathologic features of PELs, with a focus on programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression, to search for genetic alterations by targeted deep sequencing analysis, and to compare the features between EBV+ and EBV- cases. All the patients were male, and the median age at diagnosis was 47 years old (interquartile range: 40 to 56 y). Reflecting the terminal B-cell differentiation, immunophenotypic profiles showed low expression levels of B-cell markers, including CD19 (0/19), CD20 (1/19), CD79a (0/19), PAX5 (1/19), BOB1 (3/19), and OCT2 (4/19), contrasting with a common expression of CD38 (10/19), CD138 (7/19), and IRF4/MUM1 (18/19). We observed a frequent aberrant expression of T-cell markers, especially CD3 (10/19), and less frequently CD2 (2/19), CD4 (3/19), CD5 (1/19), and CD8 (0/19). Only 2 cases were PD-L1 positive on tumor cells and none PD-1 positive. With respect to immune cells, 3 samples tested positive for PD-L1 and 5 for PD-1. Our 36-gene lymphopanel revealed 7 distinct variants in 5/10 PELs, with either a single or 2 mutations per sample: B2M (n=2), CD58 (n=1), EP300 (n=1), TNFAIP3 (n=1), ARID1A (n=1), and TP53 (n=1). Finally, we did not observe any major clinical, pathologic, or immunohistochemical differences between EBV+ and EBV- PELs and the outcome was similar (2-y overall survival probability of 61.9% [95% confidence interval, 31.2-82.1] vs. 60.0% [95% confidence interval, 12.6-88.2], respectively, P=0.62).

Ebv-Mir-BART11-3p, Ebv-Mir-BART9 and Ebv-Mir-BART10 Are Present in the Plasma of HIV-Infected Subjects with Lymphoma and Are Potential Lymphoma Biomarkers

Epstein Barr virus (EBV) has been implicated in the lymphomagenesis, particularly of HIV-related lymphomas. EBV-infected cells are able to share miRNAs with other cells via exosomes and certain EBV-miRNAs were found in cells not infected with the virus but from patients with increased levels of EBV copies in plasma such as HIV-infected individuals. Thus, EBV-miRNAs might be detected in the plasma and might be relevant for the diagnosis and follow-up of HIV-related lymphomas.This case-control study included a group of 26 HIV-infected patients with lymphoma that responded to treatment and a control-group of HIV-infected subjetcs without lymphoma matched for age, gender, CD4-lymphocyte counts, plasma HIV viremia and time from HIV infection. We evaluated the presence of 43 EBV-miRNAs in frozen plasma samples from patients with lymphoma at diagnosis (Dx-group, N=26), one year before diagnosis (Pre-group, N=15) and complete response (CR-group, N=26). RNA was extracted from 200µl of plasma using Trizol LS (Ambion, Carlsbad, CA) and cel-miR-39 was used as spike-in. The detection of EBV-miRNAs was assessed by QRT-PCR in a BioMark™ HD System of Fluidigm (San Francisco, CA) using TaqMan® microRNA assays and TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA). The following clinical and biological parameters were collected from records: age, gender, ECOG score, extranodal and bulky disease, B symptoms, Ann-Arbor stage, serum lactate dehydrogenase (LDH) and beta2-microglobulin, International Prognostic Index (IPI), HCV and HBV serology, history of opportunistic infection and of AIDS-defining illnesses, onset of combination antiretroviral therapy, CD4-lymphocyte counts, plasma HIV viremia. McNemar's and Wilcoxon tests were used for paired comparisons between groups. P-values of less than .05 were considered statistically significant.Overall, 30 EBV-miRNAs were detected in the Dx-group whereas only 8 EBV-miRNAs where found in the control-group and 19 in the CR-group. EBV-miRNAs were detected more frequently in the Dx-group (17 out of 26) than in the control-group (7 out of 26) (P =.002) and in the CR-group (11 out of 26) (P=.02). The presence of 6 EBV-miRNAs (ebv-miR-BART11-3p, ebv-miR-BART9, ebv-miR-BART10, ebv-miR-BART15, ebv-miR-BART31, and ebv-miR-BART19) could be associated with the lymphoma condition, since they were detected significantly different in the Dx-group and the control-group (Figure 1). Importantly, 3 of those EBV-miRNAs (ebv-miRBART11-3p, ebv-miR-BART9 and ebv-miRBART10) were found to be significantly less frequent in the CR group, reinforcing the idea that they could be derived from lymphoma cells and be used as biomarkers for diagnosis and follow up of HIV-related lymphoma. EBV-miRNAs cannot be used as early biomarkers of lymphoma in HIV-infected patients because none of the 3 EBV-miRNAs associated with lymphoma was significantly found in samples before diagnosis. The detection in plasma of ebv-miR-BART11-3p, ebv-miR-BART10 or ebv-miR-BART9 was not associated with having tumor cells infected with EBV (Figure 1). Only the detection of ebv-miR-BART9 was associated with detectable EBV loads [7/14 (50%) vs. 1/12 (8.3%), P=.036] (Figure 1). The following were the statistically significant associations between the presence of the 3 potential EBV-miRNA lymphoma biomarkers and the clinical-biological features studied. The presence of ebv-miR-BART10 in plasma was associated with IPI>2 [8/14 (57.1%) vs. 1/9 (11.1%), P=.004] and ECOG>2 [8/14 (57.1%) vs. 1/11 (9.1%), P=.011]. Also, more patients with ebv-miR-BART11-3p expression in plasma had ECOG>2 than patients without it [7/13 (53.8%) vs. 1/12 (8.3%), P=.030].Ebv-miR-BART11-3p, ebv-miR-BART9 and ebv-miR-BART10 can be detected in the plasma of patients with HIV-related lymphoma, independently of the presence of EBV in tumor cells or of EBV plasma viremia. They are potential biomarkers of lymphoma to be used in the diagnosis and follow up of HIV-infected subjects with the advantage of being easily determined by QRT-PCR employing noninvasive procedures.This work was supported in part by 2014 SGR225 (GRE) from CERCA Programme/Generalitat de Catalunya, and by funds from Josep Carreras International Foundation, “la Caixa” Foundation, DKMS, and Celgene Spain. [Display omitted] DisclosuresBaptista:DKMS: Research Funding; la Caixa Foundation: Research Funding; Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding; Celgene Spain: Research Funding. Sancho:Roche: Honoraria; Laboratorios Servier: Consultancy; Mundipharma: Honoraria; Kern Pharma: Honoraria; Gilead: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Ribera:Celgene: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Amgen Inc.: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; Roche: Honoraria. Navarro:Celgene Spain: Research Funding; DKMS: Research Funding; la Caixa Foundation: Research Funding; Josep Carreras International Foundation: Research Funding; CERCA Programme/Generalitat de Catalunya: Research Funding.

Treatment Efficacy and Outcomes in HIV-Related Plasmablastic Lymphoma: The Results of Multicenter Retrospective Study in Russia

Background Plasmablastic lymphoma (PbL) is a rare and aggressive B-cell malignancy highly associated with HIV. Despite improved understanding of this disease, its prognosis remains poor with short overall survival. There is no standard of care for this entity. Recent advances in the treatment of HIV-associated and aggressive lymphomas have not yet significantly improved the outcomes of patients with PbL. Methods We investigate epidemiological characteristics and the results of the treatment of the HIV-related PbL in large cohort of HIV-related lymphoma patients for a 7-year period (2014-2020). During the observation period, 22 cases of HIV-related PbL were registered in three centers and selected for the analysis from the national multicenter retrospective study database. The median follow-up was 17,8 (4-57,4) months. Results The PbL accounted for 8,9% of lymphomas in HIV-infected patients (22/247). The median age was 42 years (32-61), males - 9 (41%). Most of the patients (n=19, 86%) had III-IV stages and B-symptoms were present in 8 patients (36%). CNS involvement was diagnosed in 8 patients (36%). The median of ECOG score was I (I-III). Half of patients had viral hepatitis as a co-infection including HCV (n=9), HCV and HBV (n=1), HCV, HBV and HDV (n=1). HIV and lymphoma were diagnosed simultaneously in 7 patients (32%). Median time from HIV infection to the lymphoma onset was 4 years (1,5 month - 17,5 years). The only one patient did not receive cART for an unknown reason. The median number of CD4+ cells at the moment of chemotherapy (CT) started was 151 cell/mcl (13 - 374). Frontline CT were following: CHOP±E - 9 (41%), EPOCH - 11 (50%), hyper-CVAD - 1 (4,5%), dexamethasone - 1 (4,5%). Bortezomib was added to frontline treatment in 3 (13,6%) patients, HDC with auto-HSCT had been done as a first line therapy in 2 (9%) patients. A total of 16 patients responded to the first line therapy with the overall response rate (ORR) of 72,7% including CR and PR in 4 (18,2%) and 12 (54,5%) patients respectively. Remaining patients had progression disease (n=5, 22,8%) and stable disease (n=1, 4,5%). The median course to achieve the ORR was 4 (2-6) cycles. Overall (OS) and progression-free survival (PFS) at 2 years after first line treatment was 59,1% and 40,9%, respectively. The median time to progression (TTP) was 7,95 (0,33-23,93) months. The addition of bortezomib and auto-HSCT in first line chemo improved OS (100% vs 47,1%, p=0,027), but non PFS (p=0,1) and TTP (p=0,4). Nine patients received second-line CT: DHAP - 4 (44,4%), ICE - 4 (44,4%), EPOCH - 1 (11,2%). Response was evaluated in 8 patients. CR, PR and progression disease was registered in 1 (12,5%), 2 (25%) and 5 (62,5%) patients respectively. PBSC harvesting was only successful in 1 of 3 cases (33%) and this patient received HDC with auto-HSCT. OS and PFS at 2 years after second line treatment was 44,4% and 22,2%, respectively. Two years after second line CT, 4 patients were still alive, including those after ICE, EPOCH (n=2), HDC with auto-HSCT (n=1) and nivolumab (27 cycles) as a third line therapy (n=1). Conclusions In a large cohort of patients PbL accounted for 8.9% of all HIV-related lymphomas. Bortezomib-containing chemotherapy and first line auto-HSCT show encouraging results, but data are obtained in a small group of patients. Prospective studies are needed for optimization of HIV-related plasmablastic lymphoma therapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: The is early clinical date on efficiency of Bortezomib in patients with plasmablastic lymphoma: https://doi.org/10.1111/bjh.15156

A longitudinal and cross-sectional study ofEpstein-Barr virus DNA load: a possible predictor of AIDS-related lymphoma in HIV-infected patients

Introduction: HIV-infected patients are more than 100-fold greater at risk for developing malignant AIDS-related lymphoma (ARL) compared to the general population. Most ARLs are EBV related. The main purpose of this study was to investigate whether a high peak EBV DNA load in HIV-infected patients is predictive of ARL, including classical Hodgkin lymphoma.Methods: From an ongoing prospective HIV positive cohort study, we conducted a case-control study between 2004 and 2016 among patients from whom at least one EBV DNA load in serum or plasma was available. We compared peak EBV DNA load between patients with (49 cases) and without ARL (156 controls).Results: The geometric mean of the peak EBV DNA load measured before diagnosis of malignant lymphoma was 52,565 IU/mL in EBER-positive lymphoma patients vs. 127 IU/mL in controls (p < .001). Patients with EBV DNA loads >100,000 IU/mL have an increased risk for diagnosis of malignant lymphoma compared to patients with EBV DNA loads ≤100,000 IU/mL (adjusted OR 12.53; 95%CI: 4.08; 38.42). In the longitudinal study, including 13 patients with at least three left-over plasma samples available for retesting, measurements of EBV-DNA during the preceding 12 months proved to be of poor value for predicting subsequent lymphoma diagnosis.Conclusions: A EBV DNA load >100,000 IU/mL can be useful in clinical setting to accelerate time to diagnosis and treatment. EBV-DNA loads in samples taken during the preceding year of ARL diagnosis showed to be of poor predictive value.

Annals for Educators - 3 January 2017

Annals for Educators - 3 January 2017

Chronic Hepatitis B and C Virus Infection and Risk for Non-Hodgkin Lymphoma in HIV-Infected Patients: A Cohort Study.

Non-Hodgkin lymphoma (NHL) is the most common AIDS-defining condition in the era of antiretroviral therapy (ART). Whether chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection promote NHL in HIV-infected patients is unclear. To investigate whether chronic HBV and HCV infection are associated with increased incidence of NHL in HIV-infected patients. Cohort study. 18 of 33 cohorts from the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). HIV-infected patients with information on HBV surface antigen measurements and detectable HCV RNA, or a positive HCV antibody test result if HCV RNA measurements were not available. Time-dependent Cox models to assess risk for NHL in treatment-naive patients and those initiating ART, with inverse probability weighting to control for informative censoring. A total of 52479 treatment-naive patients (1339 [2.6%] with chronic HBV infection and 7506 [14.3%] with HCV infection) were included, of whom 40219 (77%) later started ART. The median follow-up was 13 months for treatment-naive patients and 50 months for those receiving ART. A total of 252 treatment-naive patients and 310 treated patients developed NHL, with incidence rates of 219 and 168 cases per 100000 person-years, respectively. The hazard ratios for NHL with HBV and HCV infection were 1.33 (95% CI, 0.69 to 2.56) and 0.67 (CI, 0.40 to 1.12), respectively, in treatment-naive patients and 1.74 (CI, 1.08 to 2.82) and 1.73 (CI, 1.21 to 2.46), respectively, in treated patients. Many treatment-naive patients later initiated ART, which limited the study of the associations of chronic HBV and HCV infection with NHL in this patient group. In HIV-infected patients receiving ART, chronic co-infection with HBV and HCV is associated with an increased risk for NHL. European Union Seventh Framework Programme.

Эпидемиология и результаты лечения ВИЧ-ассоциированных лимфом: многоцентровое ретроспективное исследование

Эпидемиология и результаты лечения ВИЧ-ассоциированных лимфом: многоцентровое ретроспективное исследование

Secondary diseases and Burkitt's lymphoma in HIV-infected patients

The authors give the clinical data of 110 human immunodeficiency virus (HIV)-infected patients who stayed in a correctional facility during 2014. Of the examinees, there were almost 50% of the patients with advanced stages (IVA-IVB) with different secondary/opportunistic diseases, among which was Burkitt's lymphoma, a rather rare malignant disease that developed in obvious immunodeficiency in the absence of antiretroviral therapy.

Epstein-Barr Virus Viral Loads and Serum Free Light Chains Levels Are Diagnostic Markers of Lymphoma in HIV-Infected Patients

IntroductionEpstein-Barr virus (EBV) viral load and serum free light chains (sFLC) are easily measurable and are possible biomarkers for screening and prognosis in HIV-related lymphomas. EBV load and sFLC levels have been shown to be increased at the diagnosis of HIV-related lymphomas but there is a lack of data on their levels at complete response (CR). We aimed to determine the clinical relevance and the potential use of combining EBV load and sFLC measurements as tumor markers in patients with HIV-related lymphomas.MethodsRetrospective study of HIV-infected patients diagnosed with non-Hodgkin (NHL) and Hodgkin’s lymphoma (HL) treated in a single institution from 1998 to 2012. EBV loads were determined in plasma by means of a commercial real-time PCR technique (EBV PCR kit, Qiagen GmbH, Hilden, Germany). Levels of κ and λ sFLC were measured in serum using a standardized assay (FREELITE, The Binding Site, Birmingham, UK). sFLC were considered elevated when κ, λ, or the sum of κ and λ were above the upper normal limit. Clinical and biological data were collected from the clinical records.ResultsSixty-eight patients were studied (53 NHL and 15 HL). At diagnosis (N=47), levels of κ, λ, and sum of κ and λ sFLC were elevated in 87%, 70%, and 81% of patients, respectively. At CR (N=29), the percentage of patients with elevated κ, λ, and κ+λ was 79%, 45%, and 62%, respectively. EBV load was detectable in 60% of the patients at diagnosis (N=50) and in 7.4% at CR (N=27). Median levels of κ, λ, and κ+λ sFLC at diagnosis were higher than at CR (6.06 mg/dL vs 3.19 mg/dL, P=0.006; 3.94 mg/dL vs 2.21 mg/dL, P=0.021; 11.38 mg/dL vs 5.43 mg/dL, P=0.004; respectively). Median levels of EBV loads at diagnosis were also higher than at CR (121.5 copies/mL vs. 0 copies/mL, P<0.001). There were fewer patients with elevated λ and κ+λ levels and detectable EBV loads at CR than at diagnosis (P=0.028, P=0.071 and P<0.001); respectively).Detectable EBV loads were associated with elevated λ (P=0.023) and κ+λ levels (P=0.055). Among the cases with detectable EBV load, 76% had elevated λ levels and 86% had elevated κ+λ levels. Moreover, median levels of κ and of κ+λ were higher in patients with detectable EBV loads than in patients with undetectable EBV loads (7.56mg/dL vs. 3.23 mg/dL, P=0.012 and 12.91mg/dL vs. 5.48mg/dL, P=0.022; respectively).EBV load and levels of sFLC were compared between groups defined by the clinical-biological features. At diagnosis, more patients with AIDS criteria before lymphoma showed increased λ sFLC than patients without AIDS criteria before lymphoma and the median levels of λ were higher in the group of patients with previous AIDS criteria. EBV loads were higher in patients without AIDS criteria before lymphoma. Patients with detectable HIV loads showed higher levels of λ than patients with undetectable HIV loads. However, all the former differences only showed a trend without reaching statistical significance.At CR, median level of λ sFLC was higher in patients who presented Bulky disease at diagnosis than in patients without Bulky (P=0.077). The median levels of κ, λ and κ+λ at CR were higher in patients with detectable HIV loads at diagnosis than in those with undetectable loads (P=0.032, P=0.064 and P=0.045; respectively). All 4 patients with undetectable HIV loads had normal κ+λ levels at CR. Unlike, only 6 out of 21 patients with detectable HIV loads had normal κ+λ levels (P=0.017) at CR. Patients treated with combination antiretroviral therapy (cART) before lymphoma presented lower κ levels at CR than patients not previously treated with cART (P=0.081). Also, increased κ and λ levels at CR were more frequently found in patients not treated with cART before lymphoma than in those previously treated (κ= 93% vs. 64%, P=0.080 and λ= 60% vs. 29%, P=0.089).Neither elevated sFLC levels nor positive EBV loads at diagnosis had impact on overall survival, progression-free survival or disease-free survival.ConclusionsIn patients with HIV-related lymphomas detectable EBV loads were associated with higher sFLC levels. At lymphoma diagnosis both sFLC levels and EBV loads were higher than at CR pointing they may be used as lymphoma markers. The control of HIV-infection was related to lower sFLC levels both at diagnosis and at CR.This work was supported in part by grants EC11-041 and RD12/0036/0029 RTICC from “Instituto Carlos III” Spain and 2014 SGR225 (GRE) from Generalitat de Catalunya, and by Josep Carreras International Foundation. DisclosuresNo relevant conflicts of interest to declare.

Prognostic Factors and Outcomes in Primary Effusion Lymphoma in HIV-Infected Patients: A Single Center Experience

Primary effusion lymphoma (PEL) is a human herpesvirus 8-associated non-Hodgkin lymphoma (NHL) that predominantly develops in serous body cavities leading to recurrent lymphomatous effusions. It is poorly understood and very uncommon, accounting for only 3% of all HIV-related NHL. While outcomes have improved in patients with HIV-associated NHL since the widespread use of HAART, the prognosis of PEL remains very poor and median survival is less than 6 months. This study reports our institution’s experience with PEL over the past decade.Between 2004 and 2014, we treated 8 patients with HIV-associated PEL. All patients were male. The median age was 46.5 years old (range 35-63), three were Caucasian, four were Hispanic, and one was African-American. The primary site of involvement was pericardial in 3 patients, pleural in 3 patients, and extra-cavitary in 2 patients. All patients were Ann Arbor stage IV at the time of diagnosis. The mean LDH and CD4 count at time of diagnosis was 625 U/L and 161 cells/mm3, respectively.Of the eight patients identified with PEL, four have achieved complete remission (CR). Prognostic factors associated with achieving CR include compliance with HAART therapy prior to PEL diagnosis as well as lower serum lactate dehydrogenase (LDH) levels (202±30 versus 1049±290, p=.03). Patients achieving CR also had a higher average CD4 count (228±93 versus 95±35, p=.22) at time of diagnosis. Median survival is nearly 6 years for those in CR whereas it was 32 days in patients that died (one from an acute stroke, one from septic shock, and two from progressive disease). All patients who achieved CR had previously diagnosed HIV whereas two of the four who died were previously undiagnosed with HIV. Interestingly, pericardial sites of involvement were associated with significantly better outcomes as compared to pleural sites in our case series, as well. There was no association between outcome and HIV viral load, duration of HIV infection prior to PEL diagnosis, or presence of AIDS-defining illnesses. The patients achieving CR were treated with HAART in addition to Hyper-CVAD (1a-3b) or 6 cycles of CHOP or EPOCH. In addition, two patients received bortezomib as initial therapy. Given its rarity, our knowledge of PEL relies heavily on case reports and small case series. Here we report our institution’s experience with PEL, identify LDH and CD4 as possible prognostic factors in PEL, and suggest bortezomib-based chemotherapy as an effective treatment option in HIV-associated PEL. DisclosuresNo relevant conflicts of interest to declare.

Haemophilia - diagnosis and management challenges.

Haemophilia care in India is slowly progressing but the diagnostic and management challenges continue until optimum care for haemophilia patients become a reality in this country. Against an anticipated severe haemophilia population of more than 0.1 million, only 16000 haemophilia patients are registered in the 74 Haemophilia Chapters across the country. As per the recent WFH Survey, 43% of the World haemophilia population live in India, Bangladesh, Indonesia and China, out of which only 12% is diagnosed in these countries. Additionally these countries represent only 2% of the Worlds total factor usage. The per capita use of FVIII in India has been shown to be 0.0075 (1IU per capita is 20000 IU FVIII per haemophilia patient) which is approximately equal to mean consumption of 1654 IUs per PWH against 112508 IUs per PWH in United States. Haemophilia in India is thus a grossly under diagnosed disorder, mainly due to lack of awareness and diagnostic facilities in this country. Except a few Corporate Hospitals and a few Medical Colleges in India majority of the 630 District hospitals and Medical Colleges do not have even screening coagulation facilities. Haemophilia Federation (India) has taken wide initiatives in providing diagnostic facilities to the PWH in this country, through various measures such as supporting the cost of diagnosis of PWH, networking private laboratory facilities, setting up coagulation laboratories in close proximity to Haemophilia Chapters, involving faculty members of Medical Colleges in the activities of Haemophilia Chapters and so on. Indian Council of Medical Research has also initiated through its Translation Research Programme several workshops in the Laboratory diagnosis of bleeding disorders at Mumbai and several places in East and North Eastern parts of India. As quality control is an important exercise in a coagulation laboratory, many of the laboratories in India fail to establish factor and inhibitor screening assays in their respective laboratories. The prevalence of inhibitors in India is estimated to be 8.2–13%. Post operative inhibitors are another important problem which our PWH is facing in India. About 30% of PWH undergoing surgeries for various indications develop inhibitors postoperatively. Diagnosing inhibitors, demands specialized laboratories and expertise. The management of PWH and inhibitors comprises several approaches involving prompt treatment of bleeding episodes, managing its complications, preventing bleeds, and conserving and restoring joint function. The ultimate goal of treating PWH and inhibitors is to permanently eradicate inhibitors by immune tolerance therapy (ITT), or by use of alternative products like rFVIIa or FEIBA. However, because of prohibitive cost and logistics constraints many of our PWH are not able to utilize these products. Availability of free factors in some states of our country is a refreshing and welcome change for PWH. Significant progress has been made in awakening and alerting the State Governments for providing free factors to all our PWH. WFH has contributed to haemophilia care in India through a series of international twinning programme by initially twinning upcoming chapters in India or institutions of repute in India with some of the best centres in Europe and USA leading to the development of expertise in the area of genetic diagnosis and physical therapy. Despite this, there are several newer challenges that the hemophilia community will face in the coming years. Normalization of patients' lives as a result of improved treatment has led to new problem areas. Malignancies specifically hepatocellular carcinoma (HCC) in HCV infected patients and non Hodgkin’s lymphoma in HIV infected patients are on the rise. About 25% of our patients is HCV infected. A less common albeit potentially severely morbid event is ICH. Osteoporosis in general has been considered to be an important cause of morbidity in patients with haemophilia and other bleeding disorders.

CD30-Targeted Therapy with Brentuximab Vedotin and DLI in a Patient with T-Cell Posttransplantation Lymphoma

CD30-Targeted Therapy with Brentuximab Vedotin and DLI in a Patient with T-Cell Posttransplantation Lymphoma

Increased T-Cell Activation and Th1 Cytokine Concentrations Prior to the Diagnosis of B-Cell Lymphoma in HIV Infected Patients

Despite the use of combined antiretroviral therapy, HIV-infected individuals have a higher risk of developing B-cell lymphoma compared to the general population. We aim to explore whether lymphocyte activation, increase in Th1 response as well as markers of EBV reactivation, may precede lymphoma diagnosis. Thirteen cases and 26 controls matched on CD4(+) T-cell count and HIV plasma viral load were identified. Samples were collected 0 to 5 years prior to B-cell lymphoma diagnosis. Seven out of 13 (54 %) and 16/26 (61.5 %) of cases and controls were receiving antiretroviral therapy at the time of sampling, respectively. CD8(+) T-cell activation and Th1 cytokine concentrations were measured before lymphoma onset, together with IgG antibodies directed against viral capsid antigen (VCA) and serum levels of EBV DNA. A higher level of CD8(+) T-cell activation was observed in patients developing lymphoma. Four out of seven Th1 cytokine serum concentrations were significantly higher in patients with lymphoma than in the control group: IL-2R, IL-12p40/70, IFN-γ-inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). Anti-VCA IgG level were significantly higher in cases than in controls. Four cases (30 %) but no controls had detectable EBV DNA in serum. A higher level of T-cell activation, Th1 cytokine serum concentration and markers of EBV replication, preceded B-cell lymphoma diagnosis. This may suggest that viral antigen stimulation is associated with the genesis of lymphoma in HIV-infected patients.

Blood Epstein–Barr virus DNA load and risk of progression to AIDS‐related systemic B lymphoma

AIDS-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the combined antiretroviral therapy (cART) era. Although most ARLs are associated with the Epstein-Barr virus (EBV), whether patients with high EBV burden are more at risk of developing ARL is unknown. This study investigated the relationship between high blood EBV DNA loads and subsequent progression to ARL. We identified 43 cases of ARL diagnosed between 1988 and 2007 within two cohorts (ANRS SEROCO/HEMOCO and PRIMO) and for which stored serum and peripheral blood mononuclear cell (PBMC) samples were available within 3 years before ARL diagnosis. For each case, two controls matched for the cohort and CD4 cell count in the year of ARL diagnosis were selected. EBV DNA was measured in PBMCs and serum samples with a commercial kit. High levels of EBV DNA in PBMCs collected a median of 10 months before diagnosis were associated with an increased risk of developing systemic B lymphoma (adjusted odds ratio 2.47; 95% confidence interval 1.15; 5.32 for each 1 log copies/10(6) PBMC increase in EBV load) but not with primary brain lymphoma. In this study, HIV-infected patients with undetectable EBV DNA in PBMCs did not develop ARL in the following 3 years, while high levels of EBV DNA in PBMCs predicted subsequent progression to systemic B lymphoma. Clinicians should be aware of the increased risk of developing systemic B lymphoma in HIV-infected patients with a high blood EBV DNA load.

Characterization of HIV-Associated Hodgkin's Lymphoma in HIV-Infected Patients

Although the incidence and prevalence of AIDS-defining malignancies has decreased in the era of highly active antiretroviral therapy (HAART), the incidence and prevalence of Hodgkin's lymphoma (HL) in the HIV-infected population continues to rise. Compared with the general population, HIV-infected patients exhibit a 5-10-fold increased risk for developing HL. A retrospective review of charts and electronic records from 2000-2010 at the HIV outpatient clinic (HOP)-Louisiana State University in New Orleans was conducted, and pathologically confirmed cases of HIV-HL were identified within this cohort. We found a prevalence of 6.3 cases per 1,000 patients per year of HIV-HL over a period of 10 years in our HIV outpatient clinic. The mean absolute CD4 count before treatment was 284 cells/mm(3) and after treatment was 194 cells/mm(3). The average time from the diagnosis of HIV infection to the diagnosis of HIV-HL was 7.6 years. The most common histopathologic type was mixed cellularity followed by lymphocytic predominance. The majority of patients had 6 cycles delivered. In terms of HL staging 87% presented with advanced stages (III B or IV). To the best of our knowledge 5 out of the 14 patients remain alive. Patients in our cohort were older than most patients identified in other cohorts. All of our patients had coexisting chronic illnesses associated with inflammation, as well as detectable HIV viral loads and CD4 count >200, suggesting a role for both HIV- and non-HIV-associated inflammation in HIV-HL pathogenesis in this population. The role of HIV virus and other oncogenic viruses (EBV, HPV, and others) in the pathogenesis of Hodgkin's lymphoma in this group of patients needs to be elucidated.

Can Serum Soluble CD23 OR CD30 Predict the Occurence of Lymphoma in HIV-Infected Patients?

Can Serum Soluble CD23 OR CD30 Predict the Occurence of Lymphoma in HIV-Infected Patients?

No increased incidence for GB‐virus C infection in a cohort of HIV‐positive lymphoma patients

Dear Sir, Until recently no pathogenic potential could be demonstrated in humans infected with GB-Virus C (GBV-C). In contrast, replicative GBV-C infection in HIV-infected individuals correlated with reduced progression to immunodeficiency (Tillmann, NEJM 2001). We therefore read with great interest, the article by Krajden et al. published recently in the International Journal of Cancer, in which the authors described a cohort of 553 patients with Non-Hodgkin lymphoma and 438 controls for evidence of serum GBV-C RNA. GBV-C RNA was found in 4.5% of NHL patients and in 1.8% of controls, a difference which under analysis achieved statistical significance (odds ratio 1⁄4 2.72, confidence interval1⁄4 1.22–6.69). This study however exclusively included apparently immunocompetent patients and therefore does not offer insight into the potential role of replicative GBV-C infection contributing to the preexisting increased risk of lymphoma in HIVinfected patients. To further clarify the prevalence of GBV-C infection in our cohort of HIV-infected patients with and without lymphoma, we performed a retrospective analysis. In total 33 HIV-positive patients with lymphoma were recruited from the HIV-outpatient clinic at Hanover Medical University for GBV-C RNA and the frequency of viremia was compared with 584 HIV-infected patients without lymphoma. From the 33 patients in the lymphoma group with a mean CD4þ T cell count of 371/lL (range 7–970 cells/lL) 7 had Hodgkin Lymphoma (HL) and 26 Non-Hodgkin Lymphoma (NHL). In total ten patients (30.3%) tested GBV-CRNA positive. In our control group 138 of 584 HIV-positive patients tested positive for GBV-C-RNA (23.6%). These results however failed to achieve statistical significance regarding an association between positive GBV-C-Status and lymphoma (p 1⁄4 0.39). Interestingly the updated results in our cohort revealed an increase in the overall incidence of GBV-C viremia from 16.8% (Tillmann et al. 2001) to 23.6%. This might indicate a general spread of GBV-C infection in our cohort with known elevated risks for parenteral or mucosal transmission of viral infections. Hence the elevated GBV-C incidence in lymphoma patients, described by Krajden et al. could be explained and a confounding phenomenon indicating elevated risks for transmission of other hypothetically oncogenic viruses. On the other hand, the persistence of GBV-C viremia in HIV-positive individuals has been explained by the prevalence of T-cellular immunodeficiency. Therefore it cannot be ruled out that an elevated incidence of GBV-C replication in lymphoma patients rather indicates a secondary or preexisting alteration of T-cell immunity than a causal factor for tumor ontogenesis. Yours sincerely, Diana Ernst Sven Pischke Mark Greer Heiner Wedemeyer Matthias Stoll